Cardionerds: A Cardiology Podcast

CardioNerds (Drs. Apoorva Gangavelli, Cory Sejo, and Joseph Kassab) discuss the hemodynamics of valvular heart disease with Dr. Michael Brener. Using pressure-volume loops and clinical cases, they explain ventricular loading, myocardial energetics, and ventricular-arterial coupling, then apply these concepts to aortic stenosis, mitral regurgitation, and tricuspid regurgitation. Audio editing by CardioNerds Academy intern, Joshua Khorsandi.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli, and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

• A normal PV loop describes one cardiac cycle. With pressure on the y-axis and volume on the x-axis, the loop moves counterclockwise through isovolumic contraction, ejection, isovolumic relaxation, and filling. The slope of the end-systolic pressure-volume relationship reflects contractility. The end-diastolic relationship describes diastolic properties, and the loop’s position along it reflects preload. Effective arterial elastance estimates afterload; the enclosed area represents stroke work. 1,2
• Coupling relates contractility to afterload, while PV area reflects energy demand. Ventricular-arterial coupling is expressed as the ratio of end-systolic elastance to effective arterial elastance. Stroke work plus potential energy gives pressure-volume area, which correlates with myocardial oxygen consumption. A greater proportion of this area devoted to stroke work reflects greater mechanical efficiency.1,3
• The normal RV loop operates at lower pressures and is more triangular than the LV loop. The RV has a shallower end-systolic pressure-volume relationship and a flatter ejection phase. Ejection can continue beyond peak elastance, making isovolumic relaxation less pronounced. Normal RV and LV diastolic properties are relatively similar.3,4
• AS produces a taller, narrower LV loop. Increased afterload raises LV systolic pressure and limits stroke volume. After aortic valve replacement, expect lower LV pressure and wall stress with increased stroke volume. Interpret immediate post-TAVR measurements cautiously because rapid ventricular pacing and other procedural effects can alter hemodynamics.5
• MR widens the LV loop and blunts its isovolumic phases. Primary MR can initially occur with preserved ventricular function. In ventricular secondary MR, the loop shifts rightward and the end-systolic relationship becomes shallower because the ventricle is already remodeled and dysfunctional. MR reduction is expected to narrow the loop, restore isovolumic contraction and relaxation, and increase systolic pressure as more ventricular force is directed into forward flow. 6
• Correcting TR increases effective RV afterload. TR produces a wider loop with blunted isovolumic phases because blood can escape into the low-pressure right atrium. Eliminating this regurgitant pathway increases afterload. Valve replacement generally leaves less residual TR than edge-to-edge repair and therefore produces a greater afterload increase, which may be poorly tolerated when RV systolic reserve is limited. 7
• Lower TAPSE/PASP suggests poorer RV-pulmonary artery coupling and less RV reserve. TAPSE reflects RV systolic function, while PASP captures one component of afterload. Ratios below 0.406 mm/mm Hg were associated with worse outcomes after transcatheter tricuspid intervention in the TriValve registry. It is important to interpret the ratio alongside invasive hemodynamics and RV imaging; it should not determine procedural selection by itself. 7
• Imaging and AI may enable more accessible hemodynamic phenotyping. Noninvasive and minimally invasive approaches may reconstruct key features of pressure-volume physiology without routine conductance-catheter studies. These tools could help identify ventricular deterioration earlier and guide the timing and choice of valve intervention.

References

• Burkhoff D, Sayer G, Doshi D, Uriel N. Hemodynamics of Mechanical Circulatory Support. J Am Coll Cardiol. 2015;66:2663–2674.
• Sarraf M, Chehab O, Nagaraja V. Understanding the Pressure-Volume Loop in Valvular Heart Disease. Heart Lung Circ. 2026;35:31–44.
• Houston BA, Brittain EL, Tedford RJ. Right Ventricular Failure. N Engl J Med. 2023;388:1111–1125.
• Brener MI, Masoumi A, Ng VG, et al. Invasive Right Ventricular Pressure-Volume Analysis: Basic Principles, Clinical Applications, and Practical Recommendations. Circ Heart Fail. 2022;15:e009101.
• van den Enden AJM, van den Dorpel MMP, Mondellini GM, et al. Immediate changes in left ventricular cardiac mechanics following transcatheter aortic valve replacement for severe aortic stenosis – an in-vivo pressure-volume analysis study. Am Heart J. 2026;293:107302.
• Gaemperli O, Biaggi P, Gugelmann R, et al. Real-time left ventricular pressure-volume loops during percutaneous mitral valve repair with the MitraClip system. Circulation. 2013;127:1018–1027.
• Brener MI, Lurz P, Hausleiter J, et al. Right Ventricular-Pulmonary Arterial Coupling and Afterload Reserve in Patients Undergoing Transcatheter Tricuspid Valve Repair. J Am Coll Cardiol. 2022;79:448–461.

CardioNerds guest hosts Dr. Apoorva Gangavelli and Dr. Georgia Vasilakis, alongside Dr. Flavia Tejada, Dr. Ahmad Ahmad, and Dr. Blanca Simon Frances from MedStar Washington Hospital Center/Georgetown University for a case discussion on rapidly progressive heart failure and the urgency of recognizing infiltrative cardiomyopathy. They discuss a 65-year-old man with newly diagnosed HFrEF and CKD who presented with acute decompensated heart failure, low-voltage ECG, concentric LV thickening, renal dysfunction, and abnormal lambda free light chains. His course was complicated by PEA arrest when laid supine, cardiogenic shock physiology, bilateral pleural effusions, and biopsy-confirmed AL cardiac amyloidosis. The episode focuses on clinical red flags, diagnostic algorithms, hemodynamic fragility, and why suspected AL amyloidosis is a hematologic and cardiac emergency. Expert commentary is provided by Dr. Ajay Kadakkal. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls

• The combination of low voltage on ECG and increased wall thickness on echocardiogram should always raise suspicion for an infiltrative cardiomyopathy, not hypertensive heart disease.
• A negative SPEP does not exclude a plasma cell dyscrasia; serum free light chains and urine immunofixation are required, and PYP should only be used to support a noninvasive ATTR diagnosis after a monoclonal process has been excluded.
• Nearly one in four ATTR patients have a coexisting MGUS, making serum markers alone insufficient to distinguish AL from ATTR; when cardiac involvement is suspected, endomyocardial biopsy remains the gold standard for confirming amyloid deposition.
• Preload dependence and low stroke volume in cardiac amyloidosis create extreme sensitivity to volume shifts and positional changes, requiring a much narrower margin of safety than typical heart failure.
• In advanced cardiac AL amyloidosis, delays in initiating anti-plasma cell therapy can rapidly narrow the therapeutic window, making urgent multidisciplinary coordination essential.

Notes

Notes were drafted by Dr. Flavia Tejada Frisancho, Dr. Ahmad Ahmad and Dr. Blanca Simon Frances.

1. What clinical features should raise suspicion for cardiac amyloidosis in a patient presenting with heart failure?

• Cardiac amyloidosis should be considered when the clinical picture does not behave like typical hypertensive, ischemic, or dilated cardiomyopathy. In this case, the key clue was pattern recognition: new heart failure, rapid progression, low-voltage ECG, severe concentric LV thickening, small LV cavity, biventricular dysfunction, renal dysfunction, pleural effusions, and abnormal light chains.
• Shared cardiac red flags include increased LV wall thickness out of proportion to hypertension or valvular heart disease, diastolic dysfunction, biatrial enlargement, restrictive filling physiology, biventricular involvement, atrial fibrillation or conduction disease, elevated natriuretic peptides and troponin out of proportion to symptoms, and intolerance of standard heart failure therapies.
• Extracardiac manifestations can provide important clues and include proteinuria, peripheral or autonomic neuropathy, bilateral carpal tunnel syndrome, lumbar spinal stenosis, and spontaneous biceps tendon rupture.
• AL-predominant clues include rapid clinical progression over weeks to months, fatigue, weight loss, nephrotic-range proteinuria or renal dysfunction, pleural effusions, hypotension or shock physiology, low-voltage ECG, and evidence of a monoclonal protein or abnormal serum free light chains.
• Pathognomonic extracardiac findings for AL amyloidosis include macroglossia, periorbital purpura, and acquired factor X deficiency.
• ATTR-predominant clues often evolve over years and include bilateral carpal tunnel syndrome, lumbar spinal stenosis, spontaneous biceps tendon rupture, aortic stenosis, and HFpEF with increased wall thickness. Low-voltage ECG can occur but is less common in ATTR than AL.
• The key bedside teaching point is to lean into the inconsistency. Hypertension can cause LVH, but hypertension does not fully explain low voltage, rapid biventricular failure, renal dysfunction with monoclonal light chains, pleural effusions, and severe hemodynamic fragility.

2. Once cardiac amyloidosis is suspected, how should we approach the diagnosis?

• The diagnostic approach begins with suspicion and then immediately separates two pathways:

• rule out AL amyloidosis
• evaluate for ATTR amyloidosis

3. Why is it so important to rule out AL amyloidosis early?

• AL amyloidosis is both a hematologic and cardiac emergency.
• The underlying plasma cell clone produces misfolded immunoglobulin light chains that:

• deposit as amyloid fibrils
• exert direct cardiotoxic effects on cardiomyocytes

• Light chains impair lysosomal function, disrupt autophagy, increase oxidative stress, and contribute to progressive cellular injury and death.
• Cardiac involvement is the primary determinant of prognosis in AL amyloidosis.
• Risk stratification commonly incorporates:

• troponin
• NT-proBNP
• serum free light chain burden

• Mayo staging systems use these biomarkers to estimate prognosis and identify patients at especially high early mortality risk.
• Patients with advanced cardiac involvement can deteriorate over days to weeks, particularly when there is hypotension, markedly elevated NT-proBNP, elevated troponin, renal dysfunction, low output physiology.
• Early hematology involvement is essential because treatment targets the plasma cell clone.
• Daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) is now considered standard first-line therapy for newly diagnosed AL amyloidosis.
• The addition of daratumumab has been associated with deeper, faster responses, improved organ outcomes and improved survival.
• Treatment logistics matter. In advanced cardiac AL amyloidosis, delaying therapy until outpatient follow-up may be dangerous if the patient is unstable or has high-risk features.
• The practical takeaway:

• once AL is suspected, do not wait for every outpatient test to return before escalating care.
• send the full monoclonal protein workup.
• involve hematology and amyloid specialists early.
• expedite tissue diagnosis and treatment planning.

4. How does cardiac amyloidosis affect hemodynamics and response to therapy?

• Amyloid infiltration produces restrictive cardiomyopathy characterized by: impaired ventricular compliance, elevated right- and left-sided filling pressures, low stroke volume, preload dependence, afterload intolerance, and limited ability to augment cardiac output.
• Because stroke volume is fixed, heart rate becomes an important contributor to cardiac output. Beta blockers, non-dihydropyridine calcium channel blockers, and aggressive vasodilators may be poorly tolerated, particularly in AL cardiac amyloidosis with hypotension or advanced restrictive physiology.
• Patients may appear profoundly volume overloaded while remaining severely forward-flow limited. This explains why diuresis can be difficult until perfusion improves, and why inotropes may produce a dramatic improvement in urine output in selected patients with low-output physiology.

• Right heart catheterization can help characterize the physiology. In this case, invasive hemodynamics showed elevated filling pressures and pulmonary hypertension due to left-sided disease: RA 12 mmHg, PA 58/26 mmHg, mean PA 39 mmHg, PCW 20 mmHg, and cardiac index approximately 2.2-2.3 L/min/m2.
• Positioning and respiratory mechanics matter. In this case, lying supine during renal ultrasound likely worsened respiratory mechanics in the setting of large pleural effusions and restrictive physiology, contributing to hypoxia and PEA arrest.

This case highlights how patients with cardiac amyloidosis can be extremely hemodynamically fragile.

5. What management principles are important once AL cardiac amyloidosis is suspected or confirmed?

• Management requires multidisciplinary coordination among Advanced Heart Failure, Hematology/Oncology, Nephrology, Critical Care, Pathology, and, when needed, amyloid specialty clinics.
• Supportive heart failure therapy centers on careful volume management. Loop diuretics are often needed, sometimes with sequential nephron blockade, but the margin between congestion and underfilling is narrow due to preload dependence.
• Guideline-directed medical therapy for conventional HFrEF may be limited by hypotension, renal dysfunction, low stroke volume, and autonomic dysfunction. The goal is not to force standard HFrEF therapy when the physiology does not support it.
• Pleural effusions may be large and recurrent. Drainage can improve respiratory mechanics, but it does not treat the underlying restrictive cardiomyopathy or plasma cell disorder.
• For AL amyloidosis, definitive therapy targets the plasma cell clone. Cardiac stabilization and chemotherapy planning must proceed in parallel, because ongoing light-chain production can drive rapid organ injury even after temporary hemodynamic improvement.
• The major clinical pearl from this case is that AL cardiac amyloidosis should be approached with the urgency of both advanced heart failure and an aggressive hematologic malignancy. Early recognition and expedited evaluation can be life-saving.

Media

References

• Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol. 2022;79(17):e263-e421.
• Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2020;142(1):e7-e22.
• Writing Committee, Kittleson MM, Ruberg FL, et al. 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis. J Am Coll Cardiol. 2023;81(11):1076-1126.
• Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554-1568.
• Falk RH, Quarta CC, Dorbala S. How to image cardiac amyloidosis. Circ Cardiovasc Imaging. 2014;7(3):552-562.
• Felker GM, Boehmer JP, Hruban RH, et al. Echocardiographic findings in fulminant and acute myocarditis. J Am Coll Cardiol. 2000;36(1):227-232.
• Ioannou A, Massa P, Patel RK, et al. Conventional heart failure therapy in cardiac ATTR amyloidosis. Eur Heart J. 2023;44(31):2893-2907.
• Palladini G, Merlini G. How I treat AL amyloidosis. Blood. 2022;139(19):2918-2930.
• Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis. J Card Fail. 2019;25(11):e1-e39.
• Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412.
• Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22(18):3751-3757. [Mayo 2004 staging]
• Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):1055-1062. [Mayo 2012 staging]
• Kastritis E, Leleu X, Arnulf B, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis (ANDROMEDA): a randomised, phase 3 trial. Lancet. 2021;397(10292):2337-2347.
• Martens P, Bhattacharya S, Longinow J, et al. Hemodynamic profiling and prognosis in cardiac amyloidosis. Circ Heart Fail. 2023;16(3):e010078.
• Porcari A, Fontana M, Gillmore JD. Transthyretin cardiac amyloidosis. Cardiovasc Res. 2023;118(18):3517-3535.
• Ruberg FL, Maurer MS. Cardiac amyloidosis due to transthyretin protein: a review. JAMA. 2024;331(9):778-791.
• Ikura H, Endo J, Kitakata H, Moriyama H, Sano M, Fukuda K. Untangling amyloidosis: recent advances in cardiac amyloidosis. Korean Circ J. 2022;52(10):725-742.
• Larsen SB, Ladefoged B, Pedersen ALD, et al. Changes of clinical characteristics, distribution of red flags and prognosis in contemporary patients with wild-type transthyretin amyloidosis cardiomyopathy. Ann Med. 2024;56(1):2398735.
• Transthyretin Cardiac Amyloidosis Evaluation and Management: 2025 ACC Concise Clinical Guidance. J Am Coll Cardiol. 2025. doi:10.1016/j.jacc.2025.09.004.

In this episode, the CardioNerds (Dr. Dinu Balanescu, Dr. Billy Joe Mullinax, and Dr. Akiva Rosenzveig) take a deep dive into the world of the surgical management of pulmonary embolism (PE) with faculty expert, Dr. Joshua Goldberg. We start from the pathophysiology of PE and its impact on right ventricular, and thereby left ventricular, hemodynamics. We then discuss the management of high-risk PE and where catheter-based therapies, surgical management and mechanical circulatory support via ECMO find their roles. Dr. Goldberg also provides a historical overview of the evolution of the surgical management of PE. We conclude by briefly discussing the management of chronic thromboembolic pulmonary hypertension (CTEPH) as a long-term complication of PE. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

NOTE: this episode was recorded before the publication of the 2026 AHA/ACC Acute PE Guidelines.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

• Beware of the RV death spiral. Hypotension occurs late in the acute PE pathophysiology as the LV function is preserved. A patient becomes hypotensive once all compensatory mechanisms have failed.
• Don’t just treat the clot. Support the RV as well and think more seriously about ECMO.
• One needs to be very careful intubating these patients, as sedating them will counteract many of the hemodynamic compensatory mechanisms and will lead to cardiac arrest.
• With the increasing role of catheter-based therapies, surgery’s role in acute PE is becoming more nuanced. Surgery is most useful in those patients with predominantly subacute clot, which is difficult to extract via catheter-based therapies.

Notes:

Notes: Notes drafted by Dr. Akiva Rosenzveig.

• What is the hemodynamic consequences of high-risk PE and what is the Right ventricular (RV) “death spiral?”

Sudden increase in RV afterload which leads to RV volume and pressure overload which leads to neurohormonal activation, increased oxygen demand and RV ischemia, reduced RV contractility leading to reduced left ventricular (LV) preload and reduced cardiac output

• What is the role of ECMO in acute PE?

We need to focus on not only treating the clot but supporting the RV concurrently. This is analogous to supporting the LV with mechanical circulatory support while also opening the culprit coronary lesion in acute myocardial infarction related cardiogenic shock (AMI-CS). The reason why High-risk/Massive PE has historically had poor outcomes may be because treatment modalities focused on treating the clot and not supporting the RV as well.

• When is surgical embolectomy considered in the treatment of acute PE?

With the increased role of catheter-based therapies, the role of surgery is narrowing to a more nuanced patient population. Surgery should be considered when we don’t have other treatment options. It remains especially useful in more subacute clots where it is more difficult to extract with catheter-based interventions. In those cases, surgical pulmonary embolectomy can be useful as you have direct visualization of the pulmonary arteries and its branches.

• What is the historical evolution of surgical management of PE?

In the early 1900’s, the Trendelenburg procedure was performed but had a very high mortality rate. This was because they waited for the patients to decompensate and then once the patient was peri-arrest, they would take them urgently to the operating room, snare the aorta and pulmonary artery and open the artery and remove the clot. By manipulating the PA in this way they detrimentally increased the RV afterload on an already failing RV. In the 1930’s, John Gibbon started working on developing cardiopulmonary bypass. Now, surgeons can put the patient on cardiopulmonary bypass and create incisions on both the left and right pulmonary arteries to extract the clot.

• Can we be reassured if the patient does not have a saddle embolus?

Contrary to what we are used to hearing, the lack of a saddle PE shouldn’t be comforting. The more distal clot is more concerning as that’s where there is more significant flow resistance. The saddle embolus takes up a small proportion of the PA cross-sectional area and, therefore, the flow obstruction does not come from there.

References:

• Goldberg JB, Spevack DM, Ahsan S, et al. Survival and Right Ventricular Function After Surgical Management of Acute Pulmonary Embolism. J Am Coll Cardiol. 2020;76(8):903-911. doi:10.1016/j.jacc.2020.06.065
• Goldberg JB, Giri J, Kobayashi T, et al. Surgical Management and Mechanical Circulatory Support in High-Risk Pulmonary Embolisms: Historical Context, Current Status, and Future Directions: A Scientific Statement From the American Heart Association. Circulation. 2023;147(9):e628-e647. doi:10.1161/CIR.0000000000001117
• Delcroix M, Pepke-Zaba J, D’Armini AM, et al. Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy. Circulation. 2024;150(17):1354-1365. doi:10.1161/CIRCULATIONAHA.124.068610

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 8.2 of the 2025 ACS Guidelines.

The question is asked by Johns Hopkins pre-medical undergraduate and CardioNerds Academy Intern Joshua Khorsandi, answered first by University of Wisconsin cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Shikha Jha, and then by expert faculty Dr. Venu Menon.

Dr. Menon is the Section Head of Clinical Cardiology, Director of the Cardiac Intensive Care Unit, and Program Director of Cardiology Fellowship at the Cleveland Clinic. He is the Mehdi Razavi Endowed Chair and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. He was also a member of the 2025 ACS Guidelines writing committee.

Question #11

A 58-year-old man with a past medical history of hypertension, hyperlipidemia, schizophrenia, atrial fibrillation (on apixaban), and prior tobacco use presents to the emergency department with chest tightness. ECG shows ST elevations in leads II, III, and aVF with reciprocal depressions in leads I and aVL. Emergency coronary angiography demonstrates 100% occlusion of the proximal RCA, and he undergoes PCI. Transthoracic echocardiogram afterward reveals normal LV function with inferior hypokinesis. On day 2, the patient experienced lightheadedness and has frequent melanic stools. His hemoglobin returns at 6 gm/dL (initial hemoglobin 11 g/dL). He undergoes EGD and colonoscopy with successful endoscopic treatment of a small gastric ulcer.

True or False: it is reasonable to administer 3-4 units of packed red blood cells for a goal Hb ≥ 10 g/dL.

True

False

Answer #11

Explanation

The correct answer is True – it would be reasonable to administer 3-4 units of packed red blood cells for a goal Hb ≥ 10 g/dL.

Anemia is common in patients with ACS and is associated with worse short- and long-term outcomes. Anemia is associated with adverse outcomes irrespective of whether the anemia is chronic and due to comorbid conditions, or acute and the result of bleeding related to antithrombotic therapy and/or invasive procedures. The adverse effects of anemia may be due to decreased myocardial oxygen delivery, increased myocardial oxygen demand due to increased cardiac output, or the avoidance of potentially beneficial antithrombotic drugs and/or procedures. Randomized trials in medically ill patients and those undergoing cardiac surgery have demonstrated similar or better outcomes with a restrictive transfusion strategy (targeting a blood hemoglobin level around 8 g/dL) than with a liberal transfusion strategy (targeting a blood hemoglobin level around 10 g/dL). However, randomized trial evidence for populations with ACS suggests possible clinical benefit for a more liberal transfusion strategy targeting a hemoglobin level above 10 g/dL compared with targeting a hemoglobin level above 7 g/dL to 8 g/dL

The MINT (Myocardial Ischemia and Transfusion) trial randomly assigned 3,504 patients with acute STEMI or NSTEMI and anemia with a blood hemoglobin level of <10 g/dL (13% with recent bleeding) to a restrictive transfusion strategy (transfusing if the hemoglobin level was <7-8 g/dL) or a liberal transfusion strategy (transfusing if the hemoglobin level was <10 g/dL). Patients were ineligible for enrollment if they had uncontrolled bleeding, were receiving palliative treatment, or were scheduled to have cardiac surgery. Transfusion could be delayed for patients with volume overload or until the day of dialysis in patients with end-stage renal disease. The primary outcome of 30-day death or recurrent MI occurred in 16.9% of patients in the restrictive strategy and 14.5% of patients in the liberal strategy (relative risk, 1.15 [95% CI, 0.99-1.34]; P = 0.07). Death occurred in 9.9% of patients in the restrictive strategy and 8.3% of patients in the liberal strategy (relative risk, 1.19 [95% CI, 0.94-1.49]), and cardiac death occurred in 5.5% of patients in the restrictive strategy and 3.2% of patients in the liberal strategy (relative risk, 1.74 [95% CI, 1.26-2.40]). Although the MINT trial did not demonstrate a statistically significant reduction in its primary endpoint, the results suggest that a liberal blood transfusion strategy targeting a hemoglobin level around 10 g/dL may provide short-term clinical benefit over a restrictive transfusion strategy targeting a hemoglobin level above 7 g/dL or 8 g/dL in patients with AMI and anemia.

The 2025 ACS guidelines give a Class 2b, LOE B-R recommendation for a liberal transfusion strategy targeting a hemoglobin of >10 g/dL in patients with ACS and acute or chronic anemia to reduce cardiovascular events.

Main Takeaway

In patients with ACS and acute or chronic anemia, blood transfusion to achieve a hemoglobin level of more than 10 g/dL may be reasonable to reduce cardiovascular events.

Guideline Loc.

Section 10.2

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 9.2 of the 2025 ACS Guidelines.

The question is asked by Johns Hopkins pre-medical undergraduate and CardioNerds Academy Intern Joshua Khorsandi, answered first by University of Wisconsin cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Shikha Jha, and then by expert faculty Dr. Venu Menon.

Dr. Menon is the Section Head of Clinical Cardiology, Director of the Cardiac Intensive Care Unit, and Program Director of Cardiology Fellowship at the Cleveland Clinic. He is the Mehdi Razavi Endowed Chair and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. He was also a member of the 2025 ACS Guidelines writing committee.

Question #9

A 74-year-old man with past medical history significant for hyperlipidemia, obstructive sleep apnea, hypertension, tobacco use, type 2 diabetes mellitus, and chronic obstructive pulmonary disease presents to the emergency department with two days of chest tightness and worsening shortness of breath at rest. He is found to have ST elevations in the anterolateral leads. Emergent coronary angiography demonstrates 90% stenosis of proximal to mid LAD and he is treated with two drug-eluting stents. Transthoracic echocardiograms during hospitalization showed an LVEF of 25% with anterior and apical wall motion abnormalities. He is discharged on dual antiplatelet therapy along with metoprolol, valsartan, spironolactone, SGLT2 inhibitor, and rosuvastatin. At follow-up 3 months later, he reports home BP readings in 90s/50s mm Hg with intermittent shortness of breath and lightheadedness. Blood pressure in the office is 92/54 mmHg. ECG shows normal sinus rhythm with anterior Q waves, a narrow QRS, and no acute ST-segment or T-wave changes. Repeat transthoracic echocardiogram shows an LVEF of 30%. What is the most appropriate next step?

A

Switch valsartan to sacubitril-valsartan

B

Consider implantable cardioverter defibrillator (ICD) placement

C

Consider cardiac resynchronization therapy

D

Consider additional cardiac rehabilitation sessions

Answer #9

Explanation

The correct answer is B – consider implantable cardioverter defibrillator (ICD) placement.

Generally, arrhythmic complications increase both morbidity and mortality rates in patients after ACS. Patients who present with AMI with reduced LVEF (≤40%) have increased risk of new-onset atrial fibrillation, bradyarrhythmias, and ventricular arrhythmias. Ventricular arrhythmias are common after ACS and more common in patients with reduced LVEF. The MADIT II trial (Multicenter Automatic Defibrillator Implantation Trial) demonstrated a 31% reduction in all-cause mortality (HR, 0.69 [95% CI, 0.51-0.93]) for prophylactic implantation of a cardiac defibrillator in patients with an LVEF ≤30% who were at least 30 days after MI or 3 months after revascularization for MI and had an anticipated life expectancy longer than 1 year. A mortality benefit for prophylactic ICD implantation has also been shown in patients with an LVEF ≤35% and New York Heart Association class II or III HF symptoms, as well as in patients with inducible ventricular tachycardia or ventricular fibrillation and an LVEF ≤40%.

This patient has an LVEF of <30% with at least NYHA class II symptoms, now 90 days post-revascularization for MI, which means he is a candidate for ICD placement for primary prevention of sudden cardiac death.

Answer choice A is incorrect because hypotension in this patient is a limitation to adding any more guideline-directed medical treatment, such as sacubitril/valsartan. This patient does not meet criteria for CRT implantation given his narrow QRS complex, so answer choice C is incorrect. Additional cardiac rehabilitation sessions (answer choice D) would not treat patients’ ongoing cardiomyopathy and SCD risk.

The 2025 ACS guidelines give a Class 1, LOE A recommendation for ICD implantation in patients post-MI with LVEF ≤40% at least 40 days post-MI and at least 90 days post-revascularization to reduce mortality.

In addition, in patients post-ACS, ICD implantation is reasonable in patients with clinically relevant ventricular arrhythmias >48 hours and within 40 days post-MI to improve survival (LOE 2a, LOE C-EO).

Some may wonder about the use of a temporary wearable cardioverter-defibrillator after the initial presentation. In the VEST trial, this strategy did not significantly reduce the primary endpoint, a composite of sudden death or death from ventricular tachyarrhythmias at 90 days) in patients with AMI and LVEF ≤ 35%. Notably, there was a lower incidence of death from any cause in the wearable vest group compared to the no-device group and overall, greater benefit was seen in those who were compliant with the device. As such, use of a wearable cardioverter-defibrillator could be considered in high-risk patients with reduced LVEF as a bridge to consideration for the need for an ICD. Per the guidelines, in patients early after MI, usefulness of a temporary wearable cardioverter-defibrillator is uncertain in patients with an LVEF ≤35% to improve survival (COR 2b, LOE B-R).

Main Takeaway

In patients post MI, implantable cardioverter defibrillator (ICD) implantation is recommended in selected patients with an LVEF of less than or equal to 40% at least 40 days post MI and at least 90 days post revascularization to reduced death.

Guideline Loc.

Section 9.2

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 9.1 of the 2025 ACS Guidelines.

The question is asked by Johns Hopkins pre-medical undergraduate and CardioNerds Academy Intern Joshua Khorsandi, answered first by Washington University cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Colin Martz, and then by expert faculty Dr. Venu Menon.

Dr. Menon is the Section Head of Clinical Cardiology, Director of the Cardiac Intensive Care Unit, and Program Director of Cardiology Fellowship at the Cleveland Clinic. He is the Mehdi Razavi Endowed Chair and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. He was also a member of the 2025 ACS Guidelines writing committee.

Question #8

A 65-year-old female with no significant prior cardiac history presents to the emergency department with 3 days of chest tightness associated with shortness of breath. ECG demonstrates anterior ST-segment elevation with reciprocal depressions. Coronary angiography reveals 100% occlusion of the mid left anterior descending artery. She undergoes PCI of the LAD. Two days later, she develops worsening shortness of breath. Her HR is 115 and BP 95/50. Lungs are clear on auscultation. Cardiac examination is significant for a harsh systolic murmur at the left sternal border with a palpable thrill. Transthoracic echocardiogram showed ventricular septal rupture with left-to-right shunt and Qp:Qs estimated at 2.5:1. What is the best next step?

A

Continue medical management

B

Proceed with repeat coronary angiogram and right heart catheterization with shunt run

C

Percutaneous ventricular septal defect closure

D

Intra-aortic balloon pump placement and cardiac surgical consultation

Answer #8

Explanation

The correct answer is D – placement of an intra-aortic balloon pump and CT surgical consultation.

Timely reperfusion therapy has reduced the incidence of mechanical complications (ventricular septal rupture, mitral valve insufficiency due to papillary muscle infarction or rupture, or free wall rupture) after AMI. Although occasionally found incidentally, mechanical complications commonly present with recurrent or refractory chest pain or a new murmur accompanied by disproportionate heart failure, cardiogenic shock, or sudden cardiac death on clinical presentation within the first week after an AMI. Medical therapy alone is associated with high risk of early death; definitive surgical correction is frequently the treatment of choice. Mortality rates with surgery are highest in subjects with cardiogenic shock and in those requiring early emergency/urgent intervention after AMI. Observed mortality rates following delayed surgery (>7 days) are lower but patient selection and survivor bias contribute to this observation.

The 2025 ACS guidelines give a Class 2a, LOE B-NR recommendation for the use of short-term MCS devices in patients with mechanical complications of ACS for hemodynamic stabilization and bridge to surgery. The availability of temporary MCS devices has led to increasing trends for delayed surgery due to concerns for the initial degree of extensive tissue destruction. Delayed surgical intervention may enable hemodynamic stabilization, lead to recovery of end-organ injury, and promote infarct tissue healing and maturation that could facilitate definitive repair. Percutaneous approaches toward repair have been used in patients with prohibitive surgical risk or contraindications to surgery as a primary or temporizing option in the setting of acute mitral regurgitation and ventricular septal rupture and

remain an evolving area of investigation. This patient is not at prohibitive risk for surgery. Select patients with mechanical complications of ACS may be considered for cardiac transplantation or durable LVAD as a primary or bailout treatment strategy to improve survival.

No RCTs evaluate the role of transfer of patients with mechanical complications after MI to dedicated centers with cardiac surgical expertise. Although overall surgical mortality is approximately 40%, it remains the treatment strategy of choice. Hemodynamic deterioration is unpredictable and can be precipitous in previously stable subjects. Consequently, transfer to a Level 1 cardiac intensive care unit (CICU) with access to various temporary MCS devices and multidisciplinary experienced teams of surgical, interventional, HF, and palliative care specialists is recommended. The guidelines give a Class 1, LOE C recommendation for management of patients with mechanical complications of ACS at centers with cardiac surgical expertise.

Main Takeaway

Patients with mechanical complications of ACS should be managed in a center with cardiac surgical expertise. In such patients, short-term MCS devices are reasonable for hemodynamical stabilization as a bridge to surgery.

Guideline Loc.

Section 9.1, Figure 9

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 8.2 of the 2025 ACS Guidelines.

The question is asked by Johns Hopkins pre-medical undergraduate and CardioNerds Academy Intern Joshua Khorsandi, answered first by University of Wisconsin cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Shikha Jha, and then by expert faculty Dr. Venu Menon.

Dr. Menon is the Section Head of Clinical Cardiology, Director of the Cardiac Intensive Care Unit, and Program Director of Cardiology Fellowship at the Cleveland Clinic. He is the Mehdi Razavi Endowed Chair and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. He was also a member of the 2025 ACS Guidelines writing committee.

Question #7

A 72-year-old gentleman with past medical history significant for hypertension, hyperlipidemia, type 2 diabetes, and tobacco use is brought to the ED with chief complaint of chest tightness. He is found to have ST elevations in leads V1 to V4 and is taken for emergency coronary angiography, which demonstrates 99% proximal LAD occlusion. During the procedure, he becomes hypotensive (BP 74/55 mm Hg) and tachycardic (HR 122 bpm). Norepinephrine is initiated. Right heart catheterization demonstrates elevated left and right-sided filling pressures with low cardiac index. Besides immediate revascularization, which of the following would be the best next step?

A

Cannulate for VA-ECMO

B

Placement of microaxial intravascular flow pump

C

Administration of intravenous fluid

D

Placement of an intraaortic balloon pump

Answer #7

Explanation

The correct answer is B – Placement of microaxial intravascular flow pump.

Cardiogenic shock is estimated to occur in approximately 10% of patients with STEMI and is associated with an early mortality rate of 40% to 50%. Several types of devices for temporary mechanical circulatory support (MCS) are available and have been studied in patients with cardiogenic shock, with variable efficacy and increased risk of vascular complications. IABP counterpulsation improves coronary perfusion and reduces cardiac afterload. It is relatively easy to use and has a smaller insertion profile (8 French), which is associated with lower rates of vascular access site complications when compared with other MCS devices. Left ventricular percutaneous microaxial flow pumps unload the LV by draining blood from the LV and pumping it to the ascending aorta. They are dependent on adequate right ventricular function to fill the LV and require adequate oxygenation of blood. VA-ECMO provides both blood flow and gas exchange, providing full cardiopulmonary bypass, but increases afterload.

Randomized trials of MCS devices remain challenging to conduct due to relative lack of equipoise on the part of treating physicians, leading to selective patient enrollment and limiting the generalizability of study results. The DanGer-Shock randomized 360 patients presenting with STEMI and cardiogenic shock of <24 hours duration to either microaxial flow pump or standard of care. The trial demonstrated a 26% reduction of all-cause mortality at 180 days (HR, 0.74 [95% CI, 0.55-0.99]; P = 0.04; absolute risk reduction, 12.7%; number needed to treat = 8) compared with standard of care. However, this came at the cost of increased risk of complications like bleeding, limb ischemia and renal replacement therapy in the microaxial flow pump group.

In light of this and other trial data, the guidelines give a Class 2a, LOE B recommendation for the use of a microaxial intravascular flow pump in patients with STEMI complicated by severe or refractory cardiogenic shock to reduce mortality. These patients should be noncomatose and have adequate peripheral vasculature to accommodate large-bore access.

Answer choice A is not correct as the use of VA-ECMO cannulation in this setting has been given a class 3 recommendation for lack of benefit. VA-ECMO has not been shown to reduce death compared with medical therapy alone in patients with cardiogenic shock in the setting of MI but increases major bleeding and vascular complications. In the absence of severe concomitant respiratory failure requiring oxygenation support, this strategy is not indicated in the patient described here. Further fluid resuscitation (answer choice C) is not likely to be helpful as right heart catheterization demonstrated elevated filling pressures. Placement of an intraaortic balloon pump (IABP) is not the next best step. The IABP-SHOCK II trial, which randomized patients with acute MI and severe cardiogenic shock to IABP or medical therapy showed no differences at 30 days or at long-term follow-up in the primary outcome of all-cause death. The use of IABP has a class 3 recommendation for lack of benefit in patients with cardiogenic shock secondary to acute myocardial infarction.

Main Takeaway

In selected patients with STEMI and severe or refractory cardiogenic shock, insertion of microaxial intravascular flow pump is reasonable to reduce death in a noncomatose patient with adequate vascular access.

Guideline Loc.

Section 8.2

CardioNerds (Drs. Billy Joe Mullinax, Dinu Balanescu, and Saahil Jumkhawala) discuss the 2026 American Heart Association (AHA)/American College of Cardiology (ACC) multisocietal guidelines for the evaluation and management of acute pulmonary embolism (PE) with Dr. Mark Creager, Director Emeritus of the Heart and Vascular Center at Dartmouth Health, past president of the AHA, and Chair of the Writing Committee for the 2026 AHA/ACC PE Guidelines. Audio editing by CardioNerds intern, Dr. Patrick Pekyi-Boateng.

Pulmonary embolism is one of the most rapidly evolving conditions in cardiovascular medicine. The 2026 AHA/ACC multisocietal guideline, endorsed by ten professional societies, is the first de novo comprehensive guideline dedicated exclusively to acute PE in adults. It introduces a new five-category A-E risk classification system, a Class I recommendation for the Pulmonary Embolism Response Team (PERT), updated guidance on anticoagulation and advanced reperfusion therapies, and a structured framework for post-PE follow-up and chronic thromboembolic pulmonary hypertension (CTEPH) screening. This episode walks through all of it, using a high-risk clinical case as the backbone.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

• The 2026 guideline replaces “massive/submassive/low-risk” language with a new five-category A-E classification. Category A is subclinical/incidental PE; B is symptomatic with a low clinical severity score; C1-C3 stratifies intermediate-risk patients by right ventricular (RV) function and biomarkers; D1-D2 captures incipient cardiopulmonary failure (transient hypotension vs. normotensive shock with end-organ dysfunction); and E1-E2 is frank cardiopulmonary failure up to cardiac arrest. Each category carries a respiratory modifier (R) for hypoxemia, tachypnea, or need for supplemental oxygen.
• PERT receives a Class I recommendation. Registry data show PERT reduces time to therapeutic anticoagulation, decreases unnecessary inferior vena cava (IVC) filter use, and shortens hospital and intensive care unit (ICU) length of stay. PERT is most impactful when advanced therapy decisions are on the table.
• Low molecular weight heparin (LMWH) is now preferred over unfractionated heparin (UFH) for initial parenteral anticoagulation in most patients (Category C and above), given superior venous thromboembolism (VTE) recurrence reduction, predictable pharmacokinetics, no routine monitoring, and lower heparin-induced thrombocytopenia (HIT) risk. UFH is still preferred when imminent reperfusion is planned, in severe renal failure, or when rapid reversal may be needed. Categories A and B go straight to a direct oral anticoagulant (DOAC).
• Advanced reperfusion therapies – systemic thrombolysis, catheter-directed thrombolysis (CDT), mechanical thrombectomy (MT), and surgical embolectomy – carry Class 2B recommendations for Category D PE because available trials used surrogate endpoints only. HI-PEITHO, which showed a composite 7-day benefit for CDT plus anticoagulation vs. anticoagulation alone, was published in March 2026 after guideline lock and could not influence the current document. More trials are coming (PEERLESS 2, PE-TRACT, PERSEVERE, TORPEDO).
• Post-PE follow-up is now structured: outreach within 1 week of discharge, office visit with a PE-experienced clinician by 3 months, and active chronic thromboembolic pulmonary disease (CTEPD) and CTEPH screening at every visit for at least 1 year. Persistent symptoms or functional limitation beyond 3 months should trigger evaluation with a ventilation-perfusion (V/Q) scan, echocardiogram, and right heart catheterization (RHC).

Notes:

Notes drafted by Dr. Saahil Jumkhawala.

• Why did the writing committee believe a new classification system was necessary in 2026?

• The 2011 AHA scientific statement used “low-risk,” “submassive,” and “massive” categories – broad, imprecise, and insufficient for guiding modern management decisions. The 2019 European Society of Cardiology (ESC) guideline improved on this with low, intermediate-low, intermediate-high, and high-risk categories, but still did not capture many clinical, imaging, and laboratory variables with reliable prognostic data.
• The writing committee wanted a classification system that:

• Was more nuanced and captured the full clinical spectrum of PE severity
• Incorporated the clinical, laboratory, and imaging variables with the strongest outcome data
• Mapped directly to management decisions and could serve as a shared communication tool

• The result is a five-category A-E system with subcategories and a respiratory modifier, easier to memorize and use in practice.

• How do we apply the new five-category system at the bedside? What data points drive category assignment, and what is the significance of the respiratory modifier?

• Category A – Subclinical/Incidental PE

• Asymptomatic; PE found incidentally (e.g., on staging computed tomography (CT) for cancer)
• Often subsegmental; typically appropriate for outpatient management

• Category B – Symptomatic, Low Severity

• Chest pain or dyspnea, but simplified Pulmonary Embolism Severity Index (sPESI) = 0
• B1: subsegmental PE; B2: non-subsegmental PE
• Outpatient management appropriate unless confounding comorbidity present

• Category C – Symptomatic, Elevated Severity Score (analogous to ESC intermediate risk)

• C1: normal RV size/function, normal biomarkers
• C2: abnormal RV function OR elevated biomarker (one of the two)
• C3: both abnormal RV function AND at least one elevated biomarker
• Respiratory modifier (R): oxygen saturation (SpO2) <90%, respiratory rate (RR) >30, or need for supplemental O2

• Category D – Incipient Cardiopulmonary Failure

• D1: transient hypotension (systolic blood pressure (SBP) <90 mmHg, but responsive/self-resolving)
• D2: normotensive shock – SBP >90 mmHg but with end-organ dysfunction (elevated lactate, rising creatinine)
• Respiratory modifier (R): >6 L nasal cannula O2 or non-rebreather mask required

• Category E – Frank Cardiopulmonary Failure

• E1: recurrent or persistent hypotension with cardiogenic shock
• E2: refractory cardiogenic shock or cardiac arrest
• Respiratory modifier (R): hypoxemic or ventilatory respiratory failure

• Mr. Osis (our case patient): tachycardic, transient SBP 84 mmHg, lactate 3.4, requiring 3L O2 – classified as D1R.

• What is the evidence behind the Class I PERT recommendation, and when should PERT be involved in the context of the new triage system?

• PERT provides:

• Improved risk stratification through multidisciplinary input
• Expert guidance on selection and timing of advanced therapies
• Implementation of evidence-based protocols
• Education of the broader care team

• PERT composition varies by institution but may include: pulmonary/critical care, general cardiology, interventional cardiology, cardiac surgery, vascular surgery, hematology/oncology, emergency medicine, and pharmacy.
• Published data supporting Class I recommendation:

• Reduced time to therapeutic anticoagulation
• Decreased unnecessary IVC filter placement
• Shorter hospital and ICU length of stay
• Possible mortality reduction (data conflicting across registries)

• PERT is most impactful in Category C3 and above, particularly when advanced therapy decisions are being contemplated – though the guideline does not restrict PERT activation to any specific category threshold.

• What does the 2026 guideline say about initial anticoagulation choice (UFH vs. LMWH)?

• LMWH is the preferred initial parenteral anticoagulant for most patients with acute PE (Category C and above).

• Meta-analytic evidence: LMWH reduces recurrent VTE more effectively than UFH without increasing bleeding
• Predictable pharmacokinetics – no routine activated partial thromboplastin time (aPTT) monitoring required
• Lower incidence of HIT

• UFH is preferred when:

• Imminent advanced reperfusion is anticipated (systemic lysis, MT, surgical embolectomy, or extracorporeal membrane oxygenation (ECMO) cannulation)
• Severe renal dysfunction (unpredictable LMWH pharmacokinetics)
• Rapid reversibility needed

• Categories A and B: proceed directly to a DOAC (no parenteral bridge needed).
• DOACs are preferred over vitamin K antagonists (VKA) for long-term therapy in most patients, including most with cancer-associated PE.

• Exception: LMWH preferred for luminal gastrointestinal (GI) or genitourinary (GU) malignancies due to bleeding risk
• DOACs are contraindicated in pregnancy; LMWH is generally used throughout gestation and for at least 6 weeks postpartum

• How does the guideline navigate Category D1-D2 patients? What is the evidence base for the Class 2B recommendation for advanced therapies, and how do we choose between CDT and MT?

• All advanced reperfusion therapies carry a Class 2B recommendation for Category D PE:

• Class 2B = “may be considered” – the intervention can be used, but evidence is less certain
• Applies to: systemic thrombolysis, CDT, MT, and surgical embolectomy

• Why Class 2B? Available trials at the time of guideline finalization (early fall 2025) relied on surrogate endpoints:

• ULTIMA: CDT vs. anticoagulation alone – surrogate RV/LV ratio endpoint
• OPTALYSE: CDT dose-finding – surrogate endpoints
• STORM-PE: surrogate endpoints
• PEERLESS (New England Journal of Medicine, 2024): MT vs. CDT – included mortality, intracranial hemorrhage (ICH), major bleed, ICU admission, but was not vs. anticoagulation alone

• HI-PEITHO (published March 2026 at the ACC annual meeting – after guideline lock):

• 7-day composite of PE-related death, clinical decompensation/collapse, or PE recurrence
• Primary outcome favored CDT plus anticoagulation vs. anticoagulation alone
• Composite driven primarily by clinical decompensation/collapse
• Could not be incorporated into current recommendations

• Upcoming trials expected to provide hard-outcome data: PEERLESS 2, PE-TRACT, PERSEVERE, TORPEDO.
• For Mr. Osis (post-op day 2, fresh anastomosis): systemic lysis and CDT carry high bleeding risk. MT is the most attractive option if hemodynamic deterioration progresses; anticoagulation alone with close monitoring is reasonable if he remains stable.

• In a Category E patient with major bleeding contraindications, how does the guideline structure the decision between systemic lysis, catheter-based therapies, surgical embolectomy, and venoarterial (VA)-ECMO?

• Category E1 (persistent hypotension with cardiogenic shock) – four options:

• Systemic thrombolysis: Class I in the absence of contraindications (alteplase 100 mg over 2 hours)
• CDT: Class 2B; a bleeding-conscious alternative to systemic lysis
• MT: Class 2A for selected E1 patients
• Surgical pulmonary embolectomy: Class 2A for selected E1; Class 2B in Category D when lysis fails or is contraindicated; preferred when cardiac surgery resources are available, and there is obstructing right heart thrombus or patent foramen ovale (PFO) clot

• VA-ECMO: explicitly endorsed in the 2026 guideline as a bridge to recovery, lysis-after-stabilization, MT, or surgical embolectomy in refractory cardiopulmonary collapse. Best outcomes when initiated early (pre-arrest is better than peri-arrest).
• Reduced-dose thrombolysis (25-50 mg alteplase): considered in patients with moderate bleeding risk; possible improvement in RV function with less bleeding, though mortality benefit unproven.
• Temporary mechanical circulatory support (MCS) – including Impella RP, ProtekDuo, and surgical right ventricular assist device (RVAD) – may bridge selected patients with refractory RV failure; data are observational and best deployed at centers with dedicated PE or shock teams.
• For Mr. Osis (post-op day 2 with fresh anastomosis): systemic lysis and CDT are essentially contraindicated. The PERT decision favored MT on VA-ECMO, which is consistent with the 2026 guideline framework for Category E patients with major bleeding contraindications.

• What is the structure of post-PE follow-up, and how do we approach anticoagulation duration in a patient with cancer-associated PE?

• Within 1 week of discharge: outreach or clinic visit (at minimum a phone call) to confirm anticoagulation adherence, assess for bleeding, and review symptoms.
• By 3 months: in-person office visit with a PE-experienced clinician to assess symptom trajectory and determine anticoagulation duration.

• Provoked PE with a resolved transient risk factor: 3-6 months is generally sufficient
• Unprovoked PE or persistent risk factors: extended anticoagulation generally warranted
• Cancer-associated PE: continue anticoagulation while cancer is active or under treatment (Class I)

• At every visit for at least 1 year: actively screen for CTEPD/CTEPH – ask about exertional dyspnea, fatigue, and functional decline.
• PERT or post-PE clinic models are associated with better adherence to follow-up and earlier CTEPH detection in registries.

• When does residual dyspnea after PE trigger a structured CTEPH workup, and what is the recommended diagnostic pathway?

• Approximately 50% of patients have residual symptoms at 3 months post-PE.
• After 3 months of therapeutic anticoagulation, persistent dyspnea or functional limitation triggers evaluation for CTEPD (chronic thromboembolic pulmonary disease) – this is a Class I recommendation.
• Diagnostic pathway:

• Echocardiogram: persistent RV dysfunction is a Class 2A indication for further evaluation
• V/Q scan: first-line imaging for CTEPH evaluation
• CT pulmonary angiography (CTPA): confirmatory imaging
• RHC: required to confirm CTEPH (mean pulmonary arterial pressure (PAP) >20 mmHg with pulmonary vascular resistance (PVR) >2 Wood units (WU) on anticoagulation)
• Cardiopulmonary exercise test (CPET): Class 2A option for patients with functional limitation but no overt pulmonary hypertension (PH) (CTEPD without H)

• Confirmed CTEPH: refer to an expert center for pulmonary endarterectomy (PEA) candidacy assessment, balloon pulmonary angioplasty (BPA), or PH-targeted medical therapy (riociguat, treprostinil).
• For Mr. Osis at 3 months (tricuspid annular plane systolic excursion (TAPSE) 16 mm, estimated pulmonary artery systolic pressure (PASP) 48 mmHg, exertional dyspnea): V/Q scan and RHC are indicated, with referral to a CTEPH center given high pre-test probability.

• Special populations: PE in pregnancy, cancer-associated PE, clot-in-transit, and IVC filters.

• Pregnancy:

• DOACs and warfarin are contraindicated (fetal harm, miscarriage risk)
• LMWH is preferred throughout pregnancy and for at least 6 weeks postpartum
• Anti-Xa monitoring is recommended in patients at weight extremes or with renal disease
• After delivery, LMWH or warfarin can be continued; insufficient data on DOACs in breastfeeding

• Cancer-associated PE:

• DOACs (apixaban, edoxaban, rivaroxaban) are first-line for most patients
• LMWH preferred for luminal GI or GU malignancies due to mucosal bleeding risk
• Long-term management: reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban after the initial treatment period may be considered
• Continue anticoagulation while cancer is active

• Clot-in-transit (right heart thrombus):

• High-risk finding warranting active intervention
• Guideline endorses mechanical or surgical thrombectomy for removal

• IVC filters:

• Indicated only when anticoagulation is contraindicated in the setting of acute PE
• Use retrievable filters with a planned removal strategy
• Routine IVC filter use is not recommended – PERT implementation has already driven down unnecessary filter use significantly

References:

• Creager MA, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults. J Am Coll Cardiol. 2026. Available at: https://www.jacc.org/
• Konstantinides SV, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405. Available at: https://pubmed.ncbi.nlm.nih.gov/31504429/
• Jaff MR, et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the American Heart Association. Circulation. 2011;123(16):1788-1830. doi:10.1161/CIR.0b013e318214914f. Available at: https://pubmed.ncbi.nlm.nih.gov/21422387/
• Piazza G, et al; HI-PEITHO Investigators. Catheter-Directed Thrombolysis in Intermediate-High-Risk Pulmonary Embolism. N Engl J Med. 2026. Available at: https://www.nejm.org/doi/10.1056/NEJMoa2503980
• Bhatt DL, et al; PEERLESS Investigators. Mechanical Thrombectomy for Intermediate-Risk Pulmonary Embolism. N Engl J Med. 2024;391:2099-2110. doi:10.1056/NEJMoa2407772. Available at: https://pubmed.ncbi.nlm.nih.gov/39555838/
• Creager MA, Geary J, Barnes J. Evidence and Future Directions in Acute Pulmonary Embolism Management. J Am Coll Cardiol. 2026. Available at: https://www.jacc.org/

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 4.4 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by University of Miami cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Saahil Jumkhawala, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.

Question #6

A 64-year-old male with a history of hypertension and dyslipidemia presents to the emergency department with crescendo angina. His ECG shows ST-segment depression in leads V4–V6, and high-sensitivity troponin levels are significantly elevated. A diagnosis of NSTE-ACS is made, and the patient is scheduled for an early invasive strategy with percutaneous coronary intervention (PCI). Which of the following parenteral anticoagulants is NOT recommended for use as a standalone agent during the PCI procedure itself?

A

Fondaparinux

B

Bivalirudin

C

Unfractionated Heparin

D

Enoxaparin

Answer #6

Explanation

The correct answer is A.

The choice of parenteral anticoagulation for a patient with Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS) undergoing Percutaneous Coronary Intervention (PCI) is governed by both efficacy in preventing ischemic events and the safety profile regarding bleeding.

The following are the recommended Agents for PCI:

Unfractionated Heparin (UFH): In patients with NSTE-ACS, intravenous unfractionated heparin (UFH) is useful to reduce ischemic events (Class 1, LOE C-EO).

Bivalirudin: This direct thrombin inhibitor is recommended as an alternative to UFH. In patients with NSTE-ACS undergoing PCI, bivalirudin may be reasonable as an alternative to UFH to reduce bleeding and mortality (Class 2b, LOE B-R)

Enoxaparin: In patients with ACS, intravenous enoxaparin may be considered as an alternative to UFH at the time of PCI to reduce ischemic events (Class 2B, LOE B)

In patients with ACS, fondaparinux should not be used to support PCI because of the risk of catheter thrombosis (Class 3: Harm; LOE B-R). The primary reason is due to the risk of catheter thrombosis. Large-scale trials (notably the OASIS-5 trial) demonstrated that using fondaparinux alone during PCI led to a significantly higher rate of thrombus formation on the diagnostic and therapeutic catheters. In the OASIS-5 trial, an increase was observed in the rate of catheter-related thrombus with fondaparinux compared with enoxaparin (0.9% versus 0.4%). Similar results were observed in the OASIS-6 trial, in which a higher rate of guiding-catheter thrombosis and more coronary complications with fondaparinux were observed when used during PCI.

Main Takeaway

– Parenteral anticoagulation for a patient with Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS) undergoing Percutaneous Coronary Intervention (PCI) is governed by both efficacy in preventing ischemic events and the safety profile regarding bleeding.

Expert Suggestions

• When to consider AC other than UFH prior to and during PCI.
• Considerations around patients with HIT.

Guideline Loc.

Section 4.4

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 4.3 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Cleveland Clinic interventional and structural cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Eunice Dugan, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.

Question #5

A 64-year-old woman with NSTE-ACS is taken to the cardiac catheterization laboratory. She is P2Y12 inhibitor-naive as she was unable to tolerate oral intake due to severe nausea and vomiting. Coronary angiography reveals a high-grade, thrombotic lesion in the mid-Right Coronary Artery. The interventionalist decides to initiate an intravenous P2Y12 inhibitor before proceeding with PCI. Which of the following is the most appropriate management strategy?

A

Administer Cangrelor as a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min infusion for at least 2 hours or the duration of PCI, whichever is longer.

B

Administer Eptifibatide (GP IIb/IIIa inhibitor) as a routine double-bolus followed by an infusion to replace the need for P2Y12 inhibition.

C

Delay the procedure for 2 hours to allow for the administration and absorption of 600 mg of oral Clopidogrel.

D

Administer Cangrelor as a 180 mcg/kg bolus followed by a 2 mcg/kg/min infusion for exactly 1 hour.

Answer #5

Explanation

The correct answer is A.

Cangrelor is the only intravenous P2Y12 inhibitor currently available. It is a direct-acting, intravenous antagonist of the P2Y12 receptor characterized by rapid and potent platelet inhibitory effects, with restoration of platelet function occurring within 1 hour of drug discontinuation. It also has a very short half-life (3–6 minutes).

Among patients with ACS undergoing PCI who have not received a P2Y12 inhibitor, intravenous cangrelor may be reasonable to reduce periprocedural ischemic events (Class 2B; LOE B-R).

Dosing Strategy:

Bolus: 30mcg/kg IV bolus administered rapidly (under 1 minute) before PCI begins.

Infusion: 4 mcg/kg/min IV infusion.

Duration: The infusion must run for at least 2 hours or for the duration of the PCI, whichever is longer.

Transition to Oral Therapy:

Ticagrelor: 180mg can be given at any time (during or after the infusion).

Prasugrel/Clopidogrel: loading dose must be given immediately after the infusion is stopped. Giving these earlier can lead to a drug-drug interaction where the Cangrelor prevents the active metabolite from binding to the receptor.

In the CHAMPION PHOENIX trial, cangrelor was studied versus clopidogrel in patients undergoing PCI for acute or stable coronary syndromes. Cangrelor was administered as an intravenous bolus prior to PCI followed by an infusion for at least 2 hours or for the duration of the procedure, whichever was longer. In the control arm, clopidogrel was administered as a 600- or 300-mg loading dose immediately before or after PCI. At 48 hours, the primary endpoint of all- cause death, MI, ischemia-driven revascularization, or stent thrombosis was significantly reduced with cangrelor, with similar effects observed among those presenting with NSTE-ACS or STEMI.

Glycoprotein IIb/IIIa receptor inhibitors are parenterally administered drugs that block platelet aggregation by preventing platelet cross-linking via fibrinogen or von Willebrand factor binding to the glycoprotein IIb/IIIa receptor. Routine administration of GP IIb/IIIa inhibitors before PCI is not recommended and is associated with increased bleeding without improving ischemic outcomes. (Class 3 – No Benefit). In

current practice, the role of glycoprotein IIb/IIIa receptor inhibitors is largely limited to adjunctive use at the time of PCI in patients with large thrombus burden or as

“rescue” or “bailout” therapy in patients with PCI complications such as no-reflow or persistent or recurring thrombus at the lesion.

B is incorrect. Routine “upstream” or periprocedural use of GP IIb/IIIa inhibitors (GPI) is Class 3 (No Benefit) for most patients. Large trials (like EARLY-ACS) showed that routine GPI use significantly increases major bleeding without a proportional decrease in ischemic events compared to modern P2Y12 inhibitors.

C is incorrect. In patients with NSTE-ACS or STEMI who are already in the lab, delaying the procedure to wait for oral drug absorption is not recommended.

D is incorrect. The correct bolus is 30mcg/kg. Cangrelor must be infused for at least 2 hours or the duration of the PCI, whichever is longer. Stopping at 1 hour would leave a “gap” in platelet inhibition before an oral agent can take effect. Because Cangrelor’s half-life is only 3–6 minutes, a premature stop increases the risk of acute stent thrombosis.

Main Takeaway

Cangrelor may be reasonable among patients with ACS undergoing PCI who have not received a P2Y12 inhibitor to reduce periprocedural ischemic events (Class 2b, LOE B-R).

Guideline Loc.

Section 4.3.3-4.3.4

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Sections 4.3.2 and 4.4 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by University of Miami cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Saahil Jumkhawala, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.

Question #4

A 78-year-old man with a history of hypertension and controlled type 2 diabetes presents to a rural emergency department with 90 minutes of persistent, crushing, substernal chest pain. His ECG reveals 3-mm STE in leads V1 through V4. The nearest PCI-capable center is approximately 140 minutes away by ground transport, and air transport is unavailable due to weather. The patient refuses transfer to another facility for the duration of this admission. The clinical team decides to proceed with fibrinolytic therapy using weight-based Tenecteplase (TNK). Which of the following is the most appropriate initial antithrombotic regimen to accompany the fibrinolytic agent?

A

Clopidogrel 300 mg loading dose; Enoxaparin 30 mg IV bolus followed by 1.0 mg/kg SC every 12 hours.

B

Clopidogrel 75 mg (no loading dose); Enoxaparin 0.75 mg/kg SC every 12 hours (no IV bolus).

C

Ticagrelor 180 mg loading dose; Unfractionated heparin (UFH) weight-based IV bolus and infusion.

D

Prasugrel 10mg (no loading dose); Fondaparinux 2.5 mg IV bolus followed by 2.5 mg SC daily.

Answer #4

Explanation

(3-8 min to read)

The correct answer is B.

Clopidogrel is the only P2Y12 inhibitor with a Class 1 recommendation for use alongside fibrinolytic therapy to reduce death and MACE (Class 1, LOE A). Of note, pharmacodynamic variability in response to clopidogrel has been well described, and hyporesponders may be at increased risk of MACE and stent thrombosis when treated with clopidogrel after PCI. Other P2Y12 inhibitors such as ticagrelor and prasugrel are more potent than clopidogrel and achieve more rapid onset of inhibition of platelet activation but with increased risk of bleeding compared with clopidogrel.

When administered concurrently with fibrinolytic as the reperfusion strategy, clopidogrel is recommended to be administered with a loading dose (300 mg, then 75 mg daily) for patients <75 years of age and starting without a loading dose (75

mg daily) for patients ≥75 years of age. In patients treated with a fibrinolytic agent who are undergoing subsequent PCI, either clopidogrel or ticagrelor (age

<75 years, within 24 hours after a fibrinolytic agent) or prasugrel (>24 hours after a fibrinolytic agent) are alternatives to support PCI.

Parenteral anticoagulation is recommended for all patients with ACS, irrespective of the initial treatment strategy, to treat the underlying pathophysiologic process (coronary atherothrombosis) and reduce the risk of recurrent MACE. The choice of a parenteral anticoagulant can be complex because it is influenced by various factors, including vascular access site, renal function, and concomitant use of other antiplatelet or anticoagulant agents. In patients with STEMI treated with fibrinolytic

therapy, parenteral anticoagulation is recommended before and after fibrinolytic therapy to reduce ischemic events.

In patients with STEMI who received fibrinolytic therapy and who are not planned for an invasive approach (as with the patient in the question stem), enoxaparin is the preferred anticoagulant over UFH. In the ExTRACT-TIMI 25 study, enoxaparin until hospital discharge or for a maximum of 8 days (whichever came first) was compared with UFH administered for at least 48 hours. The primary endpoint of death or nonfatal recurrent MI through 30 days occurred in 12% in the UFH group compared with 9.9% in the enoxaparin group. In a meta-analysis of 14 randomized trials, UFH did not reduce reinfarction or death in patients treated with fibrinolytic therapy. In contrast, low-molecular- weight heparin reduced the risk of reinfarction and death compared with placebo and the risk of reinfarction.

In patients >75 years of age, the dosing must be modified: Omit the initial 30 mg IV bolus. Reduce the subcutaneous dose to 0.75 mg/kg (instead of the standard 1.0 mg/kg). The first two SC doses should also be capped at a maximum of 75 mg each.

After receiving the fibrinolytic and adjusted antithrombotics, the patient should be transferred to a PCI center to facilitate immediate or early catheterization depending on the clinical circumstances, if this is in-line with the patient’s wishes. Hospitals should have transfer protocols in place to allow for a seamless transfer to the PCI-capable facility as soon as it is safe to do so. A detailed assessment of clinical status is critical to determine the timing of angiography.

A is incorrect: This is the standard dose for patients under 75 years of age. In a 78-year-old, the IV bolus of Enoxaparin and the Clopidogrel load significantly increase the risk of a fatal brain bleed.

B is incorrect: Ticagrelor is not recommended as an adjunct to fibrinolysis in the 2025 ACS guidelines.

D is incorrect: While fondaparinux may be used alongside lytic therapy when not planning an invasive strategy, prasugrel does not have a Class 1 recommendation for use with fibrinolytic therapy.

Main Takeaway

– Clopidogrel is the only P2Y12 inhibitor with a Class 1 recommendation for use alongside fibrinolytic therapy

Guideline Loc.

Sections 4.3.2 and 4.4

Table 10

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 3.2 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Cleveland Clinic interventional and structural cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Eunice Dugan, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.

Question #3

A 55-year-old woman is brought to the Emergency Department after an out-of-hospital cardiac arrest. She had a witnessed collapse with an initial shockable rhythm. Return of Spontaneous Circulation (ROSC) was achieved after 15 minutes of Advanced Cardiac Life Support (ACLS). Her post-resuscitation ECG shows diffuse ST-segment depression but no ST-segment elevation. She remains comatose.

Which of the following is the most appropriate next step in her management regarding coronary angiography?

A

Immediate emergency coronary angiography (within 2 hours) should be performed.

B

Routine emergency coronary angiography is not recommended in the absence of ST-segment elevation or hemodynamic instability.

C

Coronary angiography should be delayed for at least 72 hours to allow for neurological recovery.

D

Fibrinolytic therapy should be administered immediately if the patient cannot reach a cath lab within 90 minutes.

Answer #3

Explanation

The correct answer is B.

In resuscitated patients who are comatose after cardiac arrest, electrically and hemodynamically stable, and without evidence of STEMI, immediate angiography is not recommended due to lack of benefit (Class 3: No Benefit; LOE A)

Patients who have been resuscitated after cardiac arrest and are noncomatose or who are comatose with favorable prognostic features and with evidence of STEMI, should undergo PPCI to improve survival. (Class 1; LOE B-NR).

For patients such as this one, a delayed or selective approach should be taken once the patient is stabilized. Early angiography should not be denied solely based on a comatose state, but it should be deferred if there are clear non-cardiac causes for the arrest or if the patient’s overall prognosis is futile.

A is incorrect because recent evidence shows no benefit to “emergency” PPCI for stable patients without ST-elevation.

C is incorrect because while we wait for stability, we don’t necessarily have a fixed 72-hour “mandatory” delay for the heart if ischemia is suspected.

D is incorrect, as fibrinolysis is generally not indicated for post-arrest patients without clear STEMI and carries risks in a post-CPR setting due to potential trauma.

The MIRACLE2 Score is a tool for neuroprognostication. It helps clinicians estimate the likelihood of a poor neurological outcome at 6 months. A high score suggests that the benefit of an invasive procedure may be outweighed by the severity of the brain injury.

Components of MIRACLE2:

M – Missed (unwitnessed) arrest
I – Initial non-shockable rhythm
R – Reactive pupils at ROSC
A – Age (points increase significantly at >60 and >80)
C – Rhythm change (e.g., VF to PEA)
L – Low pH (pH < 7.20)
E – Epinephrine (any dose given)

Clinical Threshold: A score of >5 indicates a high risk of poor neurological recovery, which may lead a Heart Team to favor stabilization over immediate emergency angiography in patients without ST-elevation.

Early recognition of STEMI in resuscitated patients and direct transfer to a PCI-capable center is associated with improved survival. Survival-to-hospital discharge in the patient who is comatose with out-of-hospital cardiac arrest is <10% regardless of etiology. Those with a witnessed arrest and a shockable rhythm have improved survival.

Outcomes for patients with STEMI who are awake after resuscitated cardiac arrest are comparable to patients with STEMI who were not in cardiac arrest. For this reason, patients with cardiac arrest who have achieved return of spontaneous circulation (ROSC) and are awake with STEMI on ECG are candidates for PPCI. However, care should be individualized in the comatose patient with rapid assessment of the patient’s clinical features and cardiac arrest characteristics before proceeding with invasive angiography. In contrast, patients who are stable without ST-segment elevation after out-of-hospital cardiac arrest do not require immediate coronary angiography. Coronary angiography in this setting can be deferred pending further risk stratification.

Main Takeaway

Patients with cardiac arrest and STEMI who have been resuscitated should preferentially be transferred by EMS to a PPCI-capable center. Certain prognostic scores can help risk stratify patients prior to catheterization.

Guideline Loc.

Section 3.2. Management of Patients Presenting With Cardiac Arrest

CardioNerds (Drs. Dr. Natalie Marrero, Dr. Ritika Tuli, and Dr. Rafael Toro Manotas) discuss multimodality imaging for risk stratification, evaluation, and management of chronic coronary artery disease with Dr. Panithaya Chareonthaitawee. Audio editing by CardioNerds intern Iman Razeghian.

This episode was produced as part of the CardioNerds Academy curriculum by House Taussig under the guidance of House Chief, Dr. Natalie Marrero and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds. This discussion was planned in collaboration with the Mayo Clinic Cardiovascular Board Review Course.

In this episode, we discuss the pathophysiology and risk stratification of chronic coronary artery disease (CAD), as well as the current landscape of non-invasive evaluation of this condition. CAD remains a leading cause of morbidity and mortality despite advances in pharmacological and non-pharmacological strategies for the prevention and treatment of atherosclerotic disease. The concept of chronic CAD has shifted from the traditional model of stable, obstructive, flow-limiting disease, toward the current understanding of a dynamic process that extends beyond obstructive epicardial lesions to include non-obstructive plaque, diffuse atherosclerosis, and microvascular disease. Similarly, the imaging modalities used to evaluate CAD have evolved, and clinicians now have an extensive menu of options, each with distinct advantages and limitations, that must be selected carefully to maximize diagnostic accuracy and optimize treatment guidance, while also considering resource availability, local expertise, and high-value care. By the end of the episode, listeners will understand the pathophysiology of chronic CAD, risk-stratify patients with suspected CAD, recognize the advantages and pitfalls of each non-invasive diagnostic modality, and select the most appropriate diagnostic tool for a given clinical scenario.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

• Chronic CAD is a complex process that extends beyond obstructive epicardial stenosis to include non-obstructive disease, dynamic plaque burden and ischemia, diffuse atherosclerosis, microvascular dysfunction, vasospasm, among others.
• When evaluating patients with suspected CAD, the diagnostic process should be guided by a specific and appropriate clinical question before ordering any tests.
• The current diagnostic tool arsenal is broadly divided into anatomic and functional imaging modalities. These are complementary, each with distinct properties and limitations, addressing different clinical questions and assessing different aspects of disease.
• Local availability and expertise, along with patient-specific considerations and contraindications, determine the choice of diagnostic modality. No single test is best for every patient.
• INOCA and coronary microvascular dysfunction represent a common and increasingly recognized entity that is diagnosable and treatable; initial evaluation includes non-invasive testing such as stress PET and stress CMR.

References

• Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;144(22):e368-e454. doi:10.1161/CIR.0000000000001029 https://pubmed.ncbi.nlm.nih.gov/34709879/
• Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45(36):3415-3537. doi:10.1093/eurheartj/ehae177 https://pubmed.ncbi.nlm.nih.gov/39210710/
• Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. doi:10.1161/CIR.0000000000001168 https://pubmed.ncbi.nlm.nih.gov/37471501/
• Edvardsen T, Asch FM, Davidson B, et al. Non-Invasive Imaging in Coronary Syndromes: Recommendations of The European Association of Cardiovascular Imaging and the American Society of Echocardiography, in Collaboration with The American Society of Nuclear Cardiology, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2022;35(4):329-354. doi:10.1016/j.echo.2021.12.012 https://pubmed.ncbi.nlm.nih.gov/35379446/
• Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372(14):1291-1300. doi:10.1056/NEJMoa1415516 https://pubmed.ncbi.nlm.nih.gov/39210710/
• Sharma A, Coles A, Sekaran NK, et al. Stress Testing Versus CT Angiography in Patients With Diabetes and Suspected Coronary Artery Disease. J Am Coll Cardiol. 2019;73(8):893-902. doi:10.1016/j.jacc.2018.11.056 https://pubmed.ncbi.nlm.nih.gov/30819356/
• SCOT-HEART Investigators, Newby DE, Adamson PD, et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. N Engl J Med. 2018;379(10):924-933. doi:10.1056/NEJMoa1805971 https://pubmed.ncbi.nlm.nih.gov/30145934/
• Li Z, Xu T, Wang Z, et al. Prognostic Significance of Computed Tomography-Derived Fractional Flow Reserve for Long-Term Outcomes in Individuals With Coronary Artery Disease. J Am Heart Assoc. 2025;14(2):e037988. doi:10.1161/JAHA.124.037988 https://pubmed.ncbi.nlm.nih.gov/39791423/
• Bateman TM, Al-Mallah MH, et al. Clinical indications for positron emission tomography myocardial perfusion imaging and myocardial blood flow quantification: An American Society of Nuclear Cardiology position statement. J Nucl Cardiol. 2026;57:102619. doi:10.1016/j.nuclcard.2025.102619 https://pubmed.ncbi.nlm.nih.gov/41482140/
• Taqueti VR, Di Carli MF. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(21):2625-2641. doi:10.1016/j.jacc.2018.09.042 https://pubmed.ncbi.nlm.nih.gov/30466521/
• Taqueti VR, Hachamovitch R, Murthy VL, et al. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation. 2015;131(1):19-27. doi:10.1161/CIRCULATIONAHA.114.011939 https://pubmed.ncbi.nlm.nih.gov/25400060/
• Mehta PK, Huang J, Levit RD, Malas W, Waheed N, Bairey Merz CN. Ischemia and no obstructive coronary arteries (INOCA): A narrative review. Atherosclerosis. 2022;363:8-21. doi:10.1016/j.atherosclerosis.2022.11.009 https://pubmed.ncbi.nlm.nih.gov/36423427/
• Kunadian V, Chieffo A, Camici PG, et al. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. EuroIntervention. 2021;16(13):1049-1069. doi:10.4244/EIJY20M07_01 https://pubmed.ncbi.nlm.nih.gov/32624456/

CardioNerds (Dr. Apoorva Gangavelli, Dr. Cory Sejo, and Dr. Joseph Kassab), discuss tricuspid regurgitation evaluation and management with Dr. Sunil Mankad.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds. This discussion was planned in collaboration with the Mayo Clinic Cardiovascular Board Review Course.

Audio editing by CardioNerds intern Emma Winakur.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Key Points:

• Tricuspid regurgitation is common and associated with increased mortality at every stage, regardless of etiology. Outcomes are worse with worsening severity, so accurate grading is critical.
• Etiology is critical to guide treatment decisions. Etiology includes primary vs secondary (atrial or ventricular) vs CIED-related TR. 3D echocardiography can be very helpful in determining TR etiology, especially in CIED-related TR.
• Diuresis with the goal of euvolemia is step one. Additionally, underlying contributory conditions (eg. pulmonary HTN, HFrEF, atrial fibrillation) should be addressed, if appropriate, and then TR severity reassessed.
• The choice between T-TEER and TTVR hinges on anatomy, RV function, pulmonary hypertension, and the ability to tolerate anticoagulation. T-TEER is generally first line in atrial functional TR with appropriate anatomy, in patients with poor RV function who cannot tolerate a sudden increase in RV afterload, or in patients who cannot tolerate the necessary anticoagulation with TTVR. TTVR is preferred with wide coaptation gaps and CIED-related TR.
• This is a team sport. Multidisciplinary discussions utilizing imaging (TTE/TEE, CT), risk scores (TRI-SCORE or TRIO), patient preference, and prior institutional experience are essential for the effective treatment of severe TR.

Notes:

• What is the clinical importance of tricuspid regurgitation?

• TR is very common with approximately 4% of people over 75 having moderate or greater severity.
• TR (even mild) is associated with increased mortality. Those outcomes worsen as the TR severity worsens, and this phenomenon is independent of the mechanism of regurgitation.

• What is unique about the tricuspid valve compared to the other cardiac valves?

• It is at an anterior location which allows it to be imaged well with transthoracic echocardiography
• It is the largest valve and composed generally of 3 leaflets (but very often can have 4+ leaflets).
• Importantly, the RV is compliant and changes size and shape readily based on loading conditions. The TV annulus similarly changes size and shape based on hemodynamic conditions such as preload.

• What is a good framework for approaching the causes of tricuspid regurgitation?

• Determine the presence and define the severity of TR.
• Using TTE, we want to measure the right atrial size, the RV size, and any other concomitant valvular lesions.
• Use TTE (2D and 3D) to characterize leaflet anatomy and characteristics.
• Subtypes of TR mechanisms (many times etiology is mixed).

• Primary: primary leaflet abnormality, occurs in ~10% of cases. Look for prolapse, flail, endocarditis, etc.
• Secondary/functional: leaflets normal but surrounding structures are abnormal.

• Atrial: RA and tricuspid annular dilation but normal RV size/shape, and can be related to arrhythmias like atrial fibrillation.
• Ventricular: RV dilated and/or dysfunctional with leaflet tethering. Can be related to pulmonary hypertension or primary RV disease.

• Cardiac implantable electronic device (CIED): Related to device (usually pacemakers or ICD) interaction with TV leaflets.

• Includes perforation, entanglement in subvalvular apparatus, impingement, etc.
• 3D TTE particularly helpful to evaluate

• How do we grade TR severity?

• It is very important to grade the severity of TR, and this is generally done with echocardiography.
• There are both quantitative and qualitative methods which use Doppler and various equations to estimate TR severity.
• Current recommendations have expanded TR severity beyond mild/moderate/severe to include “massive” and “torrential” categories.
• The most important parameters measured/calculated are vena contracta width, regurgitant volume, regurgitant fraction, and effective regurgitant orifice area. Helpful qualitative metrics include hepatic venous flow reversal.

• When should additional studies beyond transthoracic echocardiography, such as transesophageal echocardiography (TEE), cardiac computed tomography (CT), and cardiac magnetic resonance imaging (MRI) be pursued?

• TEE is particularly helpful if TTE views are poor. Since TEE is used during transcatheter intervention, a pre-procedure TEE to define anatomy, determine procedure candidacy, and plan for the procedure is critical.
• CT is also helpful for procedure planning and has particular strengths in defining annulus size and geometry. A CT is required prior to transcatheter tricuspid valve replacement (TTVR).
• MRI is helpful for measuring RV volumes and function, but is not generally used to assess TR severity.

• What is the approach to the treatment for severe tricuspid regurgitation?

• The first step is to try to determine the etiology. For secondary TR, treating the underlying condition is indicated. For example, pulmonary vasodilators for pulmonary HTN or guideline therapy for heart failure with reduced ejection fraction.
• Diuretics are the mainstay for treatment, with the goal to obtain euvolemia. This may require inpatient admission to optimize volume status and medication regimen.
• Once reversible etiologies are addressed, if the patient is still symptomatic from TR, additional therapies can be considered.

• What is the role of right heart catheterizations (RHC) in patients with severe TR?

• RHC is very helpful for many reasons. We use it in TR to help determine volume status, cardiac output, and RV function. Additionally, identifying and characterizing pulmonary hypertension (with pulmonary artery pressures and calculating pulmonary vascular resistance) is an important factor when choosing future therapies.

• With severe tricuspid regurgitation, when should we refer for intervention (either with surgery or transcatheter repair or replacement)?

• Once reversible etiologies are addressed and euvolemia has been achieved, if the patient is still symptomatic from TR despite aggressive medical optimization, additional therapies can be considered.
• Once euvolemic, a repeat TTE should be ordered to reassess the severity of the TR.
• Use calculators (for example, either the TRI-SCORE or TRIO score) to predict operative mortality for isolated TR surgery.

• What are our transcatheter treatment options in severe tricuspid regurgitation, and how do we choose between them?

• The primary approved transcatheter treatment options for severe TR include transcatheter tricuspid edge-to-edge repair (T-TEER) and transcatheter tricuspid valve replacement (TTVR), of which the Edwards EVOQUE valve is the only one currently approved by the FDA. There are other TTVR device under investigation.
• These decisions should be made with a multi-disciplinary team including representation from cardiac imaging, interventional cardiology, and cardiothoracic surgery.
• Factors that go into the decision between T-TEER and TTVR include anatomy (annulus width, coaptation gap, leaflet length), RV reserve, pulmonary hypertension presence, ability to tolerate anticoagulation, patient preference, and institutional experience.
• T-TEER is generally the first line with atrial functional and suitable anatomy. It is successful at reducing TR but does not generally eliminate it.
• TTVR with EVOQUE is preferred in certain anatomic considerations like a large coaptation gap or when there is CIED-related TR (as this was excluded in T-TEER trials).

• Patients must be suitable for anticoagulation to receive TTVR as there is risk of leaflet thrombosis without it.
• If moderate/severe pulmonary hypertension is present, or there is poor RV function, TTVR may be avoided as the sudden elimination of TR causes a sudden increase in RV afterload which may not be tolerated.

• What is the role in advanced metrics for evaluating RV function?

• Advanced metrics like RV/PA coupling are under investigation but have not made it into the guidelines. The clinical utility is not yet known.
• Assessing the RV function is important as stated above. Dr. Mankad prefers using 3D TTE to calculate an RVEF, or tracking RV longitudinal free wall strain.

• If you do encounter CIED-related TR, how do you treat it?

• Evaluate with TTE or TEE. 3D is very helpful to identify relative anatomy and leaflet-device interactions.
• There is no clear consensus about treatment if CIED-related TR is the primary mechanism of severe TR. If recently implanted, repositioning may be a valid option, but requires discussions with multiple teams including electrophysiology, advanced cardiac imaging, CT surgery, and interventional cardiology.

References

• O’Gara PT, Lindenfeld J, Hahn RT, et al. 10 Issues for the Clinician in Tricuspid Regurgitation Evaluation and Management: 2025 ACC Expert Consensus Decision Pathway. J Am Coll Cardiol. 2025;S0735-1097(25)07047-0.
• O’Gara PT, Little SH, Badhwar V, et al. Operator and Institutional Recommendations and Requirements for Tricuspid Interventions: 2026 ACC/AHA/ASE/HRS/STS Expert Consensus Systems of Care Document. J Am Coll Cardiol. 2026;S0735-1097(26)05481-1.
• Hahn RT. Tricuspid Regurgitation. N Engl J Med. 2023;388(20):1876-1891.
• Davidson LJ, Tang GHL, Ho EC, et al. The Tricuspid Valve: A Review of Pathology, Imaging, and Current Treatment Options: A Scientific Statement From the American Heart Association. Circulation. 2024;149(22):e1223-e1238.

CardioNerds (Dr. Apoorva Gangavelli, Dr. Rebecca Garber, and Dr. Tina Reddy), discuss pre-pregnancy risk stratification and counseling with Dr. Katie Young across a range of risks.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds. This discussion was planned in collaboration with the Mayo Clinic Cardiovascular Board Review Course.

Audio editing by CardioNerds intern, Dr. Patrick Pekyi-Boateng.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

CardioNerds Episode Page
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Notes:

• Why is pregnancy considered a “physiologic stress test,” and why does risk extend beyond delivery?

• Blood volume, heart rate, and cardiac output rise while systemic vascular resistance falls, peaking in the late second/early third trimester; underlying (even undiagnosed) heart disease can be unmasked or worsened.
• Postpartum (“fourth trimester”) is a high-risk period, not a safe zone – fluid shifts, rising SVR, and bleeding risk can precipitate decompensation in patients with heart failure, pulmonary hypertension, valvular disease, or aortopathy.
• Adverse pregnancy outcomes (hypertensive disorders, gestational diabetes, preterm birth, fetal growth restriction, peripartum cardiomyopathy) are markers of future cardiovascular risk and warrant long-term preventive follow-up.

• What is the practical framework for approaching pre-pregnancy cardiovascular risk?

• Four broad categories: (1) patients who may need cardiac screening before pregnancy, (2) patients needing risk-factor/medication optimization, (3) known cardiovascular disease where pregnancy is reasonable with structured risk stratification, and (4) high-risk disease where pregnancy may need to be delayed, modified by intervention, or discouraged.
• Testing should be targeted, not blanket – reserved for symptoms, abnormal exam, concerning family history, or reduced functional capacity.

• How is risk stratified in patients with known cardiovascular disease?

• Use a combination of tools per 2025 ESC guidelines: mWHO 2.0 (broad maternal risk category), CARPREG II (additional predictors of maternal cardiac events), and ZAHARA (useful in congenital heart disease).
• Key lesion-specific factors: aortic size/growth, valve severity, ventricular function, symptoms, blood pressure, and family history of dissection.
• Translate risk into practical terms for patients rather than leading with a numerical score.

• Which cardiovascular medications require review before conception?

• ACE inhibitors, ARBs, and ARNIs should be transitioned off before pregnancy; statins, MRAs, and SGLT2 inhibitors also need review.
• DOACs are contraindicated in pregnancy and lactation; mechanical valve anticoagulation requires individualized shared decision-making, as no strategy is risk-free for mother and fetus.
• Medication changes are best made proactively, before conception, rather than reactively.
• This is not an exhaustive list! The medication list needs to be reviewed carefully.

• Which conditions carry high or prohibitive risk in pregnancy?

• Pulmonary arterial hypertension, Eisenmenger syndrome, severe ventricular dysfunction, prior peripartum cardiomyopathy with residual LV dysfunction, severe left-sided obstructive valve disease (e.g., severe mitral stenosis), mechanical valves, significant aortopathy, cyanotic congenital heart disease, and Fontan physiology.
• Common theme: limited cardiovascular reserve and high risk of decompensation, thrombosis, arrhythmia, heart failure, aortic dissection, or death. These patients need expert multidisciplinary evaluation before pregnancy.
• Severe mitral stenosis is poorly tolerated because tachycardia shortens diastolic filling time and raises left atrial pressure, risking pulmonary edema and decompensation.

• When should genetic testing or counseling be offered?

• Consider when a diagnosis may be inherited or affect the patient, pregnancy, or family members: inherited cardiomyopathies, aortopathies, channelopathies, select congenital heart disease, and some pulmonary hypertension syndromes.
• Recurrence risk of congenital heart disease in offspring is roughly 6-10% when the mother has CHD; fetal echocardiography should be offered.

• How should contraception be approached in high-risk cardiac patients?

• Frame contraception as part of the cardiac care and reproductive safety plan to prevent unplanned high-risk pregnancy.
• Long-acting reversible contraception is often preferred; progestin-only methods are generally safer than estrogen-containing options with thrombosis risk, pulmonary hypertension, or mechanical valves.

• What are key delivery-planning considerations for cardiac patients?

• Vaginal delivery is preferred unless there is an obstetric indication for cesarean or a specific cardiac reason (e.g., unstable maternal status, therapeutic INR) to avoid labor.
• Planning should address delivery location, anesthesia involvement, telemetry needs, fluid management, and postpartum monitoring, clearly communicated across the multidisciplinary team in advance.

• How should clinicians counsel patients when pregnancy is discouraged but strongly desired?

• Acknowledge the patient’s goals and the emotional weight of the conversation; separate the goal (family building) from the timeline (safety now vs. after optimization).
• If pregnancy remains prohibitively risky, discuss alternatives for family building and ensure adequate patient support.

• What are the key gaps and future directions in cardio-obstetric risk stratification?

• Current risk tools (mWHO, CARPREG II, ZAHARA) provide common language but do not fully capture functional status, prior pregnancy history, or how risk evolves over time.
• Future direction: individualized, dynamic risk prediction incorporating imaging, biomarkers, exercise capacity, and social drivers of health, with better long-term links between pregnancy complications and cardiovascular prevention.

References

1. European Society of Cardiology. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy.

2. Mehta LS, et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association. Circulation. 2020;141:e884-e903. PMID: 32362133. doi:https://doi.org/10.1161/CIR.0000000000000772

3. ACOG Practice Bulletin No. 212. Pregnancy and Heart Disease. Obstet Gynecol. 2019;133(5):e320-e356. PMID: 31022123. doi:https://doi.org/10.1097/AOG.0000000000003243

CardioNerds Dr. Rohit Nathani, Dr. Atefeh Ghorbanzadeh, and Dr. Mariam Riad, discuss Obesity-related Heart Failure with Preserved Ejection Fraction (HFpEF) with Dr. John Ostrominski.

This episode was produced as part of the CardioNerds Academy curriculum by House Jones under the guidance of House Chief, Dr. Mariam Riad and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

This episode highlights the diverse clinical phenotypes and complex, multifaceted pathophysiology of HFpEF. We take a deep dive into the therapeutic advances that represent paradigm shift in metabolic modulation aimed at improving outcomes in patients with HFpEF and metabolic syndrome.

Audio editing by CardioNerds intern Pacey Wetstein.

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Pearls

• HFpEF is a constellation of symptoms often with different underlying pathophenotypes; cardiometabolic type is rising in incidence.
• Diagnosis is predominantly based on the clinical scenario along with supporting evidence from imaging modalities such as echocardiogram, cardiac MRI, and right heart catheterization.
• Cardiometabolic HFpEF is a complex syndrome characterized by dysregulated lipid metabolism, systemic inflammation, and hemodynamic abnormalities, all of which contribute to exercise intolerance and frailty.
• Lifestyle interventions, comorbidities management, and HFpEF therapeutics go hand in hand for comprehensive HFpEF care and offer opportunities for multispecialty collaboration to achieve optimal patient outcomes.

References

• Ostrominski, J, Højbjerg Lassen, M, Butt, J. et al. Adiposity-Related Anthropometrics and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Participant-Level Pooled Analysis of Randomized Clinical Trials. JACC. 2025 Nov, 86 (20) 1760–1777.https://doi.org/10.1016/j.jacc.2025.08.012
• Packer, M. The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment. JACC. 2025 Oct, 86 (16) 1269–1373.https://doi.org/10.1016/j.jacc.2025.06.055
• Ahmed, N., Dalmasso, C., Turner, M.B. et al. From fat to filter: the effect of adipose tissue-derived signals on kidney function. Nat Rev Nephrol 21, 417–434 (2025). https://doi.org/10.1038/s41581-025-00950-5
• Alicic, R.Z., Neumiller, J.J. & Tuttle, K.R. GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease. Nat Rev Nephrol 22, 265–282 (2026). https://doi.org/10.1038/s41581-025-01036-y
• Ostrominski, J, Harrington, J, Claggett, B. et al. Anthropometric Measures, Cardiovascular Outcomes, and Treatment Effects of Finerenone in Cardiovascular-Kidney-Metabolic Disease: Pooled Participant-Level Analysis of 3 Global Trials. JACC. 2025 Nov, 86 (20) 1781–1801.https://doi.org/10.1016/j.jacc.2025.08.039

CardioNerds (Drs. Apoorva Gangavelli, Jenna Skowronski, and Hannah Every) discuss the continuum of prevention and heart failure with Drs. Anu Lala and Martha Gulati. Grounded in a clinical case of a 55-year-old woman with uncontrolled hypertension, type 2 diabetes, and obesity who is on the trajectory toward heart failure, this episode unpacks a paradigm-shifting framework from a joint HFSA/ASPC Scientific Statement. The discussion explores how prevention should not be siloed from heart failure management but rather integrated across a patient’s lifespan—from primary prevention in at-risk individuals, to secondary prevention in those with established heart failure, to tertiary prevention in patients with advanced therapies such as LVADs and heart transplantation. The experts highlight the importance of aggressive risk factor management, biomarker-guided screening, the AHA’s Life’s Essential 8, and the need for multidisciplinary collaboration and systems-level change to shift heart failure care from reactive to proactive. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

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Pearls

• Systemic inflammatory diseases are associated with an elevated CVD risk that has significant implications for early detection, risk Heart failure prevention is a continuum, not a checkpoint. Prevention applies at every stage—from at-risk (Stage A) through advanced/post-transplant care—and every clinical encounter is an opportunity to intervene. The AHA’s Life’s Essential 8 (diet, physical activity, nicotine exposure, sleep, BMI, blood lipids, blood glucose, blood pressure) forms the foundation at every stage.
• Hypertension carries the highest population-attributable risk for heart failure of any modifiable risk factor. In the Framingham Heart Study, 91% of patients with newly diagnosed HF had pre-existing hypertension. The SPRINT trial demonstrated a 38% reduction in HF incidence with intensive blood pressure targets (<120 mm Hg systolic). Agent selection matters: ACE inhibitors, ARBs, and thiazide diuretics should be prioritized for HF prevention.
• Overlapping risk factors should prompt parallel, not sequential, intervention. Pharmacotherapies such as SGLT2 inhibitors and GLP-1 receptor agonists target multiple pathways simultaneously (diabetes, obesity, CKD, HF risk), making them ideal for patients with cardiometabolic multimorbidity. The cardio-kidney-metabolic (CKM) syndrome framework reinforces this integrated approach.
• Biomarker screening with BNP/NT-proBNP should be used proactively in high-risk populations, not just reactively in the emergency department. Even modestly elevated natriuretic peptide levels (e.g., BNP >30 ng/L or NT-proBNP >125 ng/L) identify individuals at heightened risk for progression to symptomatic HF. The ACC/AHA/HFSA guidelines give a Class IIa recommendation for natriuretic peptide screening in at-risk patients. Urine albumin-to-creatinine ratio (UACR) is an underutilized screening tool that provides additional insight into CKM risk.
• The heart failure label does not close the prevention window—it accentuates it. Secondary prevention through GDMT optimization (quadruple therapy in HFrEF) and continued risk factor management remains critical. Tertiary prevention extends to post-LVAD and post-transplant patients, where hypertension, diabetes, obesity, and CKD management remain essential to long-term outcomes.

Show notes

For a comprehensive review, please review the full HFSA/ASPC Joint Scientific Statement: Lala A, Beavers C, Blumer V, et al. The Continuum of Prevention and Heart Failure in Cardiovascular Medicine. J Card Fail. 2026;32:75-105. doi:10.1016/j.cardfail.2025.06.013

1. What is the “continuum of prevention” framework, and how does it differ from traditional approaches to heart failure prevention?

• Historically, prevention and heart failure management have been treated as separate disciplines—primary prevention handled by preventive cardiologists and treatment managed by heart failure specialists. This joint HFSA/ASPC Scientific Statement reframes prevention as a dynamic, continuous process that spans a patient’s entire lifespan, regardless of HF stage or ejection fraction.
• The framework maps onto the ACC/AHA HF staging system:

• Primary prevention targets Stage A (“at risk”) and Stage B (“pre-HF”) patients to reduce the burden of incident HF.
• Secondary prevention targets Stage C (symptomatic) and Stage D (advanced) patients to reduce the impact of established HF through GDMT optimization and ongoing risk factor management.
• Tertiary prevention encompasses risk factor management in patients with LVADs or heart transplants—populations where hypertension, diabetes, and obesity still drive outcomes.

• The Central Figure of the statement illustrates that Life’s Essential 8 (blood pressure and lipid control, diabetes management, exercise, sleep, smoking cessation, weight management, and diet/nutrition counseling) forms the foundation at every stage, with pharmacologic and device-based therapies layered on top as disease progresses (Figure)

2. How do traditional risk factors drive heart failure, and what should clinicians prioritize?

• Hypertension carries the greatest population-attributable risk for HF. In the Framingham Heart Study (N=5,143), HTN was associated with a 2- to 3-fold increased risk of HF, with a population-attributable risk of 39% in men and 59% in women. The SPRINT trial showed a 38% reduction in HF incidence and 25% reduction in the primary composite outcome with intensive BP targets (<120 mm Hg). Not all antihypertensives are equal for HF prevention: the ALLHAT trial showed that amlodipine carried a 38% higher risk and lisinopril a 19% higher risk of incident HF compared with chlorthalidone. The statement recommends prioritizing ACE inhibitors, ARBs, or thiazide diuretics as first-line agents when HF prevention is a goal.
• Type 2 diabetes confers a 5-fold risk of HF in women and 2-fold in men. Each 5-year increment in diabetes duration is associated with a 17% increased risk of incident HF. SGLT2 inhibitors have a Class 1 recommendation for HF prevention in patients with T2DM and established CVD or high cardiovascular risk. Finerenone (nonsteroidal MRA) reduced new-onset HF by 32% in the FIGARO-DKD trial among patients with T2DM and CKD. GLP-1 receptor agonists reduce CV events in patients with T2DM and ASCVD and are recommended in current guidelines.
• Obesity independently leads to myocardial dysfunction through the leptin-aldosterone-neprilysin framework, ectopic fat deposition, and neurohormonal dysregulation. The SELECT trial demonstrated that semaglutide reduced HF composite endpoint events (HR 0.84; 95% CI 0.74–0.97) in patients with obesity and established CVD without T2DM. Women with obesity are at highest risk for HFpEF, while men with obesity are at highest risk for HFrEF.
• Chronic kidney disease with albuminuria is deliberately included as a traditional risk factor in this statement. Albuminuria confers a 2- to 3-fold increased risk of incident HF. UACR screening is recommended for patients with T2DM and those at risk for CKD.

3. How can risk stratification tools and biomarkers be used to identify patients on the trajectory toward heart failure?

• Natriuretic peptides (BNP/NT-proBNP): The ACC/AHA/HFSA guidelines give a Class IIa recommendation for BNP or NT-proBNP screening in patients at risk for HF. Even modestly elevated levels (BNP >30 ng/L or NT-proBNP >125 ng/L) are associated with heightened risk for progression to symptomatic HF. In the ARIC study, incorporating NT-proBNP reclassified 20% of older adults without HF into Stage B. Factors that affect interpretation include age, sex, obesity (lower values), and CKD (higher values).
• High-sensitivity cardiac troponin (hs-cTn): Concentrations above the 99th percentile are now included in the definition of Stage B HF. Troponin testing may complement natriuretic peptides, particularly when BNP/NT-proBNP values are ambiguous.
• Risk scores: The PCP-HF equation predicts 10-year HF risk using traditional risk factors plus QRS duration. The AHA PREVENT score incorporates HF risk calculation and includes markers of kidney function (albuminuria, eGFR), though it may underestimate risk in men and Black adults. The CKM syndrome staging framework (Stages 0–4) provides a holistic approach to assessing systemic cardiovascular-kidney-metabolic risk.

4. What are the key nontraditional risk factors and cross-cutting themes in heart failure prevention?

• Genetics: Pathogenic cardiomyopathy variants exist in ~1 in 200 individuals in the general population. The HFSA and ACMG recommend cascade testing to identify at-risk family members. Polygenic risk scores for dilated cardiomyopathy show a 3.8-fold risk for DCM in the top 10th percentile compared with the median.
• Sex-specific considerations: Women have 2.8 times the odds of developing HFpEF, while men have similarly increased odds of HFrEF. A complete obstetric/gynecologic history is essential—preeclampsia is associated with a 4-fold increased risk of HF. Peripartum cardiomyopathy requires intentional screening in high-risk populations.
• Cardiotoxic exposures: Clinicians should be aware of medications that cause direct myocardial toxicity (e.g., anthracyclines, trastuzumab, tyrosine kinase inhibitors). A team-based approach with pharmacists can help optimize medication selection and risk factor modification.
• Social determinants of health: Environmental exposures (air pollution, arsenic, lead, cadmium), food insecurity, financial instability, and limited healthcare access contribute to HF risk and progression. Equity-focused, risk-based prevention strategies are needed.
• Psychological health: Depression is common in HF and independently associated with worse outcomes. Screening with brief questionnaires (e.g., PHQ-2) is recommended. Meditation, spirituality, and holistic wellness approaches remain underutilized.

5. What systems-level and policy changes are needed to move the needle on heart failure prevention?

• Multidisciplinary HF prevention clinics that bring together preventive cardiologists, HF specialists, endocrinologists, nephrologists, dietitians, pharmacists, exercise physiologists, and genetic counselors are advocated by the statement.
• EHR-embedded risk stratification could proactively flag patients on a trajectory toward HF—analogous to sepsis alerts or fall risk flags—enabling earlier intervention, particularly for patients who may not reach a cardiologist.
• Cardiac rehabilitation remains underutilized, particularly in HFrEF (Class 2b recommendation) and HFpEF (not yet covered by Medicare). The HF-ACTION trial showed quality-of-life benefits, and the REHAB-HF trial showed particular benefit in older patients with HFpEF.
• Policy priorities include expanding insurance coverage for preventive screening and novel therapies (SGLT2i, GLP-1 RAs, nsMRAs), reducing clinical inertia through team-based care models with closer follow-up intervals, and ensuring equitable access to evidence-based therapies across diverse populations.
• Digital health and AI hold promise for personalized risk prediction, remote monitoring (e.g., wearable devices, implantable PA pressure monitors), and virtual cardiac rehabilitation to overcome access barriers.

Figure

Lala A, Beavers C, Blumer V, et al. The continuum of prevention and heart failure in cardiovascular medicine: a joint scientific statement from the Heart Failure Society of America and the American Society for Preventive Cardiology. J Card Fail. 2026;32(1):75-105. doi:10.1016/j.cardfail.2025.06.013)

References

Key references are bolded.

• Lala A, Beavers C, Blumer V, et al. The continuum of prevention and heart failure in cardiovascular medicine: a joint scientific statement from the Heart Failure Society of America and the American Society for Preventive Cardiology. J Card Fail. 2026;32(1):75-105. doi:10.1016/j.cardfail.2025.06.013
• Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
• Lloyd-Jones DM, Allen NB, Anderson CAM, et al. Life’s Essential 8: updating and enhancing the American Heart Association’s construct of cardiovascular health: a presidential advisory from the American Heart Association. Circulation. 2022;146(5):e18-e43. doi:10.1161/CIR.0000000000001078
• SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939
• Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275(20):1557-1562. doi:10.1001/jama.1996.03530440037034
• Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
• Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-153. doi:10.1056/NEJM200001203420301
• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
• Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038
• Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. doi:10.1056/NEJMoa2206286
• Filippatos G, Anker SD, Agarwal R, et al. Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial. Circulation. 2022;145(6):437-447. doi:10.1161/CIRCULATIONAHA.121.057983
• Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024;391(16):1475-1485. doi:10.1056/NEJMoa2407107
• Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
• Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet. 2024;404(10454):773-786. doi:10.1016/S0140-6736(24)01498-3
• Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963
• Ndumele CE, Neeland IJ, Tuttle KR, et al. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation. 2023;148(20):1636-1664. doi:10.1161/CIR.0000000000001175
• Khan SS, Matsushita K, Sang Y, et al. Development and validation of the American Heart Association’s PREVENT equations. Circulation. 2024;149(6):430-449. doi:10.1161/CIRCULATIONAHA.123.067626
• Khan SS, Ning H, Shah SJ, et al. 10-year risk equations for incident heart failure in the general population. J Am Coll Cardiol. 2019;73(19):2388-2397. doi:10.1016/j.jacc.2019.02.057
• Bozkurt B, Fonarow GC, Goldberg LR, et al. Cardiac rehabilitation for patients with heart failure: JACC expert panel. J Am Coll Cardiol. 2021;77(11):1454-1469. doi:10.1016/j.jacc.2021.01.030
• Packer M. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Circulation. 2018;137(15):1614-1631. doi:10.1161/CIRCULATIONAHA.117.032474
• Lala A, Tayal U, Hamo CE, et al. Sex differences in heart failure. J Card Fail. 2022;28(3):477-498. doi:10.1016/j.cardfail.2021.10.006
• Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure. Eur J Heart Fail. 2021;23(3):352-380. doi:10.1002/ejhf.2115
• Hershberger RE, Givertz MM, Ho CY, et al. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail. 2018;24(5):281-302. doi:10.1016/j.cardfail.2018.03.004
• Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological health, well-being, and the mind-heart-body connection: a scientific statement from the American Heart Association. Circulation. 2021;143(10):e763-e783. doi:10.1161/CIR.0000000000000947
• Ezekowitz JA, Colin-Ramirez E, Ross H, et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet. 2022;399(10333):1391-1400. doi:10.1016/S0140-6736(22)00369-5

CardioNerds co-chairs Dr. Dinu Balanescu and Dr. Billy Joe Mullinax, along with FIT lead Dr. Shiavax Rao, discuss the evolving landscape of randomized controlled trials in pulmonary embolism with Dr. Jay Giri, interventional cardiologist, Associate Professor of Medicine, and Director of the Cardiovascular Catheterization Laboratories at the Hospital of the University of Pennsylvania. This episode examines the historical evidence behind systemic thrombolysis, the emergence of catheter-directed therapies and mechanical thrombectomy, and the landmark RCTs - STORM-PE, PEERLESS, HI-PEITHO, and PEERLESS II - that are reshaping intermediate-risk PE management. The discussion highlights challenges in PE trial design, the critical importance of clinical deterioration as an endpoint, and why this era represents an unprecedented wave of evidence generation in PE. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

Systemic thrombolysis in intermediate-risk PE reduces hemodynamic decompensation but at the cost of ~1.5–2% intracranial hemorrhage risk - a near-zero net benefit that has driven the search for safer catheter-based alternatives.

"Focus on clinical deterioration, not mortality" - Due to crossover design in contemporary PE RCTs, control-arm patients who decompensate are rescued with advanced therapies, biasing mortality toward the null. Clinical deterioration is the most informative endpoint to watch in HI-PEITHO, PRAGUE-26, and PEERLESS II.

HI-PEITHO is the first large RCT to demonstrate that catheter-directed fibrinolysis plus anticoagulation significantly reduces the composite of PE-related death, cardiorespiratory decompensation, or PE recurrence versus anticoagulation alone (RR 0.39; 95% CI 0.20–0.77; P=0.005), with no intracranial hemorrhage in either arm.

The four major upcoming/recently reported PE RCTs (HI-PEITHO, PRAGUE-26, PEERLESS II, PE-TRACT) enroll progressively different risk populations - from the most enriched (HI-PEITHO) to the most permissive (PE-TRACT, which includes intermediate-low risk patients) - enabling a nuanced understanding of which patients benefit most from intervention.

PE device clearance follows a fundamentally different FDA pathway than structural heart devices (single-arm safety/efficacy studies vs. mandated RCTs), yet market forces and clinical need have ultimately driven industry and government to sponsor large-scale RCTs - a lesson in how evidence development can evolve organically alongside regulatory frameworks.

Notes:

Notes drafted by Dr. Shiavax Rao.

Question #1: What is the current evidence behind advanced PE therapies?

Systemic thrombolysis: Sixteen RCTs over 40 years (1972–2014) enrolling nearly 2,000 patients have studied systemic thrombolysis in intermediate-risk PE. The landmark PEITHO trial (n=1,006) showed that tenecteplase reduced the composite of death or hemodynamic collapse (2.6% vs. 5.6%; P=0.015), driven primarily by reduced hemodynamic decompensation (1.6% vs. 5.0%; P=0.002). However, this came at the cost of increased major bleeding (6.3% vs. 1.5%; P<0.001) and a ~2% rate of intracranial hemorrhage. Meta-analyses of systemic thrombolysis trials show a small absolute mortality benefit (~1–2%) that is closely offset by bleeding risk, explaining why guidelines have not broadly recommended systemic thrombolysis for intermediate-risk PE.

Catheter-directed thrombolysis (CDT): The ULTIMA trial (n=59) was the first RCT of ultrasound-assisted CDT (EkoSonic/EKOS system) vs. anticoagulation alone in intermediate-risk PE. CDT showed superior RV/LV ratio improvement at 24 hours (decrease of 0.30 ± 0.20 vs. 0.03 ± 0.16; P<0.001), but this difference was no longer significant at 90 days. The CANARY trial, initiated in Iran in 2019, was halted prematurely due to the COVID-19 pandemic but largely verified ULTIMA's findings, with a signal that RV benefits may persist at 90 days.

Mechanical thrombectomy - single-arm data: The FLARE trial demonstrated a 25% reduction in RV/LV ratio at 48 hours with large-bore aspiration thrombectomy (FlowTriever). The EXTRACT-PE trial showed significant RV/LV ratio reduction with the Indigo aspiration system with a low major adverse event rate. The FLASH registry (FlowTriever) reported a mean 7.6 mmHg drop in mean PA pressure and RV/LV ratio decrease from 1.23 to 0.98 at 48 hours.

STORM-PE (2025): The first RCT of mechanical thrombectomy (computer-assisted vacuum thrombectomy [CAVT] with the Indigo/Penumbra system) vs. anticoagulation alone. One hundred patients were randomized across 22 sites. CAVT was superior for the primary endpoint of 48-hour RV/LV ratio reduction (0.52 vs. 0.24; difference 0.27; P<0.001), with earlier normalization of vital signs and comparable major adverse event rates (4.3% vs. 7.5%; P=0.681). Two PE-related deaths occurred in the CAVT arm. The trial was not powered for mortality or longer-term outcomes.

PEERLESS (2025): The first RCT comparing two interventional strategies head-to-head - large-bore mechanical thrombectomy (FlowTriever) vs. CDT - in 550 patients with intermediate-risk PE. The primary hierarchical win ratio composite favored LBMT (win ratio 5.01; 95% CI 3.68–6.97; P<0.001), driven primarily by fewer clinical deterioration/bailout events (1.8% vs. 5.4%; P=0.04) and substantially less post-procedural ICU use (41.6% vs. 98.6% admission rates). No significant differences in mortality, intracranial hemorrhage, or major bleeding were observed. RV/LV ratio reduction was similar between arms. LBMT was associated with shorter hospital stays and fewer 30-day readmissions.

Question #2: What are the challenges with conducting RCTs in PE?

Crossover and rescue therapy: Unlike early TAVR trials where control-arm patients could not cross over to the device arm, contemporary PE trials allow crossover upon clinical deterioration. This is ethically necessary given available therapies but biases mortality toward the null, making it unlikely that any individual trial - or even a meta-analysis of the four major trials (~2,400–3,000 patients combined) - will demonstrate a mortality difference.

Heterogeneity of intermediate-risk PE: Two patients meeting ESC intermediate-high risk criteria (RV dysfunction + elevated troponin) can look clinically very different - one may be tachypneic on 5 liters of oxygen, while another is comfortable on room air. This heterogeneity complicates enrollment, endpoint detection, and generalizability.

Endpoint selection: Early PE trials relied on surrogate imaging endpoints (RV/LV ratio, PA pressure reduction, Miller score). While these demonstrate proof-of-concept, they have not moved guidelines. Clinically relevant endpoints - mortality, clinical deterioration, functional status, quality of life - are needed but require larger sample sizes and longer follow-up.

Funding and maturation of the field: Trials require buy-in from government or industry funders. It took time for the field to mature enough to estimate effect sizes for trial powering, accumulate sufficient operator experience to ensure internal validity, and for industry to recognize that market adoption required randomized evidence despite existing FDA clearance.

FDA regulatory pathway: PE devices are cleared via a 510(k) pathway requiring single-arm studies (~100–150 patients) demonstrating safety and RV/LV ratio improvement - a much lower bar than the pre-market approval pathway requiring RCTs mandated for structural heart devices (e.g., TAVR, MitraClip). While this has enabled rapid innovation and market competition, it initially reduced the incentive for industry-sponsored RCTs.

Question #3: What are the upcoming/recently reported RCT trials in PE?

HI-PEITHO (published 2026, NEJM): Multinational adaptive-design RCT of ultrasound-facilitated CDT (EkoSonic system, alteplase 2 mg bolus + 1 mg/hr/catheter × 7 hours) plus anticoagulation vs. anticoagulation alone in 544 patients with enriched intermediate-high risk PE (RV/LV ≥1.0, elevated troponin, plus ≥2 of: SBP ≤110, HR ≥100, RR >20). Primary composite of PE-related death, cardiorespiratory decompensation/collapse, or symptomatic PE recurrence within 7 days: 4.0% intervention vs. 10.3% control (RR 0.39; 95% CI 0.20–0.77; P=0.005). Effect driven by reduced cardiorespiratory decompensation. Major bleeding at 7 days: 4.1% vs. 2.2% (P=0.32). No intracranial hemorrhage in either arm. Clinical deterioration measured using the National Early Warning Score (NEWS), a validated ordinal scoring system incorporating vital signs - more sensitive at detecting decompensation than binary clinical criteria.

PRAGUE-26: Czech Republic government-sponsored RCT with a design essentially identical to HI-PEITHO in terms of sample size and primary endpoint, but using standard (non-ultrasound-assisted) CDT catheters in the interventional arm. Enrolling well; results anticipated in the near term.

PEERLESS II: Industry-sponsored (Inari/Boston Scientific) RCT of large-bore mechanical thrombectomy (FlowTriever) plus anticoagulation vs. anticoagulation alone in up to 1,200 patients with enriched intermediate-high risk PE (enrichment criteria slightly less stringent than HI-PEITHO). Five-component hierarchical primary endpoint assessed via win ratio: (1) mortality, (2) clinical deterioration (defined by binary clinical criteria - pressor initiation,...

CardioNerds (Drs. Apoorva Gangavelli, Rebecca Garber, and Tina Reddy discuss INOCA with Dr. Claire Raphael. Audio editing by CardioNerds Academy intern, student doctor Pacey Wetstein.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli, and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

Non-obstructive coronary artery disease (CAD) is more common than often recognized, particularly in women and individuals with risk factors like diabetes or hypertension. Conditions such as INOCA, ANOCA, and MINOCA can cause ischemia and chest pain despite “clean” angiograms, often due to microvascular dysfunction, coronary spasms, or subtle plaque. Diagnosing these conditions requires advanced imaging or invasive studies to assess blood flow and vessel function. Treatment focuses on reducing cardiovascular risk with aspirin, statins, ACE inhibitors, or ARBs, and managing symptoms with beta-blockers or calcium channel blockers. The key takeaway: A normal angiogram doesn’t rule out disease, and these patients need a comprehensive, evidence-based approach to care.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

When patients present with chest pain but do not have obstructive coronary artery disease, the story does not end there! Other pathologies that must be ruled out include spontaneous coronary artery disease (SCAD), coronary vasospasm, microvascular disease, Takotsubo, and cardiomyopathy. A TTE can help rule out other pathologies. Cardiac MRI can help identify myocardial fibrosis, scarring, or edema that may suggest prior events or alternative diagnoses.

About 60-70% of INOCA cases are in women. However, it is estimated that about half of the patients with so-called “normal” angiograms actually have positive stress tests. Patients with elevated troponins are more likely to have recurrent events. Patients with INOCA are more likely to come back to the ER multiple times before getting diagnosed. These patients have a 1.4x increased risk of adverse cardiovascular events (such as HFpEF, MI, and recurrent hospitalizations for cardiac chest pain).

INOCA is a complex condition with a variety of causes, primarily linked to microvascular disease. Within microvascular disease, there are different "endotypes" (types or subcategories) classified by specific characteristics. In centers that conduct microvascular testing, patients are categorized as endothelium-independent or endothelium-dependent, based on their responses to adenosine or acetylcholine during testing. Additionally, microvascular disease can be classified as either structural or functional, depending on the results of tests measuring microvascular resistance.

The field is moving towards the term ANOCA, or angina with non-obstructive coronary arteries, to include patients with anginal symptoms without objective ischemia.

The field is moving toward using genotyping and hemodynamic testing to guide first-line therapies for microvascular disease, a heterogeneous condition. Current treatments mostly come from obstructive coronary artery disease, but specialized approaches—like the coronary sinus reducer—may offer unique benefits for microvascular disease.

Treatment includes sublingual nitroglycerin, ACE inhibitors/ARBs, and beta-blockers. Remember to also treat any additional comorbidities, such as diabetes, hypertension, and hyperlipidemia. Unfortunately, many of these patients may still have refractory chest pain, so it is important to reassure them. These patients can still exercise, but they may be hesitant to do so for fear of having chest pain. Cardiac rehab may be helpful for these patients as it helps them build up their tolerance.

References

Lawton JS, Tamis-Holland JE, Bangalore S, et al; Writing Committee Members. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(3):e18-e114. doi:10.1161/CIR.0000000000001039

Hwang D, Park S, Koo B-K. Ischemia with nonobstructive coronary artery disease. JACC: Asia. 2023;3(2):169-180. doi:10.1016/j.jacasi.2023.01.004

Yukselen Z, Majmundar V, Dasari M, Kumar PA, Singh Y. Chest pain risk stratification in the emergency department: current perspectives. Open Access Emerg Med. 2024;16:29-43. doi:10.2147/OAEM.S419657

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes. The following question refers to Section 5.2.1 of the 2025 ACS Guidelines.The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Henry Ford Interventional cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Li Pang, and then by expert faculty Dr. Michelle O’Donoghue.Dr. O’Donoghue is a cardiologist, senior investigator with the TIMI Study Group, and Associate Professor of Medicine at Harvard Medical School who holds the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital. She was the Vice Chair of the Writing Committee for the 2025 ACS Guidelines.

Question #2
A 63-year-old woman presented to the emergency room for chest pain. She described having exertional chest pain for the past two months and had an episode of severe pain after dinner 3 days ago. She went to bed and slept it off. She told her children today at a family gathering, and was immediately brought to the ED by her daughter. She has a history of hypertension and hyperlipidemia. She was asymptomatic and normotensive in the ED. Labs show a down-trending troponin and an elevated NT-proBNP but are otherwise unremarkable. Her ECG showed Q waves with ST elevation in V2-V4. She was treated with aspirin and heparin drip, and taken to the cath lab. Coronary angiogram showed complete proximal LAD occlusion with right-to-left collaterals, without significant residual disease elsewhere. She remains asymptomatic and is stable, both hemodynamically and electrically.What is the next best step with regard to reperfusion and anti-thrombotic management?AProceed with primary PCI to LAD BMedical management with aspirin and enoxaparin CMedical management with aspirin and clopidogrelDMedical management with aspirin and ticagrelor

Answer #2
Explanation The Correct answer is DIn patients who are stable with STEMI and have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit. (Class 3, LOE B-R)The benefit of PPCI begins to diminish after >12 hours from symptom onset, but there appears to be continued benefit through approximately 24 hours. In stable asymptomatic patients with an occluded artery >48 hours after symptom onset, routine PCI has not been shown to be beneficial in the absence of ongoing ischemia. The relative utility of routine PCI for asymptomatic patients with STEMI between 24 and 48 hours from symptom onset is less rigorously tested.PCI is not recommended for an occluded infarct-related artery if the patient is asymptomatic and has a completed infarct. MACE outcomes were similar in those with an occluded infarct-related artery who underwent medical therapy versus those who underwent PCI 3 to 28 days after an MI (Occluded Artery Trial [OAT]), and results were no different at 7-year follow-up. Similar findings were noted in the DECOPI (Desobstruction Coronaire en Post-Infarctus) trial, which enrolled patients with an occluded artery and Q waves on the ECG presenting 2 to 15 days after symptom onset.However, coronary revascularization should be considered for patients with late presentations with continued signs and symptoms of ischemia, including cardiogenic shock, acute severe HF, persistent angina, and life-threatening arrhythmias. Main TakeawayIn patients who are stable with STEMI who have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit.Guideline Loc.Section 5.2.1