COMPETENCE Trial: The EVAHEART 2 continuous flow left ventricular assist device.

BACKGROUND: Continuous flow left ventricular assist devices have improved outcomes in patients with end-stage heart failure that require mechanical circulatory support. Current devices have an adverse event profile that has hindered widespread application. The EVAHEART®2 left ventricular assist device (EVA2) has design features such as large blood gaps, lower pump speeds and an inflow cannula that does not protrude into the left ventricle that may mitigate the adverse events currently seen with other continuous flow devices. METHODS: A prospective, multi-center randomized non-inferiority study, COMPETENCE Trial, is underway to assess non-inferiority of the EVA2 to the HeartMate 3 LVAS when used for the treatment of refractory advanced heart failure. The primary end-point is a composite of the individual primary outcomes: Survival to cardiac transplant or device explant for recovery; Free from disabling stroke; Free from severe Right Heart Failure after implantation of original device. Randomization is in a 2:1 (EVA2:HM3) ratio. RESULTS: The first patient was enrolled into the COMPETENCE Trial in December of 2020, and 25 subjects (16 EVA2 and 9 HM3) are currently enrolled. Enrollment of a safety cohort is projected to be completed by third quarter of 2022 at which time an interim analysis will be performed. Short-term cohort (92 EVA2 subjects) and long-term cohort is expected to be completed by the end of 2023 and 2024, respectively. CONCLUSIONS: The design features of the EVA2 such as a novel inflow cannula and large blood gaps may improve clinical outcomes but require further study. The ongoing COMPETENCE trial is designed to determine if the EVA2 is non-inferior to the HM3.

Left Ventricular Assist Device in Patients With Alcohol Abuse or Illicit Drug Use.

The impact of substance abuse, including alcohol abuse or illicit drug use, on outcomes after left ventricular assist device (LVAD) implantation, has not been fully elucidated. Accordingly, to test the hypothesis that such a history would be associated with worse outcomes, we analyzed the Interagency Registry for Mechanically Assisted Circulatory Support registry. All patients from the Interagency Registry for Mechanically Assisted Circulatory Support registry who received a continuous-flow LVAD from June 2006 to December 2017 were included. The median follow-up duration was 12.9 months (interquartile range, 5.3 to 17.5). The final study group consisted of 15,069 patients, of which 1,184 (7.9%) had a history of alcohol abuse and 1,139 (7.6%) had a history of illicit drug use. The overall mortality rates in the alcohol, illicit drug, and control groups were 25%, 21%, and 29%, respectively. Cox regression analysis showed that having a history of alcohol abuse (hazard ratio, 0.97, 95% confidence interval, 0.84 to 1.13, p = 0.72) or illicit drug use (hazard ratio, 1.02, 95% confidence interval, 0.86 to 1.21, p = 0.81) was not significantly associated with increased risk of all-cause mortality when compared with general LVAD population. On the contrary, after adjusting for other covariates, a history of alcohol abuse or illicit drug use was significantly associated with increased device malfunction/pump thrombosis, device-related infection, or all-cause hospitalization (all p <0.05). Furthermore, After LVAD implantation, these patients had a lower quality of life assessed by the Kansas City Cardiomyopathy Questionnaire compared with those who did not. In conclusion, our findings suggest that patients with a history of alcohol abuse or illicit drug use are at risk for adverse device-related events with a lower quality of life after continuous-flow LVAD implantation compared with the general LVAD population.

Left Ventricular End-Diastolic Dimension and Clinical Outcomes After Centrifugal Flow Left Ventricular Assist Device Implantation.

The impact of preoperative end-diastolic left ventricular dimension (preLVEDD) on long-term outcomes with centrifugal continuous-flow left ventricular assist device (CF-LVAD) is not well established. Accordingly, we performed an analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry to study this relationship. All patients with centrifugal CF-LVAD in the INTERMACS registry from June 2006 to December 2017 were screened. The final study group consisted of 3,304 patients. After a median follow-up of 9.0 months (interquartile range [IQR], 4.2-18.8 months), 2,596 (79%) patients were alive. After adjusting for significant covariates, increased preLVEDD was associated with lower mortality (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84-0.98; p = 0.01), stroke (HR, 0.85; 95% CI, 0.77-0.93; p < 0.001), and gastrointestinal bleeding (HR, 0.88; 95% CI, 0.80-0.97; p = 0.01), although there were more arrhythmias (HR, 1.14; 95% CI, 1.05-1.24; p = 0.003). Our study suggests that preLVEDD is an independent predictor of mortality and adverse events in patients treated with centrifugal CF-LVAD. preLVEDD should be considered an important preimplant variable for risk stratification when considering a CF-LVAD.

Transcatheter Aortic Valve Replacement and Left Ventricular Geometry: Survival and Gender Differences.

BACKGROUND: The aim of this study was to examine the relationship between baseline left ventricular (LV) geometry and outcomes after transcatheter aortic valve replacement (TAVR). METHODS: Patients undergoing TAVR (n = 206) had baseline LV geometry classified as (1) concentric hypertrophy, (2) eccentric hypertrophy, (3) concentric remodeling, or (4) normal. Descriptive statistics, Kaplan-Meier time-to-event analysis, and Cox regression were performed. RESULTS: Distribution of baseline LV geometry differed between male and female patients (χ2 = 16.83, P = .001) but not at 1 month (χ2 = 2.56, P = .47) or 1 year (χ2 = 5.68, P = .13). After TAVR, a majority of patients with concentric hypertrophy evolved to concentric remodeling. Survival differed across LV geometry groups at 1 year (χ2[3] = 8.108, P = .044, log-rank test) and at 6.5 years (χ2[3] = 9.023, P = .029, log-rank test). Compared with patients with concentric hypertrophy, patients with normal geometry (hazard ratio, 2.25; 95% CI, 1.12-4.54; P = .023) and concentric remodeling (hazard ratio, 1.89; 95% CI, 1.12-3.17; P = .016) had higher rates of all-cause mortality. CONCLUSIONS: Baseline concentric hypertrophy confers a survival advantage after TAVR. Although baseline patterns of LV geometry appear gender specific (with women demonstrating more concentric hypertrophy), this difference resolves after TAVR.

Impact of High Baseline Left Ventricular Filling Pressure on Transcatheter Aortic Valve Replacement Outcomes in Patients with Significant Mitral Annular Calcification.

BACKGROUND: Left ventricular filling pressure (LVFP) has been demonstrated to be a major predictor of poor cardiovascular outcomes. However, estimation of LVFP in patients with aortic stenosis is limited by the high prevalence of significant mitral annular calcification. The aim of this study was to investigate the effect of transcatheter aortic valve replacement on LVFP and the relationship of LVFP to mortality and hospitalization. METHODS: This was a single-center, retrospective study of 140 consecutive patients in sinus rhythm with significant mitral annular calcification who underwent transcatheter aortic valve replacement for severe aortic stenosis from May 2011 to June 2015. Mean follow-up duration was 3.06 ± 1.48 years (minimum, 2.4 years; maximum, 6.5 years). Diastolic function was assessed using recently proposed criteria for those with significant mitral annular calcification. High LVFP was defined as a mitral E/A ratio > 1.8 or a ratio of 0.8 to 1.8 and isovolumic relaxation time < 80 msec. RESULTS: At baseline, the proportion of patients with high LVFP was 40.7%, similar to 1 month (39.7%) (P = .86). However, the proportion of patients with high LVFP was significantly decreased at 1 year compared with those at baseline (26.9% vs 40.7%, P = .02). Multivariate analysis showed that high LVFP at baseline significantly increased risk for all-cause mortality compared with patients with normal LVFP (hazard ratio, 2.84; 95% confidence interval, 1.33-6.05; P = .007). CONCLUSIONS: High baseline LVFP was associated with a significantly increased all-cause mortality, and LVFP does not improve in the short term but only at 1 year after transcatheter aortic valve replacement.

Efficacy and Safety of Tolvaptan in Patients Hospitalized With Acute Heart Failure.

BACKGROUND: The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF). OBJECTIVES: The TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure) study was conducted to address the acute use of tolvaptan to improve congestion in AHF. METHODS: The TACTICS-HF study randomized patients (n = 257) within 24 h of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 h, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 h. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. RESULTS: Dyspnea relief by Likert scale was similar between groups at 8 h (25% moderately or markedly improved with tolvaptan vs. 28% placebo; p = 0.59) and at 24 h (50% tolvaptan vs. 47% placebo; p = 0.80). Need for rescue therapy was also similar at 24 h (21% tolvaptan, 18% placebo; p = 0.57). The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared with placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. CONCLUSIONS: In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 h, despite greater weight loss and fluid loss. (Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure [TACTICS-HF]; NCT01644331).

Tolvaptan in Patients Hospitalized With Acute Heart Failure: Rationale and Design of the TACTICS and the SECRET of CHF Trials.

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials.

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration.

Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration.

Comparison of right and left ventricular function and size in Duchenne muscular dystrophy.

INTRODUCTION: Right ventricular (RV) size and function in Duchenne muscular dystrophy (DMD) have not been well described. Using cardiac magnetic resonance (CMR) imaging we describe the relationship of RV and left ventricular (LV) size and function in a large DMD cohort. METHODS: Latest CMR scans of 272 patients consecutively seen at a single tertiary referral center (2011-2014) with skeletal muscle biopsy confirmed DMD were included. 1.5 and 3 Tesla CMR scanners were used. Biventricular ejection fraction (EF), end-diastolic volume index (EDVI), mass and mass index were compared across categories of LVEF. RESULTS: Mean age was 13.5 ± 4.9 years. 71% had normal (≥ 55%) LVEF while mild (EF 45-54%), moderate (EF 30-44%), and severe LV dysfunction (EF <30%) was present in 20%, 6% and 3% respectively. The correlation between RVEF and LVEF was weak. Even in patients with severe LV dysfunction, RVEF (49.7% ± 12.9%) was relatively preserved. There were no significant differences in RVEDVI and RV mass index across categories of LV function. CONCLUSION: In a large DMD cohort, RVEF was relatively preserved and RV size was preserved across categories of LV dysfunction.

The relationship between cardiac resynchronization therapy and diastolic function.

Cardiac resynchronization therapy (CRT) improves measures of systolic function and clinical status. However, its effect on diastolic function is not well established. Commonly used parameters of diastolic function are measured from echocardiography, using pulse wave and tissue Doppler technologies, as well as timing and deformation data. Review of the existing studies that address the relationship between diastolic function and CRT shows conflicting data, but general trends can be deduced. Baseline elevated filling pressure appears to identify patients most likely to derive improvement in that particular parameter. Intrinsic relaxation does not appear to be significantly impacted by CRT. Generally, changes in diastolic properties after CRT appear to be linked to changes in systolic function. Specific therapy aimed at diastolic asynchrony is lacking, partly due to an unclear relationship between diastolic asynchrony and diastolic dysfunction, and the inability to specifically impact diastolic timing with a systolic intervention such as CRT.

Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients.

BACKGROUND: Ultrafiltration (UF) is a widely used technology for inpatient management of acute decompensated heart failure in patients with volume overload. However, the safety and efficacy of UF in patients with heart failure and preserved left ventricular ejection fraction (heart failure with preserved ejection fraction [HFPEF]) need further clarification. We hypothesized that UF could be used in this population with outcomes similar to acute decompensated heart failure patients with low left ventricular ejection fraction (HFLEF). METHODS AND RESULTS: Prospective evaluation was performed on 2 patient cohorts admitted to a single institution for acute decompensated heart failure and treated with UF: HFLEF (left ventricular ejection fraction ≤ 40%; n=87) and HFPEF (left ventricular ejection fraction >40%; n=97). Selected demographic and clinical data were compared, including clinical and serological information, as well as in-hospital and 90-day postdischarge mortality. HFPEF patients were more likely to be women, have higher blood pressures, and less likely to have ischemic heart disease. There were no significant differences in total weight loss (7.7% in HFLEF and 7.0% in HFPEF), electrolyte and renal disturbances, or in-hospital mortality (3.4% in HFLEF and 3.3% in HFPEF) between the 2 groups. Mortality at 90 days tended to be greater in HFLEF (24.1%) than in HFPEF (15.5%). CONCLUSIONS: Therapeutic responses in patients with HFPEF meeting current indication for UF are similar to those with HFLEF. Larger studies are warranted to better characterize acute heart failure management with UF in this population.

Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.

Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life. Yet, there is little or no significant cardiac muscle regeneration after an injury such as acute myocardial infarction. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre-recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labelled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocyte populations. These findings have implications for promoting regeneration of the injured human heart.

Proteomic analysis of hyperdynamic mouse hearts with enhanced sarcoplasmic reticulum calcium cycling.

Depressed sarcoplasmic reticulum (SR) Ca-cycling is a hallmark of human and experimental heart failure. Strategies to improve this impairment by either increasing SERCA2a levels or decreasing phospholamban (PLN) activity have been suggested as promising therapeutic targets. Indeed, ablation of PLN gene in mice was associated with greatly enhanced cardiac Ca-cycling and performance. Intriguingly, this hyperdynamic cardiac function was maintained throughout the lifetime of the mouse without observable pathological consequences. To determine the cellular alterations in the expression or modification of myocardial proteins, which are associated with the enhanced cardiac contractility, we performed a proteomics-based analysis of PLN knockout (PLN-KO) hearts in comparison to isogenic wild-types. By use of 2-dimensional gel electrophoresis (2-DE), approximately 3300 distinct protein spots were detected in either wild-type or PLN-KO ventricles. Protein spots observed to be altered between PLN-KO and wild-type hearts were subjected to tryptic peptide mass fingerprinting for identification by MALDI-TOF mass spectrometry in combination with LC/MS/MS analysis. In addition, two-dimensional 32P-autoradiography was performed to analyze the phosphorylation profiles of PLN-KO cardiomyocytes. We identified alterations in the expression level of more than 100 ventricular proteins, along with changes in phosphorylation status of important regulatory proteins in the PLN-KO. These protein changes were observed mainly in two subcellular compartments: the cardiac contractile apparatus, and metabolism/energetics. Our findings suggest that numerous alterations in protein expression and phosphorylation state occurred upon ablation of PLN and that a complex functional relationship among proteins involved in calcium handling, myofibrils, and energy production may exist to coordinately maintain the hyperdynamic cardiac contractile performance of the PLN-KO mouse in the long term.

Phosphoproteome analysis of cardiomyocytes subjected to beta-adrenergic stimulation: identification and characterization of a cardiac heat shock protein p20.

Posttranslational modification of target substrates underlies biological processes through activation/inactivation of signaling cascades. To concurrently identify the phosphoprotein substrates associated with cardiac beta-adrenergic signaling, the mouse myocyte phosphoproteome was analyzed using 2-D gel electrophoresis in combination with 32P autoradiography. Phosphoprotein spots, detected by silver staining, were identified using MALDI-TOF mass spectrometry in conjunction with computer-assisted protein spot matching. Stimulation with isoproterenol (1 micromol/L for 5 minutes) was associated with maximal increases in myocyte contractile parameters, and significant stimulation of the phosphorylation of troponin I (190+/-23%) and succinyl CoA synthetase (160+/-16%), whereas the phosphorylation of pyruvate dehydrogenase (48+/-10%), NADH-ubiquinone oxidoreductase (46+/-6%), heat shock protein 27 (18+/-3%), alphaB-crystallin (20+/-3%), and an unidentified 26-kDa protein (29+/-7%) was significantly decreased, compared with unstimulated cells (100%). After sustained (30 minutes) stimulation with isoproterenol, only the alterations in the phosphorylation levels of troponin I and NADH-ubiquinone oxidoreductase were maintained and de novo phosphorylation of a phosphoprotein (approximately 20 kDa and pI 5.5) was observed. The tryptic peptide fragments of this phosphoprotein were sequenced using postsource decay mass spectrometry, and the protein was subsequently cloned and designated as p20, based on its high sequence homology with rat and human skeletal p20. The mouse cardiac p20 contains the conserved domain sequences for heat shock proteins, and the RRAS consensus sequence for cAMP-PKA substrates. LC-MS/MS phosphorylation mapping confirmed phosphorylation of Ser16 in p20 on beta-agonist stimulation. Adenoviral gene transfer of p20 was associated with significant increases in contractility and Ca transient peak in adult rat cardiomyocytes, suggesting an important role of p20 in cardiac function. These findings suggest that cardiomyocytes undergo significant posttranslational modification via phosphorylation in a multitude of proteins to dynamically fine-tune cardiac responses to beta-adrenergic signaling.

Proteomic analysis of the reactive phenotype of astrocytes following endothelin-1 exposure.

Reactive gliosis is an invariant feature of the pathology of central nervous system (CNS) injury and a major determinant of neuronal survival and regeneration. To begin to understand the alterations in astrocyte protein expression that drive glial changes that occur following injury, we used an established model system (endothelin-1 stimulation of hypertrophy) and proteomic analysis to define a discrete set of differentially expressed proteins and post-translational modifications that occur as the astrocytes change from a quiescent to a reactive state. This orchestrated set of changes included proteins involved in cytoskeletal reorganization (caldesmon, calponin, alpha B-crystallin, stathmin, collapsing response mediator protein-2), cell adhesion (vinculin, galectin-1), signal transduction (RACK-1) and astrocyte differentiation (glutamine synthetase). Using proteomic analysis to understand what drives astrocyte expression of these functionally divergent molecules may offer insight into the mechanisms by which astrocytes can exhibit both pro-regenerative and anti-regenerative activities following CNS injury.

Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis.

The endothelins (ETs) are a family of peptides that exert their biological effects via two distinct receptors, the endothelin A receptor (ET(A)R) and the endothelin B receptor (ET(B)R). To more clearly define the potential actions of ETs following spinal cord injury, we used immunohistochemistry and confocal microscopy to examine the protein expression of ET(A)R and ET(B)R in the normal and injured rat spinal cord. In the normal spinal cord, ET(A)R immunoreactivity (IR) is expressed by vascular smooth muscle cells and a subpopulation of primary afferent nerve fibers. ET(B)R-IR is expressed primarily by radial glia, a small population of gray and white matter astrocytes, ependymal cells, vascular endothelial cells, and to a lesser extent in smooth muscle cells. Fourteen days following compression injury to the spinal cord, there was a significant upregulation in both the immunoexpression and number of astrocytes expressing the ET(B)R in both gray and white matter and a near disappearance of ET(B)R-IR in ependymal cells and ET(A)R-IR in primary afferent fibers. Conversely, the vascular expression of ET(A)R and ET(B)R did not appear to change. As spinal cord injury has been shown to induce an immediate increase in plasma ET levels and a sustained increase in tissue ET levels, ETs would be expected to induce an initial marked vasoconstriction via activation of vascular ET(A)R/ET(B)R and then days later a glial hypertrophy via activation of the ET(B)R expressed by astrocytes. Strategies aimed at blocking vascular ET(A)R/ET(B)R and astrocyte ET(B)Rs following spinal cord injury may reduce the resulting ischemia and astrogliosis and in doing so increase neuronal survival, regeneration, and function.