Hypotension on cardiopulmonary stress test predicts 90 day mortality after LVAD implantation in INTERMACS 3-6 patients.

AIMS: Cardiopulmonary stress test (CPX) is routinely performed when evaluating patient candidacy for left ventricular assist device (LVAD) implantation. The predictive value of hypotensive systolic blood pressure (SBP) response during CPX on clinical outcomes is unknown. This study aims to determine the effect of hypotensive SBP response during to clinical outcomes among patients who underwent LVAD implantation. METHODS AND RESULTS: This was a retrospective single center study enrolling consecutive patients implanted with a continuous flow LVAD between 2011 and 2022. Hypotensive SBP response was defined as peak exercise SBP below the resting value. Multivariable Cox-regression analysis was performed to evaluate the relationship between hypotensive SBP response and all-cause mortality within 30 and 90 days of LVAD implantation. A subgroup analysis was performed for patients implanted with a HeartMate III (HM III) device. Four hundred thirty-two patients underwent LVAD implantation during the pre-defined period and 156 with INTERMACS profiles 3-6 met our inclusion criteria. The median age was 63 years (IQR 54-69), and 52% had ischaemic cardiomyopathy. Hypotensive SBP response was present in 35% of patients and was associated with increased 90 day all-cause mortality (unadjusted HR 9.16, 95% CI 1.98-42; P = 0.0046). Hazard ratio remained significant after adjusting for age, INTERMACS profile, serum creatinine, and total bilirubin. Findings were similar in the HM III subgroup. CONCLUSIONS: Hypotensive SBP response on pre-LVAD CPX is associated with increased perioperative and 90 day mortality after LVAD implantation. Additional studies are needed to determine the mechanism of increased mortality observed.

Heart Failure Care Delivery in the COVID-19 Era: The Patients' Perspective.

Purpose: The SARS-CoV-2 pandemic is changing healthcare delivery around the world with hospital systems experiencing a dramatic decline in patient volumes. Surveying our center's heart failure (HF) clinic population, we aimed to understand our patients' perception of coronavirus disease 2019 (COVID-19) and care delivery preferences. Methods: Patients with chronic HF presenting either in-person or virtually were approached to complete a ten question, anonymous, voluntary survey. Acutely decompensated patients and heart transplant recipients were excluded. Results: 109 patients completed the survey. Average age was 62 ± 14 years, 67% were male, and 59% had HF with reduced ejection fraction (HFrEF). Overall, patients were worried about contracting COVID-19 and believed they were prone to more severe infection given their underlying HF. However, they were not hesitant to initiate healthcare contact for symptoms and preferred in-person appointments over virtual visits. Although the difference did not reach statistical significance, female patients and those with HF with preserved ejection fraction (HFpEF) were more concerned. Conclusions: Patients with HF are concerned about their increased risk of contracting COVID-19. However, they are actively seeking healthcare contact and prefer in-person over virtual visits.

Update on COVID-19 Myocarditis.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gained worldwide attention at the end of 2019 when it was identified to cause severe respiratory distress syndrome. While it primarily affects the respiratory system, we now have evidence that it affects multiple organ systems in the human body. Cardiac manifestations may include myocarditis, life threatening arrhythmias, acute coronary syndrome, systolic heart failure, and cardiogenic shock. Myocarditis is increasingly recognized as a complication of Coronavirus-19 (COVID-19) and may result from direct viral injury or from exaggerated host immune response. The diagnosis is established similar to other etiologies, and is based on detailed history, clinical exam, laboratory findings and non-invasive imaging studies. When available, cardiac MRI is the preferred imaging modality. Endomyocardial biopsy may be performed if the diagnosis remains uncertain. Current management is mainly supportive with the potential addition of interventions recommended for severe COVID-19 disease, such as remdesivir, steroids, and convalescent plasma. In the setting of cardiogenic shock and refractory, life-threatening arrhythmias that persist despite medical therapy, advanced mechanical circulatory support devices should be considered. Ultimately, early recognition and aggressive intervention are key factors in reducing morbidity and mortality. Our management strategy is expected to evolve further as we learn more about COVID-19 disease and the associated cardiac complications.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week.

The term "inotrope" is familiar and intimately connected with pharmaceuticals clinically used for treatment of low cardiac output with cardiogenic shock. Traditional inotropic agents exert their effect by modulating calcium signaling in the myocardium. Their use is associated with poor long-term outcomes. Newer molecules in development intend to break from calcium mediation and the associated detrimental long-term effects by targeting distinct mechanisms of action to improve cardiac performance. Thus, "inotropy" does not sufficiently describe the range of potential novel pharmaceutical products. To enhance communication around and evaluation of current, emerging, and potential therapies, this review proposes a novel nuanced and holistic framework to categorize pharmacological agents that improve myocardial performance based on 3 myocardial mechanisms: calcitropes, which alter intracellular calcium concentrations; myotropes, which affect the molecular motor and scaffolding; and mitotropes, which influence energetics. Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes.

Plasma renin activity in patients with heart failure and reduced ejection fraction on optimal medical therapy.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) activation in heart failure with reduced ejection fraction (HFREF) is detrimental through promotion of ventricular remodeling and salt and water retention. AIMS: The aims of this article are to describe RAAS activity in distinct HFREF populations and to assess its prognostic impact. METHODS: Venous blood samples were prospectively obtained in 76 healthy volunteers, 72 patients hospitalized for acute decompensated HFREF, and 78 ambulatory chronic HFREF patients without clinical signs of congestion. Sequential measurements were performed in patients with acute decompensated HFREF. RESULTS: Plasma renin activity (PRA) was significantly higher in ambulatory chronic HFREF (7.6 ng/ml/h (2.2; 18.1)) compared to patients with acute decompensated HFREF (1.5 ng/ml/h (0.8; 5.7)) or healthy volunteers (1.4 ng/ml/h (0.6; 2.3)) (all p < 0.05). PRA was significantly associated with arterial blood pressure and renin-angiotensin system blocker dose. A progressive rise in PRA (+4 ng/ml/h (0.4; 10.9); p < 0.001) was observed in acute decompensated HFREF patients after three consecutive days of decongestive treatment. Only in acute HFREF were PRA levels associated with increased cardiovascular mortality or HF readmissions ( p = 0.035). CONCLUSION: PRA is significantly elevated in ambulatory chronic HFREF patients but is not associated with worse outcome. In contrast, in acute HFREF patients, PRA is associated with cardiovascular mortality or HF readmissions.

Cardiac safety profile of patients receiving high cumulative doses of pegylated-liposomal doxorubicin: use of left ventricular ejection fraction is of unproven value.

PURPOSE: One of the great conundrums for both oncologists and cardiologists is how to best monitor the potential and actual cardiotoxicity of doxorubicin. Pegylated-liposomal doxorubicin (PLD) has a safer cardiotoxicity profile than bolus administration of doxorubicin. Although ejection fraction (EF) is commonly performed to monitor doxorubicin-induced cardiotoxicity, evidence for its predictive utility is limited. We examined the incidence of doxorubicin-induced heart failure (HF) in patients who received a large cumulative dose of doxorubicin as PLD and its relation to EF and HF. METHODS: A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes after previous free doxorubicin treatment, was performed to examine the incidence of doxorubicin-induced heart failure (HF) and its relation to EF and development of HF. RESULTS: No definite doxorubicin-induced clinical HF was observed among 56 patients (median age 54; 15-93) who received a cumulative doxorubicin dose (free + PLD) of >450 mg/m2. Of these, 49 received >500 mg/m2, 28 > 700 mg/m2, 19 > 800 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients treated with PLD in the absence of symptoms or signs of heart failure, and was not particularly useful in making decisions regarding further dosing. CONCLUSIONS: Pegylated-liposomal doxorubicin was associated with a low risk of doxorubicin-induced HF in a retrospective cohort of patients receiving large cumulative doses of doxorubicin and long-term follow-up. EF did not predict doxorubicin-induced cardiotoxicity in our cohort of adult patients receiving PLD. Given the lack of prognostic clarity regarding modest EF changes, regular EF monitoring may not be warranted, at least when PLD is used in adults. Modest changes in EF should probably not be used to limit a patient's access to PLD, but may warrant cardiology consultation for long-term follow-up after completion of therapy.

Cardiovascular impact in patients undergoing maintenance hemodialysis: Clinical management considerations.

Patients undergoing maintenance hemodialysis develop both structural and functional cardiovascular abnormalities. Despite improvement of dialysis technology, cardiovascular mortality of this population remains high. The pathophysiological mechanisms of these changes are complex and not well understood. It has been postulated that several non-traditional, uremic-related risk factors, especially the long-term uremic state, which may affect the cardiovascular system. There are many cardiovascular changes that occur in chronic kidney disease including left ventricular hypertrophy, myocardial fibrosis, microvascular disease, accelerated atherosclerosis and arteriosclerosis. These structural and functional changes in patients receiving chronic dialysis make them more susceptible to myocardial ischemia. Hemodialysis itself may adversely affect the cardiovascular system due to non-physiologic fluid removal, leading to hemodynamic instability and initiation of systemic inflammation. In the past decade there has been growing awareness that pathophysiological mechanisms cause cardiovascular dysfunction in patients on chronic dialysis, and there are now pharmacological and non-pharmacological therapies that may improve the poor quality of life and high mortality rate that these patients experience.

ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design.

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a double-blind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a "seamless" WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.

A Test in Context: Critical Evaluation of Natriuretic Peptide Testing in Heart Failure.

Circulating natriuretic peptide measurements have been used extensively over the past 15 years to diagnose and monitor patients with heart failure. We are still learning how complex the dynamics of natriuretic peptides can be in the interpretation of test results in individual patients. Although natriuretic peptide measurements are widely used in practice, there are questions regarding why these peptides may not necessarily track with blood volume or invasive hemodynamic measurements in individual patients. Interpretation of natriuretic peptide measurements will depend on many factors, including special patient populations, obesity, renal function, the state of congestion or decongestion, and whether patients are receiving specific therapies. Natriuretic peptide measurements have clearly revolutionized clinical care for patients with heart failure, but further research should provide insights to help use these measurements to individualize patient care beyond the current guidelines.