One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy.

Mavacamten is a first-in-class cardiac myosin ATPase inhibitor, approved by the United States Food and Drug Administration for the treatment of hypertrophic cardiomyopathy with obstructive physiology (oHCM). Here, we present the real-world use of mavacamten in 50 patients with oHCM at a tertiary care referral center. In both our highlighted case and in our aggregate data, we report significant improvement in wall thickness, mitral regurgitation, left ventricular outflow tract obstruction and New York Heart Association symptom class. Moreover, in our center's experience, neither arrhythmia burden, nor contractility have worsened in the vast majority of patients: we note a clinically insignificant mean decrease in left ventricular ejection fraction (LVEF), with only two patients requiring temporary mavacamten discontinuance for LVEF < 50%. Adverse events were rare, unrelated to mavacamten itself, and seen solely in patients with disease too advanced to have been represented in clinical trials. Moreover, our multidisciplinary pathway enabled us to provide a large number of patients with a novel closely-monitored therapeutic within just a few months of commercial availability. These data lead us to conclude that mavacamten, as a first-in-class cardiac myosin inhibitor, is safe and efficacious in real-world settings.

Implementation of evidence-based heart failure management: Regional variations between Japan and the USA.

The implementation of optimal medical therapy is a crucial step in the management of heart failure with reduced ejection fraction (HFrEF). Over the prior three decades, there have been substantial advancements in this field. Early and accurate detection and diagnosis of the disease allow for the appropriate initiation of optimal therapies. The initiation and uptitration of optimal medical therapy including renin-angiotensin system inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor in the early stage would prevent the progression and morbidity of HF. Concurrently, individualized surveillance to recognize and treat signs of disease progression is critical given the progressive nature of HF, even among stable patients on optimal therapy. However, there remains a wide variation in regional practice regarding the initiation, titration, and long-term monitoring of this therapy. To cover the differences in approaches toward HFrEF management and the implementation of guideline-based medical therapy, we discuss the current evidence in this arena, differences in present guideline recommendations, and compare practice patterns in Japan and the USA using a case of new-onset HF as an example. We will discuss pros and cons of the way HF is managed in each region, and highlight potential areas for improvement in care.

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-ß-Blocking R-Enantiomer Carvedilol.

BACKGROUND: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. ß-Adrenergic receptor antagonists (ß-blockers) are the first-line therapy for HCM. However, ß-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. METHODS: We screened 21 ß-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (MYH7R403Q/+). RESULTS: We identified that carvedilol, a ß-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a ß1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of ß-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes. CONCLUSIONS: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies.

Hypertrophic cardiomyopathy (HCM) affects more than 1 in 500 people in the general population with an extensive burden of morbidity in the form of arrhythmia, heart failure, and sudden death. More than 25 years since the discovery of the genetic underpinnings of HCM, the field has unveiled significant insights into the primary effects of these genetic mutations, especially for the myosin heavy chain gene, which is one of the most commonly mutated genes. Our group has studied the molecular effects of HCM mutations on human ß-cardiac myosin heavy chain using state-of-the-art biochemical and biophysical tools for the past 10 years, combining insights from clinical genetics and structural analyses of cardiac myosin. The overarching hypothesis is that HCM-causing mutations in sarcomere proteins cause hypercontractility at the sarcomere level, and we have shown that an increase in the number of myosin molecules available for interaction with actin is a primary driver. Recently, two pharmaceutical companies have developed small molecule inhibitors of human cardiac myosin to counteract the molecular consequences of HCM pathogenesis. One of these inhibitors (mavacamten) has recently been approved by the FDA after completing a successful phase III trial in HCM patients, and the other (aficamten) is currently being evaluated in a phase III trial. Myosin inhibitors will be the first class of medication used to treat HCM that has both robust clinical trial evidence of efficacy and that targets the fundamental mechanism of HCM pathogenesis. The success of myosin inhibitors in HCM opens the door to finding other new drugs that target the sarcomere directly, as we learn more about the genetics and fundamental mechanisms of this disease.

Severe Cardiovascular Complications Following Liver Transplantation in Patients With Iron Overload.

We report 4 cases of our institutional experience with liver transplantation that illustrate the high risk of heart failure and cardiogenic shock in the setting of cardiac iron overload. We then discuss a pragmatic approach to assess the cardiovascular risk in liver transplantation candidates with cardiac iron overload. (Level of Difficulty: Advanced.).

Multimorbidity, guideline-directed medical therapies, and associated outcomes among hospitalized heart failure patients.

AIMS: Multimorbidity is common among heart failure (HF) patients and may attenuate guideline-directed medical therapy (GDMT). Multimorbid patients are under-represented in clinical trials; therefore, the effect of multimorbidity clustering on the prognosis of HF patients remains unknown. We evaluated the prevalence of multimorbidity clusters among consecutively registered hospitalized HF patients and assessed whether GDMT attenuated outcomes. METHODS AND RESULTS: We examined 1924 hospitalized HF patients with reduced left ventricular ejection fraction (<50%) in a multicentre registry (West Tokyo HF Registry: WET-HF). Ten comorbid conditions in the WET-HF were abstracted: coronary artery disease, atrial fibrillation, stroke, anaemia, chronic obstructive pulmonary disease, renal dysfunction, obesity, hypertension, dyslipidaemia, and diabetes. Patients were divided into three groups (0-2: n = 451; 3-4: n = 787; and ≥5: n = 686) based on the number of comorbid conditions. The primary composite endpoint was all-cause mortality and HF rehospitalization. The most prevalent comorbidities were renal dysfunction (67.9%), hypertension (66.0%), and anaemia (53.8%). Increased comorbidity was associated with increased adverse outcomes [3-4: hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.13-1.77, P = 0.003; ≥5: HR 2.12, 95%CI 1.69-2.65, P < 0.001; and reference: 0-2] and lower GDMT prescription rate (0-2: 69.2%; 3-4: 57.7%; and ≥5: 57.6%). GDMT was associated with decreased adverse outcomes; this association was maintained even as the comorbidity burden increased but tended to weaken (0-2: HR 0.53, 95%CI 0.35-0.78; P = 0.001; 3-4: HR 0.82, 95%CI 0.65-1.04, P = 0.095; and ≥5: HR 0.81, 95%CI 0.65-1.00, P = 0.053; P for interaction = 0.156). CONCLUSIONS: Comorbidity clusters were prevalent and associated with poorer outcomes. GDMT remained beneficial regardless of the comorbidity burden but tended to weaken with increasing comorbidity burden. Further research is required to optimize medical care in these patients.

Assessment of Physical Activity Using Waist-Worn Accelerometers in Hospitalized Heart Failure Patients and Its Relationship with Kansas City Cardiomyopathy Questionnaire.

The health benefits of physical activity have been widely recognized, yet there is limited information on associations between accelerometer-related parameters and established patient-reported health status. This study investigated the association between the waist-worn accelerometer measurements, cardiopulmonary exercise testing (CPX), and results of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in heart failure (HF) patients hospitalized for acute decompensation. A total of 31 patients were enrolled and wore a validated three-axis accelerometer for 2 weeks and completed the short version of the KCCQ after removing the device. Daily step counts, exercise time (metabolic equivalents × hours), and %sedentary time (sedentary time/device-equipped time) were measured. Among the measured parameters, the best correlation was observed between %sedentary time and the KCCQ overall and clinical summary scores (r = -0.65 and -0.65, each p < 0.001). All of the individual domains of the KCCQ (physical limitation, symptom frequency, and quality of life), with the exception of the social limitation domain, showed moderate correlations with %sedentary time. Finally, oxygen consumption assessed by CPX demonstrated only weak associations with the accelerometer-measured parameters. An accelerometer could complement the KCCQ results in accurately assessing the physical activity in HF patients immediately after hospitalization, albeit its correlation with CPX was at most moderate.

Time-sensitive approach in the management of acute heart failure.

Acute heart failure (AHF) has become a global public health burden largely because of the associated high morbidity, mortality, and cost. The treatment options for AHF have remained relatively unchanged over the past decades. Historically, clinical congestion alone has been considered the main target for treatment of acute decompensation in patients with AHF; however, this is an oversimplification of the complex pathophysiology. Within the similar clinical presentation of congestion, significant differences in pathophysiological mechanisms exist between the fluid accumulation and redistribution. Tissue hypoperfusion is another vital characteristic of AHF and should be promptly treated with appropriate interventions. In addition, recent clinical trials of novel therapeutic strategies have shown that heart failure management is 'time sensitive' and suggested that treatment selection based on individual aetiologies, triggers, and risk factor profiles could lead to better outcomes. In this review, we aim to describe the specifics of the 'time-sensitive' approach by the clinical phenotypes, for example, pulmonary/systemic congestion and tissue hypoperfusion, wherein patients are classified based on pathophysiological conditions. This mechanistic classification, in parallel with the comprehensive risk assessment, has become a cornerstone in the management of patients with AHF and thus supports effective decision making by clinicians. We will also highlight how therapeutic modalities should be individualized according to each clinical phenotype.

Hospital meal intake in acute heart failure patients and its association with long-term outcomes.

BACKGROUND: Risk prediction for hospitalised heart failure (HF, HHF) patients remains suboptimal. We aimed to determine the prognostic value of hospital food intake (FI) immediately before discharge among HHF patients. METHOD: We analysed the data of 255 HHF patients extracted from the records of a single university hospital. The FI percentage of the three meals the day before hospital discharge was averaged. Patients were stratified into adequate FI (100% consumption) and inadequate FI (less than 100% consumption) groups. The primary outcome was the composite of all-cause mortality and/or HF readmission within 1 year. RESULTS: Only 49.3% of HHF patients consumed 100% of their meals. Patients with inadequate FI were older; predominantly women; and had a lower body mass index, higher brain natriuretic peptide levels and Clinical Frailty Scale scores at discharge than those with adequate FI. Inadequate FI was significantly associated with adverse outcomes after adjustments (HR 2.00; 95% CI 1.09 to 3.67; p=0.026). The effect of interaction by ejection fraction (EF) was highly significant: HF with preserved EF (≥40%) was significantly associated with inadequate FI with adverse outcomes (HR 4.95; 95% CI 1.71 to 14.36; p=0.003) but HF with reduced EF (<40%) was not (HR 0.77; 95% CI 0.31 to 1.95; p=0.590). CONCLUSIONS: The hospital FI assessment might be a simple, useful tool for predicting and stratifying risk for HHF patients.

Physical therapy in successful venoarterial extracorporeal membrane oxygenation bridge to orthotopic heart transplantation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a temporary mechanical circulatory support system that may be used as a lifesaving therapy for patients in acute heart failure and as a bridge to definitive management. Physical therapy in these patients remains challenging, with limited protocols to guide practitioners. METHODS: We describe a case of a 37-year-old gentleman who presented with familial cardiomyopathy and cardiogenic shock. RESULTS: Our patient underwent urgent peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) followed by successful heart transplantation. While on ECMO support he was enrolled in a physical therapy program that included the VitalGo Tilt Bed to improve lower body weight bearing while avoiding hip flexion and damage to the peripheral ECMO cannulae. The patient was discharged home expeditiously after heart transplant due to aggressive physical rehabilitation while on full VA-ECMO support. CONCLUSIONS: Early intensive physical rehabilitation is feasible and safe and may result in improved outcomes and expeditious discharge in VA ECMO patients. Protocol driven multidisciplinary physical therapy with a patient on femorally cannulated VA-ECMO retains the advantages of lower extremity peripheral cannulation while eliminating the risks of immobility. The new UNOS allocation system may result in a successful bridge to transplantation in patients on VA-ECMO due to the increased prioritization of this population to receive donor organs.

Controlling load-dependent kinetics of ß-cardiac myosin at the single-molecule level.

Concepts in molecular tension sensing in biology are growing and have their origins in studies of muscle contraction. In the heart muscle, a key parameter of contractility is the detachment rate of myosin from actin, which determines the time that myosin is bound to actin in a force-producing state and, importantly, depends on the load (force) against which myosin works. Here we measure the detachment rate of single molecules of human ß-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. Our results suggest that activating versus inhibitory perturbations of cardiac myosin are discriminated by the aggregate result on duty ratio, average force, and ultimately average power output and suggest that cardiac contractility can be controlled by tuning the load-dependent kinetics of single myosin molecules.

Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human ß-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force-holding capacity due to the reduced occupancy of the force-holding state.

Biophysical properties of human ß-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the ß-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human ß-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human ß-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production.

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human ß-cardiac myosin.

Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental force-generating protein machinery of the cardiac muscle sarcomere, including human ß-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human ß-cardiac myosin. We are using a recombinantly expressed human ß-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

Quantification of gene transcripts with deep sequencing analysis of gene expression (DSAGE) using 1 to 2 µg total RNA.

Deep sequencing analysis of gene expression (DSAGE) measures global gene transcript levels from only 1 to 2 µg total RNA by massively parallel sequencing of cDNA tags. This unit describes the construction of 21-bp cDNA tag libraries appropriate for massively parallel sequencing and analysis of the resulting sequence data. The adapter oligonucleotides used are optimized for sequencing with current Illumina massively parallel sequencers, and a step-by-step implementation of the analysis protocol is described. The expression profiles obtained are highly reproducible, enabling sensitive detection of differences between experimental conditions as well as assessment of the relative transcript abundance of different genes.

Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy.

Unknown molecular responses to sarcomere protein gene mutations account for pathologic remodeling in hypertrophic cardiomyopathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC(403/+)) and an Mef2-dependent ß-galactosidase reporter transgene. In young, prehypertrophic MHC(403/+) mice the reporter was not activated. In hypertrophic hearts, activation of the Mef2-dependent reporter was remarkably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC(403/+) myocytes with Mef2-dependent reporter activation reexpressed the fetal myosin isoform (ßMHC), a molecular marker of hypertrophy, although MHC(403/+) myocytes with or without ßMHC expression were comparably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC(403/403) mice, which have accelerated remodeling, widespread myocyte necrosis, and neonatal lethality. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC(403/403) hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2-dependent reporter activity before death. Our data dissociate myocyte hypertrophy, a consistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial relationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC(403/+) and MHC(403/403) hearts defines Mef2 activation as a molecular signature of stressed HCM myocytes that are poised to die.

Endogenous regulation of cardiovascular function by apelin-APJ.

Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.