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 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.

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.

Adverse drug reactions in patients with cardiovascular disease.

Adverse drug reactions (ADRs) occur frequently in modern medical practice, increasing morbidity and mortality and inflating the cost of care. Patients with cardiovascular disease are particularly vulnerable to ADRs due to their advanced age, polypharmacy, and the influence of heart disease on drug metabolism. The ADR potential for a particular cardiovascular drug varies with the individual, the disease being treated, and the extent of exposure to other drugs. Knowledge of this complex interplay between patient, drug, and disease is a critical component of safe and effective cardiovascular disease management. The majority of significant ADRs involving cardiovascular drugs are predictable and therefore preventable. Better patient education, avoidance of polypharmacy, and clear communication between physicians, pharmacists, and patients, particularly during the transition between the inpatient to outpatient settings, can substantially reduce ADR risk.

Impact of myocardial function on cystatin C measurements in chronic systolic heart failure.

BACKGROUND: The influence of myocardial function on plasma levels of cystatin C (CysC), a sensitive marker of renal function, in chronic systolic heart failure (HF) has not been well established. METHODS: We prospectively identified 139 subjects with stable, chronic HF (left ventricular ejection fraction < or = 35%) and measured plasma levels of CysC. We prospectively tracked patients' long-term adverse clinical outcomes (death, cardiac transplantation, and HF hospitalizations). RESULTS: Plasma levels of CysC were elevated in 41% of patients with preserved renal function and directly correlated with N-terminal prohormone brain natriuretic peptide (r = 0.57, P < .0001). There was a significant association between CysC and mitral E/septal E' ratio (r = 0.34, P < .001), right ventricular systolic dysfunction severity (r = 0.30, P < .001), and mitral regurgitation severity (r = 0.31, P < .001), but not left ventricular ejection fraction. At the cutoff of 1.23 mg/dL, CysC remains a significant independent risk factor for adverse clinical outcomes (hazard ratio 1.88, 95% confidence interval 1.15-3.09, P = .012) after adjusting for estimated glomerular filtration rate, left ventricular ejection fraction, and E/septal E'. CONCLUSION: CysC is associated with more advanced left ventricular diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis in chronic systolic HF after adjusting for myocardial factors.

Outcomes of patients with stable heart failure undergoing elective noncardiac surgery.

OBJECTIVE: To evaluate modern surgical outcomes in patients with stable heart failure undergoing elective major noncardiac surgery and to compare the experience of patients with heart failure who have reduced vs preserved left ventricular ejection fraction (EF). PATIENTS AND METHODS: We retrospectively studied 557 consecutive patients with heart failure (192 EF less than or equal to 40% and 365 EF greater than 40%) and 10,583 controls who underwent systematic evaluation by hospitalists in a preoperative clinic before having major elective noncardiac surgery between January 1, 2003, and March 31, 2006. We examined outcomes in the entire cohort and in propensity-matched case-control groups. RESULTS: Unadjusted 1-month postoperative mortality in patients with both types of heart failure vs controls was 1.3% vs 0.4% (P equals .009), but this difference was not significant in propensity-matched groups (P equals .09). Unadjusted differences in mean hospital length of stay among heart failure patients vs controls (5.7 vs 4.3 days; P less than .001) and 1-month readmission (17.8% vs 8.5%; P less than .001) were also markedly attenuated in propensity-matched groups. Crude 1-year hazard ratios for mortality were 1.71 (95% confidence interval [CI], 1.5-2.0) for both types of heart failure, 2.1 (95% CI, 1.7-2.6) in patients with heart failure who had EF less than or equal to 40%, and 1.4 (95% CI, 1.2-1.8) in those who had EF greater than 40% (P less than .01 for all 3 comparisons); however, the differences were not significant in propensity-matched groups (P equals .43). CONCLUSION: Patients with clinically stable heart failure did not have high perioperative mortality rates in association with elective major noncardiac surgery, but they were more likely than patients without heart failure to have longer hospital stays, were more likely to require hospital readmission, and had a substantial long-term mortality rate.

Comparative sensitivities between different plasma B-type natriuretic peptide assays in patients with minimally symptomatic heart failure.

Plasma B-type natriuretic peptide (BNP) assays have become widely used to diagnose and manage patients with heart failure. However, differences in assay characteristics may have important implications when BNP is used as a screening test for heart failure at a specific cutoff value. We performed a prospective comparison of 2 commercially available assays--one that is a laboratory-based, microparticle enzyme immunoassay (MEIA) that uses EDTA plasma specimens and one that is a point-of-care (POC), single-use fluorescence immunoassay that uses EDTA--anticoagulated whole blood or plasma specimens-in patients with heart failure and healthy controls. Despite the overall concordance between different SNP assays for the diagnosis of heart failure, their sensitivities may differ when compared at the approved diagnostic cutoff value of 100 pg/mL. At this cutoff value, the MEIA on AxSYM demonstrated greater sensitivity than POC Triage BNP assay in minimally symptomatic patients with heart failure. Therefore, for screening purposes, cutoff values for plasma BNP or N-terminal pro-BNP levels should be specific for each assay to optimize test performance. These findings suggest that there is a relationship between the decision statistics used in screening for left ventricular dysfunction and the type of diagnostic assay used.

Neurohormonal response to left ventricular reconstruction surgery in ischemic cardiomyopathy.

OBJECTIVES: Activation of the neuroendocrine axis in congestive heart failure is of prognostic significance, and neurohumoral blocking therapy prolongs survival. The hypothesis that surgical reduction of left ventricular size and function decreases neuroendocrine activation is less established. We evaluated the neurohormonal response to left ventricular reconstruction surgery in ischemic cardiomyopathy. METHODS: Norepinephrine, plasma renin activity, and angiotensin II were measured in 10 patients before and 12 months after left ventricular reconstruction. In an additional 5 patients, brain natriuretric peptide was measured before and 3 months postoperatively. Three-dimensional cardiovascular imaging was used to assess ejection fraction and left ventricular end-diastolic volume index. RESULTS: Concurrent with improvements of New York Heart Association functional class (2.9 +/- 0.5 preoperatively vs 2.0 +/- 0.4 postoperatively, P <.001), ejection fraction (23.9% +/- 6.6% vs 36.2% +/- 6.2%, P <.01), and left ventricular end-diastolic volume index (140.8 +/- 33.8 mL/m(2) vs 90.6 +/- 18.3 mL/m(2), P <.01), considerable reductions were observed for median plasma profiles of norepinephrine (562.0 pg/mL vs 319.0 pg/mL, P <.05), plasma renin activity (5.75 microg/L/h vs 3.45 microg/L/h, P <.05), angiotensin II (41.0 ng/mL vs 23.0 ng/mL, P =.051), and brain natriuretric peptide (771.0 pg/mL vs 266.0 pg/mL, P <.05). The more plasma renin activity or angiotensin II decreased after left ventricular reconstruction, the higher was the increase in ejection fraction (R = -.745, P <.05 [plasma renin activity]; R = -.808, P <.05 [angiotensin II]). CONCLUSIONS: Surgical improvements of ejection fraction and left ventricular end-diastolic volume index by left ventricular reconstruction were accompanied by improvement of both the neuroendocrine activity and the functional status in patients with congestive heart failure. Whether this favorable neurohormonal response is predictive of an improved survival requires further evaluation.

Plasma B-type natriuretic peptide levels predict postoperative atrial fibrillation in patients undergoing cardiac surgery.

BACKGROUND: Postoperative (postop) atrial fibrillation (AF) occurs in up to 60% of patients after cardiac surgery, leading to longer hospital stays and increased healthcare costs. Recently, B-type natriuretic peptide (BNP) has been reported to predict occurrence of nonpostoperative AF. This study evaluates whether elevated preoperative (preop) plasma BNP levels predict the occurrence of postop AF. METHODS AND RESULTS: One hundred eighty-seven patients with no history of atrial arrhythmia who had a preoperative BNP level and had undergone cardiac surgery were identified. Their records were reviewed, and postoperative ECG and telemetry strips were analyzed for AF until the time of discharge. Postop AF was documented in 80 patients (42.8%). AF patients were older (68+/-11 versus 64+/-14 years, P=0.04), but there was no difference in sex distribution, hypertension, left ventricular (LV) function, LV hypertrophy (LVH), left atrial size, history of coronary artery disease (CAD), or beta-blocker use. Preop plasma BNP levels were higher in the postop AF patients (615 versus 444 pg/mL, P=0.005). After adjustment for age, sex, type of surgery, hypertension, LV function, LVH, left atrial size, CAD, and beta-blocker use, the odds ratios of postop AF according to increasing quartiles, compared with patients with lowest quartile, were 1.8, 2.5, and 3.7 (P(trend)=0.03). CONCLUSIONS: An elevated preop plasma BNP level is a strong and independent predictor of postop AF. This finding has important implications for identifying patients at higher risk of postop AF who could be considered for prophylactic antiarrhythmic or beta-blocker therapy.

Cardiac troponins in renal insufficiency and other non-ischemic cardiac conditions.

The emergence of cardiac troponins has been an interesting step in the diagnosis of ACS. It has clearly helped us to better triage patients toward a more aggressive posture in performing early cardiac catheterization, and in some cases, early use of adjunctive Gp IIb/IIIa antagonists and percutaneous or surgical myocardial revascularization. However, with this step forward has come uncertainty and many cardiology consults regarding positive cardiac troponins in patients without ACS or myocardial infarction. In general, increased cardiac troponins imply a worse prognosis. This is clearly true of patients with ESRD and advanced heart failure. It is also true of patients with severe, noncardiac illnesses. In other situations, such as acute pericarditis and cardiac surgery, slightly elevated cardiac troponins do not seem to predict a worse prognosis, and can probably be disregarded. The elevation of cardiac troponins after successful percutaneous coronary interventions is not unexpected, and the level of cardiac troponin release seems to predict problems, but lively controversy persists. Last, monitoring cardiac troponins in cardiac transplant recipients and those receiving certain cardiotoxic chemotherapies may be of some diagnostic value, but clearly more experience and clinical research are needed.

Aspirin and clopidogrel in acute coronary syndromes: therapeutic insights from the CURE study.

Platelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspirin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 production and adenosine diphosphate-induced platelet aggregation pathways, respectively. Aspirin has proven benefits in primary and secondary prevention of coronary artery disease. Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study demonstrates for the first time the benefit of adding clopidogrel to aspirin rather than using aspirin alone in patients having acute coronary syndromes without ST-segment elevation myocardial infarction. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events and may derive special benefit from the combination therapy. Aspirin resistance can be assessed through platelet aggregometry testing, measurement of urinary thromboxane metabolites, and, possibly, genomic testing in the future.