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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 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. CardioNerds Pulmonary Embolism Page CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron! 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) 30, or need for supplemental O2 Category D – Incipient Cardiopulmonary Failure D1: transient hypotension (systolic blood pressure (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 o

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 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 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. CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron! 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. CardioNerds Episode Page CardioNerds Academy Cardionerds Healy Honor Roll CardioNerds Journal Club Subscribe to The Heartbeat Newsletter! Check out CardioNerds SWAG! Become a CardioNerds Patron! 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 R

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. CardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! 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. Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here. CardioNerds Heart Success Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! 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. CardioNerds Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! 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 (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 (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,...

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. CardioNerds Pulmonary Embolism PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! 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%; P20). 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. CardioNerds Pulmonary Embolism PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! 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