Cardionerds: A Cardiology Podcast

The following question refers to Section 7.7 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by St. George’s University medical student and CardioNerds Intern Chelsea Tweneboah, answered first by Baylor College of Medicine Cardiology Fellow and CardioNerds Ambassador Dr. Jamal Mahar, and then by expert faculty Dr. Michelle Kittleson. Dr. Kittleson is Director of Education in Heart Failure and Transplantation, Director of Heart Failure Research, and Professor of Medicine at the Smidt Heart Institute, Cedars-Sinai. She is Deputy Editor of the Journal of Heart and Lung Transplantation, on Guideline Writing Committees for the American College of Cardiology (ACC)/American Heart Association, is the Co Editor-in-Chief for the ACC Heart Failure Self-Assessment Program, and on the Board of Directors for the Heart Failure Society of America. Her Clinician’s Guide to the 2022 Heart Failure guidelines, published in the Journal of Cardiac Failure, are a must-read for everyone! The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #10 Ms. Heffpefner is a 54-year-old woman who comes to your office for a routine visit. She does report increased fatigue and dyspnea on exertion without new orthopnea or extremity edema. She was previously diagnosed with type 2 diabetes, morbid obesity, obstructive sleep apnea, and TIA. She is currently prescribed metformin 1000mg twice daily, aspirin 81mg daily, rosuvastatin 40mg nightly, and furosemide 40mg daily. In clinic, her BP is 140/85 mmHg, HR is 110/min (rhythm irregularly irregular, found to be atrial fibrillation on ECG), and BMI is 43 kg/m2. Transthoracic echo shows an LVEF of 60%, moderate LV hypertrophy, moderate LA enlargement, and grade 2 diastolic dysfunction with no significant valvulopathy. What is the best next step? A Provide reassurance B Refer for gastric bypass C Refer for atrial fibrillation ablation D Start metoprolol and apixaban Answer #10 Explanation The correct answer is D – start metoprolol and apixaban. Ms. Hefpeffner has a new diagnosis of atrial fibrillation (AF) and has a significantly elevated risk for embolic stroke based on her CHA2DS2-VASc score of 6 (hypertension, diabetes, heart failure, prior TIA, and female sex). The relationship between AF and HF is complex and the presence of either worsens the status of the other. Managing AF in patients with HFpEF can lead to symptom improvement (Class 2a, LOR C-EO). However, large, randomized trial data are unavailable to specifically guide therapy in patients with AF and HFpEF.   Generally, management of AF involves stroke prevention, rate and/or rhythm control, and lifestyle / risk-factor modification. With regards to stroke prevention, patients with chronic HF with permanent-persistent-paroxysmal AF and a CHA2DS2-VASc score of ≥2 (for men) and ≥3 (for women) should receive chronic anticoagulant therapy (Class 1, LOE A). When anticoagulation is used in chronic HF patients with AF, a DOAC is recommended over warfarin in eligible patients (Class 1, LOE A). The decision for rate versus rhythm control should be individualized and reflects both patient symptoms and the likelihood of better ventricular function with sinus rhythm. For patients with HF and symptoms caused by AF, AF ablation is reasonable to improve symptoms and QOL (Class 2a, LOE B-R). However, referring for catheter ablation would be premature before first attempting rate control and instituting anticoagulation therapy.   Traditionally, beta-blockers and nondihydropyridine calcium channel blockers are used as first-line agents for rate control in AF. Interestingly, a small open-label trial, RATE-AF in elderly patients with AF and symptoms of HF (mostly with preserved LVEF), compared bisoprolol to digoxin. Although the primary endpoint of quality of life at 6 months was similar between the 2 groups, several secondary QOL endpoints, functional capacity, and reduction in NT-proBNP favored digoxin at 12 months, with similar rate reductions in both groups. More side effects (such as dizziness, lethargy, and hypotension) were seen with bisoprolol than with digoxin. However, digoxin has a narrow therapeutic window and needs to be monitored more closely. Option A (provide reassurance) is inappropriate as this patient has heart failure with preserved EF, defined by signs and symptoms of HF in patients with an LVEF of 50% or more. Echocardiogram hints in this case include LV hypertrophy and diastolic dysfunction. Our patient also has comorbidities frequently associated with HFpEF such as hypertension, diabetes, OSA, and obesity. Other common comorbidities include CAD, CKD, and atrial arrhythmias. When diagnosing HFpEF, care must be taken to rule out mimicking conditions such as pulmonary hypertension or amyloidosis. A large portion of the management of HFpEF includes managing comorbid conditions such as hypertension, OSA, and atrial fibrillation. At this time, she is symptomatic with atrial fibrillation and rapid ventricular response, and warrants both rate control and stroke prophylaxis.   Although gastric bypass should be considered for patients with a BMI >35 kg/m2 with comorbidities (such as HTN or diabetes) and patients with a BMI > 40 kg/m2 independent of comorbid conditions, this is not the best next step at this time. First, she should receive anticoagulation to reduce the risk of stroke and achieve better control of her HR and BP.   Patients with HFpEF and hypertension should have medication titrated to attain blood pressure targets in accordance with published clinical practice guidelines to prevent morbidity (Class 1, LOE C-LD). Although the optimal BP goal and antihypertensive regimen in patient with HFpEF is not known, HFpEF trials so far have shown that RAAS antagonists including ACEi, ARB, MRA and possibly ARNi could be first-line agents to treat HTN in patients with HFpEF. Beta blockers may be used to treat hypertension in patients with a history of MI, symptomatic CAD, or AF with rapid ventricular response. These effects need to be balanced with the potential contribution of chronotropic incompetence to exercise intolerance in some patients. Main Takeaway In patients with HFpEF, the diagnosis and management of comorbidities are very important, especially the treatment of HTN (Class 1, LOE C-LD) and AF (Class 2a, LOE C-EO). Guideline Loc. Section 7.7.1, Figure 12 Section 10.2 Decipher the Guidelines: 2022 Heart Failure Guidelines PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron!

The following question refers to Section 7.6 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by premedical student and CardioNerds Intern Pacey Wetstein, answered first by Baylor College of Medicine Cardiology Fellow and CardioNerds Ambassador Dr. Jamal Mahar, and then by expert faculty Dr. Nancy Sweitzer. Dr. Sweitzer is Professor of Medicine, Vice Chair of Clinical Research for the Department of Medicine, and Director of Clinical Research for the Division of Cardiology at Washington University School of Medicine. She is the editor-in-chief of Circulation: Heart Failure. Dr. Sweitzer is a faculty mentor for this Decipher the HF Guidelines series. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #9 Mr. Flo Zin is a 64-year-old man who comes to discuss persistent lower extremity edema and dyspnea with mild exertion. He takes amlodipine for hypertension but has no other known comorbidities. In the clinic, his heart rate is 52 bpm and blood pressure is 120/70 mmHg. Physical exam reveals mildly elevated jugular venous pulsations and 1+ bilateral lower extremity edema. Labs show an unremarkable CBC, normal renal function and electrolytes, a Hb A1c of 6.1%, and an NT-proBNP of 750 (no prior baseline available). On echocardiogram, his LVEF is 44% and nuclear stress testing was negative for inducible ischemia. What is the best next step in management? A Add furosemide BID and daily metolazone B Start empagliflozin and furosemide as needed C Start metoprolol succinate D No change to medical therapy Answer #9 Explanation The correct answer is B – start empagliflozin and furosemide as needed. The patient described here has heart failure with mildly reduced EF (HFmrEF), given LVEF in the range of 41-49%. In patients with HF who have fluid retention, diuretics are recommended to relieve congestion, improve symptoms, and prevent worsening HF (Class 1, LOE B-NR). For patients with HF and congestive symptoms, addition of a thiazide (eg, metolazone) to treatment with a loop diuretic should be reserved for patients who do not respond to moderate or high-dose loop diuretics to minimize electrolyte abnormalities (Class 1, LOE B-NR). Therefore, option A is not correct as he is only mildly congested on examination, and likely would not require such aggressive decongestive therapy, particularly with normal renal function. Adding a thiazide diuretic without first optimizing loop diuretic dosing would be premature. The EMPEROR-Preserved trial showed a significant benefit of the SGLT2i, empagliflozin, in patients with symptomatic HF, with LVEF >40% and elevated natriuretic peptides. The 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death was driven mostly by a significant 29% reduction in time to HF hospitalization, with no benefit on all-cause mortality. Empagliflozin also resulted in a significant reduction in total HF hospitalizations, decrease in the slope of the eGFR decline, and a modest improvement in QOL at 52 weeks. Of note, the benefit was similar irrespective of the presence or absence of diabetes at baseline. In a subgroup of 1983 patients with LVEF 41% to 49% in EMPEROR-Preserved, empagliflozin, an SGLT2i, reduced the risk of the primary composite endpoint of cardiovascular death or hospitalization for HF. Therefore, in patients with HFmrEF, SGLT2i can be beneficial in decreasing HF hospitalizations and cardiovascular mortality (Class 2a, LOE B-R). Furthermore, by inhibiting glucose reabsorption in the kidney, they have a diuretic effect which may help ease congestion and limit loop diuretic dosing. SGLT2i are beneficial to the vast majority of cardiovascular patients but are contraindicated in patients with type 1 diabetes or prior episodes of diabetic ketoacidosis as they may cause euglycemic DKA. Option C is incorrect. Among patients with current or previous symptomatic HFmrEF (LVEF, 41%–49%), use of evidence-based beta blockers for HFrEF, ARNi, ACEi, or ARB, and MRAs may be considered to reduce the risk of HF hospitalization and cardiovascular mortality, particularly among patients with LVEF on the lower end of this spectrum (Class 2b, LOE B-NR). However, the patient’s heart rate is already low and so initiating a beta blocker would be inappropriate. Switching his calcium channel blocker to ARNi may be considered. Option D is not correct as we can help counsel him on lifestyle and medication changes which can relieve his symptoms and reduce his risk of HF hospitalizations and mortality. Main Takeaway In patients with HFmrEF, diuretics are useful for decongestion and symptomatic improvement (Class 1) and there is a role for GDMT including SGLT2i (Class 2a) and BB, ARNI, ACEi/ARB, MRA (Class 2b). Guideline Loc. Section 7.6.1, Figure 11 Decipher the Guidelines: 2022 Heart Failure Guidelines 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!

The following question refers to Section 7.3 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by MedStar Washington Hospital Center cardiology hospitalist & CardioNerds Academy Graduate Dr. Luis Calderon, and then by expert faculty Dr. Gregg Fonarow. Dr. Fonarow is the Professor of Medicine and Interim Chief of UCLA’s Division of Cardiology, Director of the Ahmanson-UCLA Cardiomyopathy Center, and Co-director of UCLA’s Preventative Cardiology Program. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #8 Ms. Flo Zinn is a 60-year-old woman seen in cardiology clinic for follow up of her chronic HFrEF management. She has a history of stable coronary artery disease, hypertension, hypothyroidism, and recurrent urinary tract infections. She does not have a history of diabetes and recent hemoglobin A1c is 5.0%. Her current medications include carvedilol, sacubitril-valsartan, eplerenone, and atorvastatin. Her friend was recently placed on an SGLT2 inhibitor and asks if she should be considered for one as well. Which of the following is the most important consideration when deciding to start this patient on an SGLT2 inhibitor? A The patient does not have a history of type 2 diabetes and so does not qualify for SGLT2 inhibitor therapy B While SGLT2 inhibitors improve hospitalization rates for HFrEF, there is no evidence that they improve cardiovascular mortality C Patients taking SGLT2 inhibitors tend to suffer a more rapid decline in renal function than patients not taking SGLT2 inhibitor therapy D Patients may be at a higher risk for genitourinary infections if an SGLT2 inhibitor is started Answer #8 Explanation   The correct answer is D – SGLT2 inhibitors have been associated with increased risk of genitourinary infections. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have gathered a lot of press recently as the new kid on the block with respect to heart failure management. While they were initially developed as antihyperglycemic medications for treating diabetes, early cardiovascular outcomes trials showed reduced rates of heart failure hospitalization amongst study participants independent of glucose-lowering effects and irrespective of baseline heart failure status – only 10-14% of patients carried a heart failure diagnosis at baseline. This prompted trials to study the effects of SGLT2 inhibitors in patients with symptomatic chronic HFrEF who were already on guideline directed medical therapy irrespective of the presence of type 2 diabetes mellitus. The DAPA-HF and EMPEROR-Reduced trials showed that dapagliflozin and empagliflozin, respectively, both conferred statistically significant improvements in a composite of heart failure hospitalizations and cardiovascular death (Option B). Most interestingly, these effects were seen irrespective of diabetes history. In light of these findings, the 2022 HF guidelines recommend SGLT2 inhibitors in patients with chronic, symptomatic HFrEF with or without diabetes to reduce hospitalization for HF and cardiovascular mortality (Class I, LOE A). The benefits of SGLT2 inhibitors extend beyond cardiovascular health. Analyses of the DAPA-HF and EMPEROR-Reduced trials showed that patients receiving SGLT2 inhibitor therapy had fewer serious renal outcomes and slower rates of decline in eGFR than patients in the control groups. As with all medications, though, SGLT2 inhibitors must be used with an awareness of some potentially serious side effects. SGLT2 inhibitors have been associated with higher rates of genitourinary infections, potentially related to the increased glycosuria associated with sodium-glucose co-transporter 2 inhibition. Trials have shown a 2 to 4-fold increased risk of vulvovaginal candidiasis for patients on SGLT2is compared to placebo. SGLT2 inhibitor use has also been associated with bacterial urinary tract infections, Fournier’s gangrene, and euglycemic ketoacidosis. Main Takeaway SGLT2 inhibitors are now a class I recommendation for patients with chronic symptomatic HFrEF regardless of whether or not they have diabetes. Although SGLT2i increased risk for genital infections, they were otherwise well tolerated in the trials. Guideline Loc. Section 7.3.4 Decipher the Guidelines: 2022 Heart Failure Guidelines PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron!

The following question refers to Section 7.3.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by MedStar Washington Hospital Center cardiology hospitalist & CardioNerds Academy Graduate Dr. Luis Calderon, and then by expert faculty Dr. Robert Mentz.  Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz is a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very 2022 heart failure Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22. Welcome Dr. Mentz!  The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #7 Ms. Valarie Sartan is a 55-year-old woman with a history of HFrEF (EF 35%) and well controlled, non-insulin dependent diabetes mellitus who presents to heart failure clinic for routine follow up. She is currently being treated with metoprolol succinate 200mg daily, lisinopril 10mg daily, empagliflozin 10mg daily, and spironolactone 50mg daily. She notes stable dyspnea with moderate exertion, making it difficult to do her yardwork. On exam she is well appearing, and blood pressure is 115/70 mmHg with normal jugular venous pulsations and trace bilateral lower extremity edema. On labs, her potassium is 4.0 mmol/L and creatinine is 0.7 mg/dL with an eGFR > 60 mL/min/1.73m2. Which of the following options would be the most appropriate next step in heart failure therapy?  A  Increase lisinopril to 40mg daily  B  Increase spironolactone to 100mg daily  C  Add sacubitril-valsartan to her regimen  D  Discontinue lisinopril and start sacubitril-valsartan in 36 hours  E  No change  Answer #7 Explanation   The correct answer is D – transitioning from an ACEi to an ARNi is the most appropriate next step in management.   The renin-angiotensin aldosterone system (RAAS) is upregulated in patients with chronic heart failure with reduced ejection fraction (HFrEF). Blockade of the RAAS system with ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), or angiotensin receptor neprilysin inhibitors (ARNi) have proven mortality benefit in these patients.   The PARADIGM-HF trial compared sacubitril-valsartan (an ARNi) with enalapril in symptomatic patients with HFrEF. Patients receiving ARNi incurred a 20% relative risk reduction in the composite primary endpoint of cardiovascular death or heart failure hospitalization. Based on these results, the 2022 heart failure guidelines recommend replacing an ACEi or ARB for an ARNi in patients with chronic symptomatic HFrEF with NYHA class II or III symptoms to further reduce morbidity and mortality (Option D). This is a class I recommendation with level of evidence of B-R and is also of high economic value. Making no changes at this time would be inappropriate (Option E).  While it would be reasonable to increase the dose of lisinopril to 40mg (Option A), this should be pursued only if ARNi therapy is not tolerated.   Mineralocorticoid receptor antagonists (MRAs) have a class I (LOE A) recommendation in patients with HFrEF and NYHA class II to IV to reduce morbidity and mortality, provided that eGFR is >30 mL/min/1.73 m2 and serum potassium is <5.0 mEq/L, and there is careful monitoring of potassium, renal function, and diuretic dosing. However, the starting dose of spironolactone (or eplerenone) is 25 mg orally daily, increased to 50 mg daily orally after a month. Higher doses may be appropriate for other indications but are not advocated for HFrEF as the sole indication and so option B is incorrect.   Guidance on starting an ARNi  While switching from an ACEi to an ARNi, note that ARNi should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi (Class 3 for Harm, LOE B-R). This recommendation comes largely from studies of omapatrilat—a combination ACEi/neprilysin inhibitor. Patients receiving omapatrilat suffered significantly increased risk of angioedema thought secondary to dual suppression of both ACE and neprilysin leading to high concentrations of bradykinin. The current guidelines therefore recommend a washout period of at least 36 hours between the last ACEi dose and the first ARNi dose. If this patient were being transitioned from an ARB such as valsartan, then the first dose of ARNi could simply be given in lieu of the next anticipated dose of ARB.   When initiating sacubitril-valsartan, it is important to monitor for signs of hypotension. With this patient’s blood pressure of 115/70 mmHg in clinic, she should have enough blood pressure room to tolerate the new medication; both PARADIGM-HF (ARNi vs ACEi in stable chronic HFrEF) and PIONEER-HF (ARNi vs ACEi in hospitalized patients with ADHF) excluded patients with SBP < 100 mmHg. That said, every patient responds differently, and anticipatory guidance should be given to anybody starting a new drug. In particular, Ms. H.F. should be counseled on symptoms that could reflect low blood pressure, such as lightheadedness or orthostatic syncope, asked to call her provider should she experience anything concerning. Laboratory follow-up should include renal function and potassium levels. ARNis should not be initiated on any patient with a history of angioedema (Class III for Harm, LOE C-LD). While this patient likely does not have this history since she is tolerating and ACEi, it is an important part of any CardioNerd’s checklist when reaching for RAAS inhibitors.   Main Takeaway  Patients with symptomatic HFrEF who are tolerating ACEi or ARB therapy should be transitioned to ARNi therapy to further reduce morbidity and mortality.  Expert Suggestions  Offer tips & tricks for initiating and monitoring ARNis in the outpatient setting.   Discuss PIONEER-HF & initiation in the inpatient setting.   Discuss ACEi & ARB combination therapy.  Guideline Loc.  Section 7.3.1   Decipher the Guidelines: 2022 Heart Failure Guidelines 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!

CardioNerds co-founder Daniel Ambinder joins Cleveland Clinic cardiology fellows, Dr. Essa Hariri, Dr. Anna Scandinaro, and Dr. Beka Bekhdatze, Clinical pharmacist at Cleveland Clinic, Dr. Ashley Kasper, and Dr. Craig Parris from Ohio State University Medical Center for a walk at Edgewater Park in Cleveland, Ohio. Dr. Andrew Higgins (Crtitical Care Cardiology and Advanced HF / Transplant Cardiology at Cleveland Clinic) provides the ECPR for this episode. They discuss the following case involving a rare cause of non-ischemic cardiomyopathy. A young African American male was admitted for cardiogenic shock following an admission a month earlier for treatment resistant psychosis. He was diagnosed with medication-induced non-ischemic cardiomyopathy, which resolved with a remarkable recovery of his systolic function after discontinuation of the culprit medication, Clozapine. Episode notes were drafted by Dr. Essa Hariri. Audio editing by CardioNerds Academy Intern, student doctor Shivani Reddy. Enjoy this case report co-published in US Cardiology Review: Clozapine-induced Cardiomyopathy: A Case Report CardioNerds is collaborating with Radcliffe Cardiology and US Cardiology Review journal (USC) for a ‘call for cases’, with the intention to co-publish high impact cardiovascular case reports, subject to double-blind peer review. Case Reports that are accepted in USC journal and published as the version of record (VOR), will also be indexed in Scopus and the Directory of Open Access Journals (DOAJ). Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – An Unusual Case of Non-ischemic Cardiomyopathy The diagnosis of drug-induced non-ischemic cardiomyopathy is usually one of exclusion. High clinical suspicion is needed to diagnose drug-induced cardiomyopathy. Missing the culprit medication causing drug-induced cardiomyopathy could be detrimental as there is a high probability of reversing a systolic dysfunction after stopping the offending medication. Clozapine is an effective medication for the treatment-resistant schizophrenia and is associated with reduced suicide risk. Clozapine is reported to cause drug-induced cardiomyopathy and is more common with rapid drug titration. Clozapine is more commonly associated with myocarditis. Close monitoring and vigilance are critical to preventing cardiac complications associated with initiating clozapine. The management of clozapine-associated cardiomyopathy includes clozapine cessation and heart failure guideline-directed medical therapy. Show Notes – An Unusual Case of Non-ischemic Cardiomyopathy We treated a case of clozapine-associated cardiomyopathy presenting in cardiogenic shock. Drug-induced cardiomyopathy is a common yet under-recognized etiology of non-ischemic cardiomyopathy. Clozapine is an FDA-approved atypical antipsychotic medication frequently prescribed for treatment-resistant schizophrenia and the only antipsychotic agent that has been proven to significantly reduce suicide among this patient population. However, Clozapine is reported to be associated with several forms of cardiotoxicity, including myocarditis (most common), subclinical clozapine associated cardiotoxicity, and least commonly, drug-induced cardiomyopathy. Clozapine-associated cardiomyopathy should be considered as a differential diagnosis in schizophrenic patients presenting with signs of acute heart failure.  Rapid titration of clozapine is a risk factor for clozapine-associated cardiomyopathy and clozapine-associated myocarditis. To date, there is no evidence or consensus supporting preemptive screening. According to the American Psychiatric Association, whenever clozapine-induced myocarditis or cardiomyopathy is suspected, a cardiology consult is warranted. Experts recommend, when initiating clozapine, to obtain baseline troponin, CRP, and echocardiography upon drug initiation. This is followed by daily symptom assessment and a hemodynamic assessment on every other day. A biochemical assessment of CRP and troponin levels is warranted every 7 days. The authors recommend clozapine caseation if troponin rises above twice the upper normal limit or if CRP levels exceeds 100 mg/L. Because clozapine is a highly effective medication in treating schizophrenia, close monitoring and vigilance is critical to prevent deleterious complications associated with drug cardiotoxicity. Several mechanisms have been proposed to explain the cardiotoxicities reported with clozapine. Most patients with clozapine-associated cardiotoxicity remain asymptomatic, while others may present with typical acute congestive heart failure. The most common presenting symptom was shortness of breath (60%) followed by palpitations (36%), and the main echocardiographic finding in all patients with this disease is systolic dysfunction with reduced ejection fraction. The management of clozapine-associated cardiomyopathy includes clozapine cessation and heart failure guideline-directed medical therapy. Clozapine suspension along with conventional heart failure management have led to a significant improvement in left ventricular function. Decisions regarding resuming clozapine therapy are highly individualized and should consider weighing in the risks and benefits of treatment. Whenever clozapine is rechallenged, very close monitoring and frequent echocardiography may be warranted to prevent subsequent cardiotoxicity. References – An Unusual Case of Non-ischemic Cardiomyopathy 1.        Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report from the American Heart Association. Circulation. 2022;145(8). doi:10.1161/CIR.0000000000001052 2.        Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the united states a policy statement from the american heart association. Circ Heart Fail. 2013;6(3). doi:10.1161/HHF.0b013e318291329a 3.        VanDyck TJ, Pinsky MR. Hemodynamic monitoring in cardiogenic shock. Curr Opin Crit Care. 2021;27(4). doi:10.1097/MCC.0000000000000838 4.        Keepers GA, Fochtmann LJ, Anzia JM, et al. The American psychiatric association practice guideline for the treatment of patients with schizophrenia. American Journal of Psychiatry. 2020;177(9). doi:10.1176/appi.ajp.2020.177901 5.        Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: A meta-analysis. Schizophr Res. 2005;73(2-3). doi:10.1016/j.schres.2004.05.015 6.        Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry. 2020;19(1):61-68. doi:10.1002/wps.20699 7.        Citrome L, McEvoy JP, Saklad SR. A guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses. 2016;10(3). doi:10.3371/1935-1232.10.3.163 8.        Knoph KN, Morgan RJ, Palmer BA, et al. Clozapine-induced cardiomyopathy and myocarditis monitoring: A systematic review. Schizophr Res. 2018;199. doi:10.1016/j.schres.2018.03.006 9.        Kanniah G, Kumar S. Clozapine associated cardiotoxicity: Issues, challenges and way forward. Asian J Psychiatr. 2020;50. doi:10.1016/j.ajp.2020.101950 10.      Curto M, Girardi N, Lionetto L, Ciavarella GM, Ferracuti S, Baldessarini RJ. Systematic Review of Clozapine Cardiotoxicity. Curr Psychiatry Rep. 2016;18(7). doi:10.1007/s11920-016-0704-3 11.      Baran DA, Grines CL, Bailey S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic shock: This document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019. Catheterization and Cardiovascular Interventions. 2019;94(1). doi:10.1002/ccd.28329 12.      Alawami M, Wasywich C, Cicovic A, Kenedi C. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2014;176(2). doi:10.1016/j.ijcard.2014.07.103 13.      Arzuk E, Karakuş F, Orhan H. Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity. Toxicology. 2021;447. doi:10.1016/j.tox.2020.152628 14.      Vaddadi KS, Soosai E, Vaddadi G. Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol. 2003;55(3). doi:10.1046/j.1365-2125.2003.01773.x 15.      Yost BL, Gleich GJ, Fryer AD. Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein. J Appl Physiol. 1999;87(4). doi:10.1152/jappl.1999.87.4.1272 16.      Yuen JWY, Kim DD, Procyshyn RM, White RF, Honer WG, Barr AM. Clozapine-induced cardiovascular side effects and autonomic dysfunction: A systematic review. Front Neurosci. 2018;12(APR). doi:10.3389/fnins.2018.00203 17.      Ronaldson KJ, Taylor AJ, Fitzgerald PB, Topliss DJ, Elsik M, McNeil JJ. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. Journal of Clinical Psychiatry. 2010;71(8). doi:10.4088/JCP.09m05024yel 18.      de Leon J, Tang YL, Baptista T, Cohen D, Schulte PFJ. Titrating clozapine amidst recommendations proposing high myocarditis risk and rapid titrations. Acta Psychiatr Scand. 2015;132(4). doi:10.1111/acps.12421 19.      Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: A case-control study. Schizophr Res. 2012;141(2-3). doi:10.1016/j.schres.2012.08.018 20.      Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Australian and New Zealand Journal of Psychiatry. 2011;45(6). doi:10.3109/00048674.2011.572852 21.      Patel RK, Moore AM, Piper S, et al. Clozapine and cardiotoxicity – A guide for psychiatrists written by cardiologists. Psychiatry Res. 2019;282. doi:10.1016/j.psychres.2019.112491 22.      Cook SC, Ferguson BA, Cotes RO, Heinrich TW, Schwartz AC. Clozapine-Induced Myocarditis: Prevention and Considerations in Rechallenge. Psychosomatics. 2015;56(6). doi:10.1016/j.psym.2015.07.002 23.      de Leon J, Schoretsanitis G, Smith RL, et al. An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels [published correction appears in Pharmacopsychiatry. 2022 Jan 20;:]. Pharmacopsychiatry. 2022;55(2):73-86. doi:10.1055/a-1625-6388  

Renal replacement therapy (RRT) is routinely utilized in the CICU. Series co-chairs Dr. Eunice Dugan and Dr Karan Desai along with CardioNerds Co-founder Dr. Daniel Ambinder were joined by FIT lead and CardioNerds Ambassador from University of Washington, Dr. Tomio Tran. Our episode expert is world-renowned nephrologist Dr. Joel Topf. Dr. Topf is Medical Director of Research at St. Clair Nephrology, and editor of the Handbook of Critical Care Nephrology. In this episode, we describe a case of cardiogenic shock due to acute myocardial infarction resulting in renal failure, ultimately requiring continuous RRT (CRRT). We discuss the most common causes of AKI within the cardiac ICU, indications for initiating RRT, evidence on the timing of RRT, different modes of RRT, basic management of the RRT circuit, and how to transition patients off of RRT during renal recovery. Episode notes were drafted by Dr. Tomio Tran. Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian. The CardioNerds Cardiac Critical Care Series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Mark Belkin, Dr. Eunice Dugan, Dr. Karan Desai, and Dr. Yoav Karpenshif. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. This episode is made possible with support from Glass.Health – The first digital notebook designed for doctors. Follow @GlassHealthHQ for the latest product updates! Pearls • Notes • References • Production Team CardioNerds Cardiac Critical Care PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes – Approach to Renal Replacement Therapy in the CICU Do not commit “Renalism” – withholding lifesaving treatments from patients with renal impairment due to fear of causing renal injury. Shared decision making is key. In the ICU, most of the time, AKI is caused by ATN due to adverse hemodynamics. Nephrologists can help determine the cause if the patient has an atypical presentation. Late dialysis initiation is non-inferior to early dialysis initiation. Early initiation may lead to higher rates of prolonged time on dialysis. Slow low efficiency daily diafiltration (SLEDD) vs CRRT are equivalent in terms of outcomes and are the preferred methods among patients with hypotension. Intermittent Hemodialysis (iHD) can be used once patients are hemodynamically stable. A “Furosemide Stress Test” can be used to test intact renal function or renal recovery by challenging the nephron to make urine. Show notes – Approach to Renal Replacement Therapy in the CICU What are the risk factors and differential for AKI in the CICU? Start by using the pre-renal vs intrinsic renal vs post-renal framework. Additional considerations in cardiac patients include contrast induced nephropathy, pigment nephropathy, cardiorenal syndrome. Enjoy Episode 262. Management of Cardiorenal Syndrome in the CICU. In the ICU setting, intrinsic renal injury due to ATN is among the most common etiology of AKI. Many risk factors for AKI are not modifiable in the ICU. Optimize renal function by avoiding nephrotoxins, minimizing contrast usage, and keeping the MAP >65-75 mmHg. Contrast nephropathy as an etiology is questionable and may be a marker of a sicker patient population. Avoid “Renalism” – providing substandard care to patients with renal disease due to fear of worsening renal function. Most etiologies are treated with supportive care. What is the approach to timing of renal replacement therapy initiation? Definitions for early vs late vs very late initiation of RRT: Early – Worsening AKI without indications for RRT Late – Worsening AKI with relative indications for RRT Very late – Worsening AKI with strict indications for RRT Late initiation is noninferior in terms of mortality; early initiation is associated with higher rates of prolonged/permanent RRT.1,2,3 Very late initiation associated with worse outcomes.4 In general, start RRT if there are absolute indications (“AEIOU) or the patient is anuric with a high BUN (~140) as delaying RRT much further is associated with worse outcomes. “Furosemide Stress Test” (FST) can be used to predict RRT need.5 1 mg/kg IV for diuretic naive, 1.5 mg/kg IV if on diuretic Goal = 200 cc urine over 1-2 hours For the non-nephrologists, what are options for RRT acutely and how do they work? There are two principles of RRT: Convection – movement of solutes through semipermeable membrane using pressure Ultrafiltration – volume removal using convection; fluid is then replaced to prevent hypovolemia Fluid removed has the same composition of the plasma Negative fluid balance is the difference between volume removed and replacement fluid; goal usually 25-250 cc/hour Diffusion – movement of solutes from high to low concentration Dialysate runs countercurrent through semipermeable membrane Typical dialysate composition – normal sodium, magnesium, low potassium, no creatinine, no BUN, high bicarbonate Does not remove fluid There are 3 types of RRT: iHD (intermittent hemodialysis), CRRT (continuous renal replacement therapy), SLEDD (slow low efficiency daily diafiltration) None have been shown to be superior in normotensive patients iHD can remove potassium and toxins more quickly SLEDD and CRRT are equivalent and preferred for hypotensive patients.6 SLEDD is less labor intensive Institutions usually have a preference of one modality over another Peritoneal dialysis has been used in the ICU in some specialized centers, but is not common. There are 3 methods of CRRT: Continuous hemodialysis Removes fluid by diffusion Uses dialysate, no replacement fluid Removes small-medium sized molecules Continuous hemofiltration Removes fluid by convection No dialysate, needs replacement fluid Removes large sized molecules Continuous hemodiafiltration Removes fluid by diffusion and convection Uses dialysate and replacement fluid What should non-nephrologists understand about daily management of patients on CVVH? CICU clinicians should frequently communicate fluid balance and hemodialysis goals with nephrology and nurses The circuit has 2 pumps: 1 to pull fluid, another to push fluid back Monitor daily pressure trends as deviations may implicate issues with the access Look at I/Os on the circuit to determine fluid balance Ask RN if filter is clotting off because this can cause blood loss anemia due to the amount of blood lost when the circuit needs to be changed Electrolyte management: After 1-2 days of normalizing hyperkalemia, try to keep potassium steady using a 4 K bath CRRT can drop phosphorous precipitously, which may cause cardiac myocyte dysfunction; add Na-Phos if necessary. Very important: frequent line checks to identify infections. If the line is in for several days and begin considering a switch to a tunneled dialysis catheter, especially if longer-term RRT is expected. How does the CICU team monitor for native renal recovery and initiate cardiovascular GDMT? The CICU team should assess daily trends in urine output. Patients may spontaneously make more urine especially as critical illness resolves. Consider trialing diuretics (FST) to assess recovery. Once hemodynamics improves, transition to iHD if there is still a persistent indication for RRT. Temporary dialysis lines are infection prone; consider exchanging for a tunneled iHD line if in place >1 week. Many GDMT medications, often crucial for CV optimization, are considered nephrotoxic and may increase serum potassium. Therefore, it is important to be thoughtful about timing of initiation. Consider initiating GDMT when the Cr is trending towards baseline. Cr is “cosmetic”, and the team should tolerate some Cr increases with life-saving GDMT. Please note that trends in potassium levels is more important than Cr with “nephrotoxic” CV meds. There may be a role for gastrointestinal potassium binders to facilitate GDMT optimization, but the clinical safety and efficacy remains unanswered (trials are underway).  It is crucial for patients to get back on GDMT for improved long term cardiac outcomes. References Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. New England Journal of Medicine. 2016;375(2):122-133. STARRT-AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, et al. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med. 2020;383(3):240-251. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the elain randomized clinical trial. JAMA. 2016;315(20):2190. Gaudry S, Hajage D, Martin-Lefevre L, et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial. The Lancet. 2021;397(10281):1293-1300. Chawla LS, Davison DL, Brasha-Mitchell E, et al. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013;17(5):R207. Rabindranath K, Adams J, Macleod AM, Muirhead N. Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev. 2007;(3):CD003773.

Join CardioNerds to learn about patent ducts arteriosus and Eisenmenger syndrome! Dr. Dan Ambinder (CardioNerds co-founder), ACHD series co-chair Dr. Dan Clark,  Dr. Tony Pastor (ACHD fellow, Harvard Medical School), and Dr. Kate Wilcox, Medicine/Pediatrics Resident, Medical College of Wisconsin join Dr. Candice Silversides (Editor-in-chief #JACCAdvances) for this terrific discussion. Notes were drafted by Dr. Kate Wilcox. .Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark. The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more Disclosures: None CardioNerds Adult Congenital Heart Disease PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – Patent Ductus Arteriosus & Eisenmenger Syndrome The ductus arteriosus, which is formed from the distal portion of the left sixth arch, is key to fetal circulation because it allows blood to bypass the high resistance pulmonary circuit present in utero. After birth there is a significant drop in pulmonary vascular resistance (PVR) which generally leads to functional ductal closure within 48 hours (permanent seal takes 2-3 weeks to form). Risk factors for having a PDA include birth before 37 weeks of gestation, trisomy 21, and congenital rubella. A PDA results in a left to right shunt (qP:qS >1) which over time overloads the left side of the heart and causes pulmonary vascular remodeling. The extra workload on the left side of the heart causes left atrial (can cause atrial arrhythmias) and left ventricular dilation. If left untreated you can eventually have shunt reversal due to very high PVR (Eisenmenger physiology). There are some treatment options at this point (pulmonary vasodilators, etc) but it’s definitely better to close the PDA before this point. One interesting physical exam finding that can stem from shunt reversal in a hemodynamically significant PDA is differential cyanosis (upper body or pre-ductal saturations will be higher than lower body/post-ductal saturations). You can also see clubbing in the toes but not the hands for the same reason. Meet Our Collaborators! Adult Congenital Heart AssociationFounded in 1998, the Adult Congenital Heart Association is an organization begun by and dedicated to supporting individuals and families living with congenital heart disease and advancing the care and treatment available to our community. Our mission is to empower the congenital heart disease community by advancing access to resources and specialized care that improve patient-centered outcomes. Visit their website (https://www.achaheart.org/) for information on their patient advocacy efforts, educational material, and membership for patients and providers CHiP Network The CHiP network is a non-profit organization aiming to connect congenital heart professionals around the world. Visit their website (thechipnetwork.org) and become a member to access free high-quality educational material, upcoming news and events, and the fantastic monthly Journal Watch, keeping you up to date with congenital scientific releases. Visit their website (https://thechipnetwork.org/) for more information. Heart UniversityHeart University aims to be “the go-to online resource” for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of educational material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practicing provider. The site provides free content to a global audience in two broad domains: 1. A comprehensive curriculum of training modules and associated testing for trainees. 2. A curated library of conference and grand rounds recordings for continuing medical education. Learn more at www.heartuniversity.org/ CardioNerds Adult Congenital Heart Disease Production Team Amit Goyal, MD Daniel Ambinder, MD

The Cardiorenal Syndrome is commonly encountered, and frequently misunderstood. Join the CardioNerds team as we discuss the complex interplay between the heart and kidneys with Dr. Elliott Miller (Assistant Professor of Medicine at Yale University School of Medicine and Associate Medical Director of the Cardiac Intensive Care Unit of Yale New Haven Hospital), and Dr. Nayan Arora (Clinical Assistant Professor of Medicine and Nephrologist at the University of Washington Medical Center). We are hosted by FIT lead Dr. Matthew Delfiner (Cardiology Fellow at Temple University), Cardiac Critical Care Series Co-Chairs Dr. Mark Belkin (AHFTC faculty at University of Chicago) and Dr. Karan Desai (Cardiologist at Johns Hopkins Hospital), and CardioNerds Co-Found Dr. Dan Ambinder. In this episode we discuss the definition and pathophysiology of the cardiorenal syndrome, explore strategies for initial diuresis and diuretic resistance, and management of the common heart failure medications in this setting. Show notes were developed by Dr. Matthew Delfiner. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. The CardioNerds Cardiac Critical Care Series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Mark Belkin, Dr. Eunice Dugan, Dr. Karan Desai, and Dr. Yoav Karpenshif. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References • Production Team CardioNerds Cardiac Critical Care PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes – Management of Cardiorenal Syndrome in the CICU Cardiorenal syndrome (CRS) represents a range of clinical entities in which there is both heart and kidney dysfunction, and can be driven by one, or both, of the organs. CRS is caused by reduced renal perfusion, elevated renal congestion, or a combination of the two. Treatment therefore focuses on increasing perfusion, by optimizing cardiac output and mean arterial pressure, and reducing congestion through diuresis. Patients should be monitored for an adequate response to the initial diuretic dose within 2 hours of administration. If the response is inadequate, the loop diuretic dose should be doubled. Diuretic resistance can be managed via sequential nephron blockade, most commonly with thiazide diuretics, but also with amiloride, high-dose spironolactone, or acetazolamide, as these target different regions of the nephron. In cases of refractory diuretic resistance, hypertonic saline can be considered with the help of an experienced clinician. Continuation or cessation of renin-angiotensin-aldosterone system (RAAS) inhibitors in the setting of CRS should be made on a case-by-case basis. Show notes – Management of Cardiorenal Syndrome in the CICU 1. Cardiorenal syndrome (CRS) is a collection of signs/symptoms that indicate injury to both the heart and kidneys. Organ dysfunction in one can drive dysfunction in the other. Cardiorenal syndrome can be categorized as: Type 1 – Acute heart failure causing acute kidney injury Type 2 – Chronic heart failure causing chronic kidney injury Type 3 – Acute kidney injury causing acute heart failure Type 4 – Chronic kidney injury causing chronic heart failure Type 5 – Co-development of heart and kidney injury by another systemic process. These categories can be helpful for education, discussion, and research purposes, but they do not usually enter clinical practice on a regular basis since different categories of cardiorenal syndrome are not necessarily treated differently. 2. CRS is caused by either reduced renal perfusion, elevated renal congestion, or a combination of the two. When dealing with CRS, note that: CRS can be caused by poor kidney perfusion, though is mostly driven by low renal perfusion pressure. Renal perfusion pressure is the gradient between renal arteries and renal veins, which can be approximated by mean arterial pressure (MAP) minus central venous pressure (CVP) CRS can therefore be treated by reducing CVP (i.e. with diuresis) or increasing MAP or cardiac output 3. Renal decongestion is achieved primarily through diuresis. For diuretic “naïve” patients, furosemide 40 mg IV is a reasonable starting dose For patients already on diuretics prior to admission, increasing their home dose by 2.5x (administered intravenously) usually achieves an adequate initial response Patients should be reassessed 1-2 hours after their initial diuretics dose. If the patient has not made 200 mL of urine, the loop diuretic dose should be doubled. Diuretic dose and urine output have a logarithmic relationship, meaning doubling the dose does not double the urine output. Once you reach a certain dose threshold, you won’t necessarily increase the quantity of diuresis, but rather you will increase the duration of diuresis. 4. It is okay if creatinine rises with diuresis, to a degree. Creatinine elevation with decongestion is more a sign of hemoconcentration and is paradoxically associated with better outcomes. However, if the creatinine rises by more than 30-50% and you are not seeing clinical evidence of decongestion, then that is likely a poor prognostic sign. 5. There are multiple ways to manage diuretic resistance. Diuretic resistance is often due to a variety of mechanisms including increased sodium reabsorption and hypertrophy of the distal convoluted tubule. Sequential nephron blockade can be considered, most commonly with a thiazide diuretic in addition to a loop diuretic, after the loop diuretic dose is sufficiently optimized. Patients with diuretic resistance may also have increased sodium reabsorption in the proximal tubule, so acetazolamide may be helpful in certain cases. Check out the CardioNerds Journal Club on the ADVOR trial! Amiloride and high doses of spironolactone can be used to target the collecting ducts. Finally, hypertonic saline has been used to address persistent diuretic resistance in certain cases, though should be done with an experienced clinician. 6. Decisions regarding cessation versus continuation of renin-angiotensin-aldosterone system (RAAS) inhibitors in the setting of CRS should be made on a case-by-case basis. RAAS inhibitors may not specifically cause harm, but they may make it difficult to discern whether a change in creatinine related to their use versus worsening renal function. On the other hand, there is an increased likelihood that RAAS inhibitors are not resumed when they are held in CRS, which is associated with worse outcomes. Therefore, it is imperative that there is a plan made to resume these medications if they are held. References Jentzer, Bihorac, Brusca et al. “Contemporary Management of Severee Acute Kidney Injury and Refractory Cardiorenal Syndrome: JACC Council Perspectives.” J Am Coll Cardiol. 2020 Sep, 76 (9) 1084-1101. https://www.jacc.org/doi/abs/10.1016/j.jacc.2020.06.070 Rangaswami J., Bhalla V., Blair J.E.A., et al. “Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association”. Circulation 2019;139:e840-e878: https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000664 Jentzer J.C., Chawla L.S. “A clinical approach to the acute cardiorenal syndrome”. Crit Care Clin 2015; 31:685-703. https://www.criticalcare.theclinics.com/article/S0749-0704(15)00048-2/abstract

Dr. Filip Ionescu (hematology-oncology fellow at Moffitt Cancer Center in Tampa, FL), Dr. Teodora Donisan (cardiology fellow at the Mayo Clinic in Rochester, MN and CardioNerds House Thomas chief), Dr. Sarah Waliany (internal medicine chief resident at Stanford University in Palo Alto, CA), Dr. Dinu Balanescu (internal medicine chief resident at Beaumont Hospital in Royal Oak, MI) and Dr. Amit Goyal (structural interventional cardiology fellow at the Cleveland Clinic, in Cleveland, OH and CardioNerds Co-Founder), discuss the cardiotoxicities of common cancer treatments with Dr. Susan Dent, a medical oncologist and one of the founders of the field of Cardio-Oncology. Using the recently published ESC Guidelines on cardio-oncology, they cover cardiovascular risk stratification in oncology patients, pretreatment testing, as well as prevention and management of established cardiotoxicity resulting from anthracyclines, trastuzumab, and fluoropyrimidines. They touch on the unique aspects of cardio-oncology encountered in patients with breast cancer, rectal cancer, and lung cancer, who are frequently the recipients of multiple cardiotoxic treatments. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah. Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Pearls • Notes • References • Production Team CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent Formal cardiovascular risk stratification must be performed prior to initiating a potentially cardiotoxic anticancer treatment regimen. Considering both drug toxicity and patient-related factors (e.g., age, smoking, hypertension etc) is important.  Anthracyclines affect the cardiomyocyte in complex ways which lead to a largely irreversible cardiomyopathy. All patients should have a pretreatment echocardiogram and ECG.  Trastuzumab cardiotoxicity, by contrast, is more like stunning the myocardium, which manifests as a reversible decrease in left ventricular ejection fraction which generally normalizes upon discontinuation of the drug.  The treatment of chemotherapy-induced cardiomyopathy should involve interdisciplinary discussions and shared decision making with the patient. Beyond guideline-directed medical therapy of heart failure with reduced ejection fraction, management can include temporarily holding or permanently discontinuing the offending agent.  Fluoropyrimidine-associated cardiotoxicity manifests as cardiac ischemia from coronary vasospasm. A 5FU infusion is essentially a stress test as it tends to unmask clinically silent atherosclerosis.  Show notes What is the basic pretreatment assessment of any oncology patient who is to receive a potentially cardiotoxic regimen?  Awareness and management of the cardiovascular toxicity of oncology treatments are of paramount importance to be able to deliver treatment safely and to achieve maximal efficacy guided by an expert multidisciplinary team. Thanks to Dr. Dent and her colleagues’ work, this year we have seen the publication of the first Cardio-Oncology guideline (1). Perhaps the most important recommendation is that cancer patients about to start a cardiotoxic regimen should undergo formal cardiovascular risk stratification by considering both the adverse profile of the planned treatment and patient-related factors (e.g., preexisting heart disease, hypertension, smoking). High-risk patients may be referred early to a cardio-oncologist who can anticipate and mitigate toxicities. In addition to risk stratification, specific treatment modalities may require additional imaging and biochemical testing as outlined next.  How does anthracycline-induced cardiotoxicity present and what are the risk factors to consider?  Anthracycline-induced cardiotoxicity generally manifests as a permanent decrease in left ventricular ejection fraction (LVEF) caused by direct toxic effect of the cytotoxic chemotherapy on the cardiomyocytes. The risk factors for developing anthracycline-induced cardiotoxicity are cumulative anthracycline dose, advanced age, pretreatment low-normal LVEF, prior cardiovascular disease, as well as other established cardiovascular risk factors (e.g., hypertension, diabetes, obesity, smoking).   What is included in the work-up of a patient about to begin an anthracycline-containing regimen?  All patients who are about to received anthracyclines require a baseline echocardiogram, ideally with global longitudinal strain, and an electrocardiogram. For patients who are at moderate-to-high risk of developing cardiomyopathy, B-type natriuretic peptide and Troponin can also be helpful for monitoring.   How is established anthracycline-induced cardiotoxicity typically managed?  When a decrease in LVEF below 50% is detected, management usually involves holding the anthracycline and repeating imaging. At this point, discussion with a cardio-oncologist about the initiation of ACC/AHA guideline-directed medical therapy (GDMT) is warranted. If there is improvement in the LVEF with this approach, the decision to rechallenge is nuanced and often part of a multidisciplinary and shared decision-making process with the patient.   What are some proven strategies to prevent or mitigate anthracycline-induced cardiotoxicity?  In the case of a rechallenge, two ways to mitigate the risk of cardiac damage are using liposomal doxorubicin, which is a less cardiotoxic anthracycline formulation, and co-administration of dexrazoxane, which is the only FDA-approved cardioprotectant for use in this setting.  What is trastuzumab and how does the cardiotoxicity associated with its use differ from that caused by anthracyclines?  Trastuzumab is a monoclonal antibody directed against the HER2 receptor molecule expressed on breast cancer cells. The actual mechanism of trastuzumab-associated cardiotoxicity is not clear, but it appears to be more akin to myocardial stunning and is generally reversible. If it occurs, a decrease in LVEF appears early and for most patients withholding the drug is effective in reversing the effect.   How is trastuzumab-associated cardiotoxicity managed?  For those patients with a nadir LVEF < 50%, there is evidence to support the efficacy of GDMT. For those with an LVEF decrease in the 40-49% range, trastuzumab can be continued concomitantly with GDMT and close monitoring of LVEF. In cases with severe LVEF decrease <40%, the decision to continue or rechallenge becomes more complicated and always should involve a multidisciplinary discussion of the risks and benefits of either approach. Depending on the goal of treatment (curative in the adjuvant setting or palliative in the metastatic setting), the actual predicted benefit and whether the cardiac function recovers with GDMT, trastuzumab could potentially be restarted.   How do novel antibody drug conjugates that contain trastuzumab differ in their cardiotoxicity profile from the naked antibody?  In recent years we have seen the advent of antibody drug conjugates (T-DM1, T-DXd) which in addition the antibody directed against HER2 (trastuzumab) also carry a cytotoxic payload (2). While the experience with these newer agents is still limited, early data suggest these are no more cardiotoxic than trastuzumab. However, the impact of long-term, sequential exposure to these agents on cardiovascular outcomes is unknown.  What are fluoropyrimidines and how does fluoropyrimidine-associated cardiotoxicity manifest clinically?  Fluoropyrimidines are analogs of nucleic acid bases which inhibit synthesis of DNA and RNA. These are some of the most widely use anticancer drugs and examples include 5-fluorouracil (5FU) and capecitabine (an oral prodrug of 5FU). Fluoropyrimidine-associated cardiotoxicity presents primarily with cardiac ischemia caused by coronary vasospasm or endothelial damage, although these are not the only mechanisms by which these drugs can damage the cardiovascular system (3). This is a phenomenon which typically occurs early in therapy after 1-2 cycles and its incidence varies greatly with the mode of administration, occurring in >10% of patients treated with a 5FU infusion (or continuous capecitabine) versus in 3-5% of those who receive the 5FU as a bolus.   What is the management of fluoropyrimidine-associated cardiotoxicity?  Rechallenge is possible in select patients who take active part in the decision-making process and who are deemed to derive substantially larger benefits than risks from continuing. When done, rechallenges usually take place in an inpatient setting with close monitoring and co-administration of calcium channel blockers and nitrates.  Is it possible to rechallenge patients with ischemic symptoms induced by fluoropyrimidine treatment?  Generally, presentations are clinically apparent with symptoms of ischemia and management necessarily includes holding the drug and performing an ischemic work-up which may require invasive testing such as coronary angiography. If there is a clear temporal association with fluoropyrimidine use and ischemic symptoms, a multidisciplinary discussion on whether treatment should be continued is warranted.   What is unique about the cardiotoxicity of oncology therapy in lung cancer patients?  Lung cancer patients are the perfect storm for cardiotoxicity. The prevalence of smoking is very high in this particular cohort which correlates with preexisting cardiovascular disease. Furthermore, radiation to the chest, tyrosine kinase inhibitors (TKIs) targeting EGFR or ALK, and immune checkpoint inhibitors are frequently part of the treatment schema and have defined cardiovascular toxicities (4). As such, these patients are very likely to benefit from cardiology consultation and optimization of cardiovascular risk factors prior to initiating cancer therapy.  What is the cardiovascular toxicity of TKIs?  These systemic treatments were initially developed for metastatic disease but are now making their way into the adjuvant setting. These drugs can maintain efficacy for a long time which translates into prolonged exposure and cardiovascular side effects such as hypertension and QT prolongation.   What is the cardiovascular toxicity of immune checkpoint inhibitors?  Immune checkpoint inhibitors can cause hyperactivation of the immune system resulting in immune attack of normal structures, such as the myocardium. While immune-mediated myocarditis is uncommon (1-2%), it can be very severe with mortality rates approaching 50%, underlining the importance of early recognition and treatment.  References – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent 1. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). European Heart Journal. Published online August 26, 2022:ehac244. doi:10.1093/eurheartj/ehac244  2. Dent SF, Morse A, Burnette S, Guha A, Moore H. Cardiovascular Toxicity of Novel HER2-Targeted Therapies in the Treatment of Breast Cancer. Current Oncology Reports. 2021;23(11). doi:10.1007/s11912-021-01114-x  3. Sara JD, Kaur J, Khodadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. doi:10.1177/1758835918780140  4. Kunimasa K, Kamada R, Oka T, et al. Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib. JACC: CardioOncology. 2020;2(1):1-10. doi:10.1016/j.jaccao.2020.02.003  Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

CardioNerds Cofounder Dr. Amit Goyal join Dr. Usman Hasnie and Dr. Will Morgan from University of Alabama at Birmingham for a hike up Red Mountain. They discuss the following case: A 75-year-old woman with prior mitral valve ring annuloplasty presented with subacute, intermittent, self-limiting neurologic deficits. Brain MRI revealed multiple subacute embolic events consistent with cardioembolic phenomena. Transesophageal echochardiogram discovered a mobile mass on the mitral valve as the likely cause for cardioembolic stroke. She was taken for surgical repair of the mitral valve. Tissue biopsy confirmed that the mass was an IgG4-related pseudotumor. Expert commentary is provided by Dr. Neal Miller (Assistant Professor of Cardiology, University of Alabama at Birmingham). Audio editing by CardioNerds Academy Intern, student doctor Adriana Mares Check out this published case report here: IgG4-Related Disease Masquerading as Culture-Negative Endocarditis! Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. This episode is made possible with support from Glass.Health – The first digital notebook designed for doctors. Follow @GlassHealthHQ for the latest product updates! CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls – Cardioembolic Stroke due to an IgG4-related pseudotumor Surgical indications for endocarditis include severe heart failure, valvular dysfunction with severe hemodynamic compromise, prosthetic valve infection, invasion beyond the valve leaflets, recurrent systemic embolization, large mobile vegetations, or persistent sepsis (in infective endocarditis) despite adequate antibiotic therapy. IgG4 related disease is rare, and likely underrecognized due to the lack of reliable biomarkers. Biopsy and histologic confirmation are imperative to clinch the diagnosis. Cardiac manifestations of IgG4-related disease are rare but are often related to aortopathies. Valvular disease is extremely rare as a manifestation of the disease. Treatment of IgG4 related disease includes steroids as the first line treatment. IgG4 related disease requires a multi-disciplinary approach to both diagnose and treat. Show Notes – Cardioembolic Stroke due to an IgG4-related pseudotumor Notes were drafted by Dr. Hasnie and Dr. Morgan IgG4-related disease has a very diverse presentation including mimicry of infection, malignancy and other autoimmune conditions. It is a fibroinflammatory condition that results in deposition of IgG4 positive plasma cells. It has been described in multiple organ systems including the pancreas, kidneys, lungs and salivary glands.  Cardiac manifestations are extremely rare and valvular disease even more so. There are thirteen cases of IgG4 related valvular disease, and of these only two had mitral valve involvement such as this case. The most commonly reported cardiovascular manifestations are related to aortopathies.  This disease remains poorly understood at this point. There are no true biomarkers that can be used to risk stratify the diagnosis for clinicians. Biopsy is imperative to the diagnosis. Even serum IgG4 levels are normal in 30% of cases despite meeting histologic criteria on biopsy making the diagnosis incredibly difficult to make.  While guidelines have not been developed to guide treatment of IgG4-related disease, steroids are considered the first line treatment option for patients. Often times dosing is 2-4 weeks with a prolonged taper. When looking for glucocorticoid sparing agents, azathioprine, mycophenolate mofetil, and methotrexate are considered alternatives.  References – Cardioembolic Stroke due to an IgG4-related pseudotumor 1. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4- related autoimmune disease. J Gastroenterol 2003;38:982-4.  2. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181-1192. doi:10.1038/modpathol.2012.72  3. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken) 2010;62:1312-8.  4. Stone JH, Khosroshahi A, Hilgenberg A, Spooner A, Isselbacher EM, Stone JR. IgG4 related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum 2009;60:313945.  5. Saeki T, Saito A, Hiura T, et al. Lymphoplasmacytic infiltration of multiple organs with immunoreactivity for IgG4: IgG4-related systemic disease. Intern Med 2006;45:163-7.  6. Kamisawa T, Takuma K, Egawa N, Tsuruta K, Sasaki T. Autoimmune pancreatitis and IgG4-related sclerosing disease. Nat Rev Gastroenterol Hepatol 2010;7:401-9.  7. Shakir A, Wheeler Y, Krishnaswamy G. The enigmatic immunoglobulin G4-related disease and its varied cardiovascular manifestations. Heart. 2021;107(10):790-798. doi:10.1136/heartjnl-2020-318041  8. Tyebally S, Chen D, Bhattacharyya S, Mughrabi A, Hussain Z, Manisty C, et al. Cardiac tumors: JACC cardio oncology state-of-the-art review. J Am Coll Cardiol CardioOnc. 2020;2:293–311  9. Selkane C, Amahzoune B, Chavanis N, et al. Changing management of cardiac myxoma based on a series of 40 cases with long-term follow-up. Ann Thorac Surg. 2003;76(6):1935-1938. doi:10.1016/s0003-4975(03)01245-1  10. Sun JP, Asher CR, Yang XS, et al. Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective and prospective study in 162 patients. Circulation. 2001;103(22):2687-2693. doi:10.1161/01.cir.103.22. 11. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539-551. doi:10.1056/NEJMra1104650 12. Hasnie UA, Herrera LN, Morgan WS, Rodriguez JM, Litovsky S, Chatham WW, Winokur T, Muzny CA. IgG4-Related Disease Masquerading As Culture-Negative Endocarditis. AIM Clinical Cases. 2022;1. doi: 10.7326/aimcc.2022.0075 13. 2016 ASE Guideline: https://www.asecho.org/wp-content/uploads/2016/01/2016_Cardiac-Source-of-Embolism.pdf 14.  Shakir A, Wheeler Y, Krishnaswamy G. The enigmatic immunoglobulin G4-related disease and its varied cardiovascular manifestations Heart 2021;107:790-798. 15. Karadeniz H, Vaglio A. IgG4-related disease: a contemporary review. Turk J Med Sci. 2020 Nov 3;50(SI-2):1616-1631. doi: 10.3906/sag-2006-375. PMID: 32777900; PMCID: PMC7672352.