Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

Humoral response to heterologous prime-booster vaccination in heart transplant recipients aged 18-70 years primed with a viral vector SARS-CoV-2 vaccine.

Solid organ transplant recipients have demonstrated a blunted immune response to standard 2-dose vaccination against SARS-CoV-2. This study sought to determine the humoral response to heterologous booster vaccination (viral vector vaccine dose 1 and 2 + mRNA booster). Heart transplant recipients, aged 18 to 70 years of age who initially received two doses of the viral vector ChAdOx1 nCoV-19 vaccine followed by a BNT162b2 mRNA booster were recruited. A detectable antibody response in the absence of prior SARS-CoV-2 was the primary outcome measured. This was defined as an anti-spike titre of ≥0.8 U/mL on the Elecsys anti-SARS-CoV-2 S immunoassay. A total of 80 heart transplant patients (mean age 49 ± 13 years, 28% female) were included. Blood samples were drawn at a median of 30 (IQR 28-33) days after the BNT162b2 mRNA booster. The frequency of a detectable antibody response increased from 37.5% (n = 30) after dose 2 to 56% (n = 45) post dose 3 (p < 0.001). A non-detectable antibody response was significantly more common in recipients with a shorter time interval from transplantation (p < 0.001), lower likelihood of cardiac allograft vasculopathy (p = 0.003) and in those prescribed a triple versus dual immunosuppressant regime (p = 0.009) and a tacrolimus versus cyclosporine basedregimen (p = 0.007). Despite heterologous prime-booster vaccination 44% of this vulnerable population ultimately continue to have no detectable antibodies.

The four pillars of HFrEF therapy: is it time to treat heart failure regardless of ejection fraction?

The syndrome of heart failure (HF) has historically been dichotomized based on clinical trial inclusion criteria into patients with a reduced or preserved left ventricular ejection fraction (LVEF) using a cut-off of above or below 40%. The majority of trial evidence for the benefits of disease-modifying pharmacological therapy has been in patients with HF with reduced ejection fraction (HFrEF), i.e. those with an LVEF ≤40%. Recently, the sodium-glucose co-transporter 2 inhibitors empagliflozin and dapagliflozin have been shown to be the first drugs to improve outcomes in HF across the full spectrum of LVEF. There is, however, growing evidence that the benefits of many of the neurohumoral modulators shown to be beneficial in patients with HFrEF may extend to those with a higher LVEF above 40% but still below the normal range, i.e. HF with mildly reduced ejection fraction (HFmrEF). Whether the benefits of some of these medications also extend to patients with HF and preserved ejection fraction (HFpEF) is an area of ongoing debate. This article will review the evidence for HF treatments across the full spectrum of LVEF, provide an overview of recently updated clinical practice guidelines, and address the question whether it may now be time to treat HF with some therapies regardless of ejection fraction.

Dynamic Assessment of Pulmonary Artery Pulsatility Index Provides Incremental Risk Assessment for Early Right Ventricular Failure After Left Ventricular Assist Device.

BACKGROUND: The pulmonary artery pulsatility index (PAPi) has been studied to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation, but only as a single time point before LVAD implantation. Multiple clinical factors and therapies impact RV function in pre-LVAD patients. Thus, we hypothesized that serial PAPi measurements during cardiac intensive care unit (CICU) optimization before LVAD implantation would provide incremental risk stratification for early RVF after LVAD implantation. METHODS AND RESULTS: Consecutive patients who underwent sequential pulmonary artery catherization with cardiac intensive care optimization before durable LVAD implantation were included. Serial hemodynamics were reviewed retrospectively across the optimization period. The optimal PAPi was defined by the initial PAPi + the PAPi at optimized hemodynamics. RVF was defined as need for a right ventricular assist device or prolonged inotrope use (>14 days postoperatively). Patients with early RVF had significantly lower mean optimal PAPi (3.5 vs 7.5, P < .001) compared with those who did not develop RVF. After adjusting for established risk factors of early RVF after LVAD implantation, the optimal PAPi was independently and incrementally associated with early RVF after LVAD implantation (odds ratio 0.64, 95% confidence interval 0.532-0.765, P < .0001). CONCLUSIONS: Optimal PAPi achieved during medical optimization before LVAD implantation provides independent and incremental risk stratification for early RVF, likely identifying dynamic RV reserve.

Performance of diagnostic criteria in patients clinically judged to have cardiac sarcoidosis: Is it time to regroup?

BACKGROUND: The diagnosis of cardiac sarcoidosis (CS) is challenging. Because of the current limitations of endomyocardial biopsy as a reference standard, physicians rely on advanced cardiac imaging, multidisciplinary evaluation, and diagnostic criteria to diagnose CS. AIMS: To compare the 3 main available diagnostic criteria in patients clinically judged to have CS. METHODS: We prospectively included patients clinically judged to have CS by a multidisciplinary sarcoidosis team from November 2016 to October 2017. We included only incident cases (diagnosis of CS within 1 year of inclusion). We applied retrospectively the following diagnostic criteria: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), the Heart Rhythm Society (HRS), and the Japanese Circulation Society (JCS) 2016 criteria. RESULTS: We identified 69 patients. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (κ = 1) but low between JCS and the others (κ = 0.326). CONCLUSIONS: A high proportion of patients clinically judged to have CS are unable to be classified according to the 3 main diagnostic criteria. There is low concordance between JCS criteria and the other 2 criteria (WASOG and HRS).

Anabolism to Catabolism: Serologic Clues to Nutritional Status in Heart Failure.

PURPOSE OF REVIEW: Malnutrition, sarcopenia, and cachexia are areas of increasing interest in the management of patients with heart failure (HF). This review aims to examine the serological markers useful in guiding the physician in identification of these patients. RECENT FINDINGS: Traditional nutritional biomarkers including albumin/prealbumin, iron, and vitamin D deficiencies predict poor prognosis in malnutrition and HF. Novel biomarkers including ghrelin, myostatin, C-terminal agrin fragment, and adiponectin have been identified as possible substrates and/or therapeutic targets in cardiac patients with sarcopenia and cachexia, though clinical trial data is limited to date. Increased focus on nutritional deficiency syndromes in heart failure has led to the use of established markers of malnutrition as well as the identification of novel biomarkers in the management of these patients, though to date, their usage has been confined to the academic domain and further research is required to establish their role in the clinical setting.

First spot urine sodium after initial diuretic identifies patients at high risk for adverse outcome after heart failure hospitalization.

BACKGROUND: Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization. METHODS: At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa >60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge. RESULTS: Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa <60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P < .006) than patients with UNa >60. CONCLUSIONS: Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization.

Clinical Significance of Early Fluid and Weight Change During Acute Heart Failure Hospitalization.

AIMS: To explore the association of changes in weight and fluid during treatment for acute heart failure (AHF) with clinical endpoints. METHODS AND RESULTS: Weight and net fluid changes recorded at 72-96 hours in 708 AHF patients enrolled in Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure studies were compared with freedom from congestion at 72-96 hours and a composite endpoint of death, rehospitalization, and unplanned hospital visit at 60 days. Weight loss was concordant with net fluid loss in 55%, discordant and less than expected for fluid loss in 34%, and paradoxically discordant or more than expected for fluid loss in 11% of patients. Weight loss, but not fluid loss, was associated with freedom from congestion (odds ratio per 1-kg weight loss = 1.11 [1.03-1.19]) and a nominal reduction in the composite endpoint (hazard ratio per 1-kg weight loss = 0.98 [0.95-1.00]). Outcomes were similar in patients with concordant and discordant weight-fluid loss. CONCLUSION: During treatment for AHF, early changes in weight may be more useful for identifying response to therapy and for predicting outcomes than net fluid output. Nearly one-half of patients receiving decongestive therapies demonstrate discordant changes in weight and fluid; however, discordance was not associated with outcomes.

Clinical Implications of Serum Albumin Levels in Acute Heart Failure: Insights From DOSE-AHF and ROSE-AHF.

BACKGROUND: Hypoalbuminemia is common in patients with chronic heart failure and, as a marker of disease severity, is associated with an adverse prognosis. Whether hypoalbuminemia contributes to (or is associated with) worse outcomes in acute heart failure (AHF) is unclear. We sought to determine the implications of low serum albumin in patients receiving decongestive therapies for AHF. METHODS AND RESULTS: Baseline serum albumin levels were measured in 456 AHF subjects randomized in the DOSE-AHF and ROSE-AHF trials. We assessed the relationship between admission albumin levels (both as a continuous variable and stratified by median albumin [≥3.5 g/dL]) and worsening renal function (WRF), worsening heart failure (WHF), and clinical decongestion by 72 hours; 7-day cardiorenal biomarkers; and post-discharge outcomes. The mean baseline albumin level was 3.5 ± 0.5 g/dL. Albumin was not associated with WRF, WHF, or clinical decongestion by 72 hours. Furthermore, there was no association between continuous albumin levels and symptom change according to visual analog scale or weight change by 72 hours. Albumin was not associated with 60-day mortality, rehospitalization, or unscheduled emergency room visits. CONCLUSIONS: Baseline serum albumin levels were not associated with short-term clinical outcomes for AHF patients undergoing decongestive therapies. These data suggest that serum albumin may not be a helpful tool to guide decongestion strategies.

Assessment of global left ventricular excursion using three-dimensional dobutamine stress echocardiography to identify significant coronary artery disease.

BACKGROUND: Quantitative three-dimensional (3D) dobutamine stress echocardiography (DSE) for myocardial ischemia detection may be an adjuvant to left ventricular (LV) wall-motion analysis. The aim of the current study was to assess the association between global 3D LV excursion during DSE and the presence of significant coronary artery disease (CAD) on coronary angiography. METHODS: Three-dimensional DSE was performed in 40 patients (67±12 years, 68% male) who underwent subsequent coronary angiography (median 1.6 months later). Using 3D echocardiography, global LV excursion was measured (in a total of 680 segments) at rest and peak dose and the change between stages was calculated (peak-rest=∆global LV excursion). Significant CAD was defined as >70% stenosis on coronary angiography. RESULTS: In total, 25 patients (63%) demonstrated significant CAD on coronary angiography. At rest, global LV excursion was similar in patients with and without significant CAD (5.1±0.2 vs 5.0±0.2 mm, P=.74). However, patients with significant CAD demonstrated a worsening in global LV excursion from rest to peak stress (from 5.1±0.2 to 4.1±0.2 mm, P<.001), while global LV excursion in patients without significant CAD remained unchanged (from 5.0±0.2 to 5.5±0.2 mm, P=.10). After adjusting for clinically relevant characteristics, ∆global LV excursion was independently associated with significant CAD (odds ratio 0.29, 95% confidence interval 0.12-0.72, P=.008). CONCLUSIONS: Analysis of 3D echocardiographic LV excursion at global level on full-protocol DSE may be a helpful tool to detect CAD on coronary angiography.

Turning Failure into Success: Trials of the Heart Failure Clinical Research Network.

The Heart Failure Clinical Research Network (HFN) was established in 2008 on behalf of the NIH National Heart, Lung and Blood Institute, with the primary goal of improving outcomes in heart failure (HF) by designing and conducting high-quality concurrent clinical trials testing interventions across the spectrum of HF. Completed HFN trials have answered several important and relevant clinical questions concerning the safety and efficacy of different decongestive and adjunctive vasodilator therapies in hospitalized acute HF, phosphodiesterase-5 inhibition and nitrate therapies in HF with preserved ejection fraction, and the role of xanthine oxidase inhibition in hyperuricemic HF. These successes, independent of the "positive" or "negative" result of each individual trial, have helped to shape the current clinical care of HF patients and serve as a platform to inform future research directions and trial designs.

Frailty in Advanced Heart Failure.

Frailty is defined as a biological syndrome reflecting impaired physiologic reserve and heightened vulnerability to stressors. The evolving profile of heart failure (HF), increased survival of aging patients with complex comorbidities in parallel with the growing population undergoing mechanical circulatory support as lifetime therapy, means that advanced HF specialists are becoming aware of the burden of frailty and its downstream consequences on postintervention outcomes in these patients. The limited data available to date suggest that frailty is highly prevalent in patients with advanced HF and appears to provide prognostic information not captured by traditional risk assessment.

QRS Fragmentation and QTc Duration Relate to Malignant Ventricular Tachyarrhythmias and Sudden Cardiac Death in Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: QRS fragmentation (fQRS) and prolonged QTc interval on surface ECG are prognostic in various cardiomyopathies other than hypertrophic cardiomyopathy (HCM). The association between fQRS and prolonged QTc duration with occurrence of ventricular tachyarrhythmias or sudden cardiac death (VTA/SCD) in patients with HCM was explored. METHODS AND RESULTS: One hundred and ninety-five clinical HCM patients were studied. QTc duration was derived applying Bazett's formula; fQRS was defined as presence of various RSR' patterns, R or S notching and/or >1 additional R wave in any non-aVR lead in patients without pacing or (in)complete bundle branch block. The endpoints comprised SCD, ECG documented sustained VTA (tachycardia or fibrillation) or appropriate implantable cardioverter defibrillator (ICD) therapies (antitachycardia pacing [ATP] or shock) for VTA in ICD recipients (n = 58 [30%]). QT prolonging drugs recipients were excluded. After a median follow-up of 5.7 years (IQR 2.7-9.1), 26 (13%) patients experienced VTA or SCD. Patients with fQRS in ≥3 territories (inferior, lateral, septal, and/or anterior) (p = 0.004) or QTc ≥460 ms (p = 0.009) had worse cumulative survival free of VTA/SCD than patients with fQRS in <3 territories or QTc <460 ms. fQRS in ≥3 territories (ß 4.5, p = 0.020, 95%CI 1.41-14.1) and QTc ≥460 ms (ß 2.7, p = 0.037, 95%CI 1.12-6.33) were independently associated with VTA/SCD. Likelihood ratio test indicated assessment of fQRS and QTc on top of conventional SCD risk factors provides incremental predictive value for VTA/SCD (p = 0.035). CONCLUSIONS: Both fQRS in ≥3 territories and QTc duration are associated with VTA/SCD in HCM patients, independently of and incremental to conventional SCD risk factors.

Position of Edwards SAPIEN transcatheter valve in the aortic root in relation with the coronary ostia: implications for percutaneous coronary interventions.

OBJECTIVES: To determine the implications of stable coverage of the coronary ostia by the Edwards SAPIEN valve frame in terms of myocardial ischemia and subsequent percutaneous coronary intervention (PCI), following transcatheter aortic valve implantation (TAVI). BACKGROUND: Edwards SAPIEN frame is frequently deployed relatively higher than recommended and may overlap the coronary ostia. METHODS: A total of 142 patients (age 81 ± 7 years, male 49%) treated with Edwards SAPIEN valve and with multi-detector row computed tomography at 1 month follow-up were evaluated. The position of the frame in relation to the coronary ostia was assessed. Levels of troponin T were measured 12-24 hr after TAVI. PCI events at follow-up were recorded. RESULTS: The left coronary ostium was fully covered in three (2.1%) patients and the right coronary ostium in 11 (7.7%). There were no differences in troponin T levels between patients with fully covered ostia versus patients with partly or non-covered ostia (0.24 (0.13-0.50) µg/L versus 0.35 (0.15-0.55) µg/L, respectively; P = 0.377). At 30 ± 15 months follow up, 10 (7%) patients underwent successful PCI. Rate of subsequent PCI was similar between patients with any covered ostium and patients with non-covered ostia [4 (7.8%) vs. 6 (6.5%), P = 0.780, respectively]. CONCLUSIONS: Full overlap of the coronary ostia by Edwards SAPIEN frame is infrequent and in most cases does not limit subsequent PCI.

Therapeutic adjustments in stage D heart failure: challenges and strategies.

The morbidity and mortality associated with heart failure (HF) represents a significant public health challenge. Stage D HF identifies a distinct subgroup of advanced HF patients characterized by adverse clinical and hemodynamic factors which warrant evaluation for specialized advanced management strategies and/or consideration of palliative care in tandem with the same recommendations for goal-directed optimal medical therapy as earlier stages of HF. In fact, one of the inherent markers of progression to stage D disease is the need to withdraw previously tolerated neurohormonal agents in the setting of systemic circulatory limitations or renal dysfunction. Furthermore, the requirement for aggressive diuresis in the setting of borderline blood pressures and renal insufficiency is often complicated by worsening renal impairment. Assessment of the appropriate need for inotropic support, given the significant complications associated with their use, is also a frequently encountered challenge complicating the medical management of Stage D HF. This review outlines some of the most relevant challenges of pharmacological therapy in stage D HF and describes current and future strategies that may be employed to overcome some of these obstacles.

Challenges in long-term mechanical circulatory support and biological replacement of the failing heart.

The burden of advanced heart failure is reaching epidemic proportions. Generally considered for cardiac transplantation, patients often cannot receive this therapy because of their advanced age, comorbidity or the scarcity of donors. Most transplants are concentrated in North America and Europe, with the average center performing fewer than 20 annual transplants. A search for nonbiological means of cardiac support has led to the advent of mechanical circulatory support (MCS), a concept now entrenched as a bridge to transplantation or, for those ineligible for transplantation, as lifetime therapy. In this review we discuss contemporary challenges posed by the changing epidemiology of cardiac transplant and MCS and outline the basis for an understanding of the future of this important therapeutic stance.