Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Role of Cardiac Energetics in Aortic Stenosis Disease Progression: Identifying the High-risk Metabolic Phenotype.

BACKGROUND: Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability. METHODS: We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging. RESULTS: Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles (Q2, 1.50 [1.21-1.71] versus Q1, 1.64 [1.53-1.94]) with a progressive decline with increasing disease severity (Q4, 1.48 [1.18-1.70]; P=0.02). Myocardial triglyceride content levels were overall higher in all the quartiles with a significant increase seen across the AV pressure gradient quartiles (Q2, 1.36 [0.86-1.98] versus Q1, 1.03 [0.81-1.56]; P=0.034). While all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment (r=0.219; P=0.03). Phosphocreatine/adenosine triphosphate was not only an independent predictor of LV wall thickness (r=-0.20; P=0.04) but also strongly associated with myocardial fibrosis (r=-0.24; P=0.03), suggesting that metabolic changes play a role in disease progression. The metabolic and functional parameters showed comparable results when graded by clinical severity of AS. CONCLUSIONS: A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression.

Repurposing the ß3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial.

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The ß3-adrenergic receptors (ß3ARs) may represent a new target, as their activation attenuates LV remodeling. Objective: To determine whether activation of ß3ARs by repurposing a ß3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF. Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022. Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months. Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication. Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial. Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03332212.

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry.

BACKGROUND: Abnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy. OBJECTIVES: The goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR). METHODS: The study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables. RESULTS: Abnormal median GLS (> -11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m2 vs 75.1 ± 19.7 g/m2; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro-B-type natriuretic peptide and troponin levels. CONCLUSIONS: Abnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.

Insights Into the Metabolic Aspects of Aortic Stenosis With the Use of Magnetic Resonance Imaging.

Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.

Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects.

Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.

Right ventricular function declines prior to left ventricular ejection fraction in hypertrophic cardiomyopathy.

BACKGROUND: The right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were to assess RV function in HCM, changes over time, and association with clinical outcomes. METHODS: Two hundred and ninety HCM patients with preserved LV ejection fraction (LVEF ≥ 55%) and 30 age- and sex-matched controls underwent cardiovascular magnetic resonance (CMR). All patients were followed up for clinical events for a median duration of 4.4 years. Sixty-three patients had a follow-up CMR undertaken at a median interval of 5.4 years. Main study measures and outcomes were RV function (RV ejection fraction (RVEF) and RV strain) at baseline, temporal changes in RV function over time and prognostic value of RV dysfunction for predicting cardiovascular outcomes in HCM. RESULTS: When compared to controls, HCM patients exhibited lower RV and LV peak global longitudinal systolic strains on feature-tracking analysis of cine images, while RVEF and LVEF were within the normal range. On follow-up CMR, both RV and LV strain parameters decreased over time. RVEF decreased at follow-up (65 ± 7% to 62 ± 7%, P < 0.001) but the change in LVEF was not significant (68 ± 10% to 66 ± 8%, P = 0.30). On clinical follow up, reduced RVEF was an independent predictor of non-sustained ventricular tachycardia (NSVT) [HR 1.10 (95% CI 1.06-1.15), P < 0.001] and composite cardiovascular events (NSVT, stroke, heart failure hospitalisation and cardiovascular death) [HR 1.07 (95% CI 1.03-1.10), P < 0.001]. RV longitudinal strain was an independent predictor of NSVT [HR 1.05 (95% CI 1.01-1.09), P = 0.029]. Patients with RVEF < 55% showed an increased risk of NSVT and composite cardiovascular events. In contrast, LVEF and LV global longitudinal strain were not predictive of such events on multivariable analysis. CONCLUSIONS: In HCM, RV function, including RV strain, and LV strain decrease over time despite preserved LVEF. Reduction in RV but not LV function is associated with adverse cardiovascular outcomes. Assessing RV function in early HCM disease might have a role in risk stratification to prevent future cardiovascular events.

Symptom Persistence Despite Improvement in Cardiopulmonary Health - Insights from longitudinal CMR, CPET and lung function testing post-COVID-19.

BACKGROUND: The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. METHODS: Fifty-eight patients and thirty matched controls (single visit), recruited between 14th March - 25th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. FINDINGS: At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O2) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m2, P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O2, although better, were abnormal in patients versus controls. 31% had reduced pV̇O2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. INTERPRETATION: In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. FUNDING: The authors' work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

Incremental value of left atrial booster and reservoir strain in predicting atrial fibrillation in patients with hypertrophic cardiomyopathy: a cardiovascular magnetic resonance study.

BACKGROUND: Left atrial (LA) size and function are known predictors of new onset atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients. Components of LA deformation including reservoir, conduit, and booster function provide additional information on atrial mechanics. Whether or not LA deformation can augment our ability to predict the risk of new onset AF in HCM patients beyond standard measurements is unknown. METHODS: We assessed LA size, function, and deformation on cardiovascular magnetic resonance (CMR) in 238 genotyped HCM patients and compared this with twenty age, sex, blood pressure and body mass index matched control subjects. We further evaluated the determinants of new onset AF in HCM patients. RESULTS: Compared to control subjects, HCM patients had higher LA antero-posterior diameter, lower LA ejection fraction and lower LA reservoir (19.9 [17.1, 22.2], 21.6 [19.9, 22.9], P = 0.047) and conduit strain (10.6 ± 4.4, 13.7 ± 3.3, P = 0.002). LA booster strain did not differ between healthy controls and HCM patients, but HCM patients who developed new onset AF (n = 33) had lower booster strain (7.6 ± 3.3, 9.5 ± 3.0, P = 0.001) than those that did not (n = 205). In separate multivariate models, age, LA ejection fraction, and LA booster and reservoir strain were each independent determinants of AF. Age ≥ 55 years was the strongest determinant (HR 6.62, 95% CI 2.79-15.70), followed by LA booster strain ≤ 8% (HR 3.69, 95% CI 1.81-7.52) and LA reservoir strain ≤ 18% (HR 2.56, 95% CI 1.24-5.27). Conventional markers of HCM phenotypic severity, age and sudden death risk factors were associated with LA strain components. CONCLUSIONS: LA strain components are impaired in HCM and, together with age, independently predicted the risk of new onset AF. Increasing age and phenotypic severity were associated with LA strain abnormalities. Our findings suggest that the routine assessment of LA strain components and consideration of age could augment LA size in predicting risk of AF, and potentially guide prophylactic anticoagulation use in HCM.

Predictors of Major Atrial Fibrillation Endpoints in the National Heart, Lung, and Blood Institute HCMR.

OBJECTIVES: This study sought to identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy. BACKGROUND: Atrial fibrillation (AF) is a common morbidity associated with hypertrophic cardiomyopathy (HCM). The HCMR (Hypertrophic Cardiomyopathy Registry) trial is a prospective natural history study of 2,755 patients with HCM with comprehensive phenotyping. METHODS: All patients received yearly telephone follow-up. Major AF endpoints were defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF. Penalized regression via elastic-net methodology identified the most important predictors of major AF endpoints from 46 variables. This was applied to 10 datasets, and the variables were ranked. Predictors that appeared in all 10 sets were then used in a Cox model for competing risks and analyzed as time to first event. RESULTS: Data from 2,631 (95.5%) patients were available for analysis after exclusions. A total of 127 major AF endpoints events occurred in 96 patients over 33.3 ± 12.4 months. In the final model, age, body mass index (BMI), left atrial (LA) volume index, LA contractile percent (active contraction), moderate or severe mitral regurgitation (MR), and history of arrhythmia the most important. BMI, LA volume index, and LA contractile percent were age-dependent. Obesity was a stronger risk factor in younger patients. Increased LA volume, reduced LA contractile percent, and moderate or severe MR put middle-aged and older adult patients at increased risk. CONCLUSIONS: The major predictors of major AF endpoints in HCM include older age, high BMI, moderate or severe MR, history of arrhythmia, increased LA volume, and reduced LA contractile percent. Prospective testing of a risk score based on these parameters may be warranted.

Design and rationale of the EMPA-VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure.

AIMS: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS. CONCLUSIONS: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

BACKGROUND: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans. METHOD: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study. CONCLUSION: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.

BACKGROUND: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. METHODS: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. FINDINGS: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p<0.0001 to 0.044). INTERPRETATION: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. FUNDING: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

COVID-19 and Major Organ Thromboembolism: Manifestations in Neurovascular and Cardiovascular Systems.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous thromboembolism in COVID-19 and articles on previous pandemics with respect to thromboembolism and compared the similarities and differences between them. The presence of thrombosis in multiple organ systems points to thromboembolism being an integral component in the pathogenesis of this disease. Thromboembolism is likely to be the main player in the morbidity and mortality of COVID -19 in which the pulmonary system is most severely affected. We also hypothesize that D-dimer values could be used as an early marker for prognostication of disease as it has been seen to be raised even in the pre-symptomatic stage. This further strengthens the notion that thromboembolism prevention is necessary. We also examined literature on the neurovascular and cardiovascular systems, as the manifestation of thromboembolic phenomenon in these two systems varied, suggesting different pathophysiology of damage. Further research into the role of thromboembolism in COVID-19 is important to advance the understanding of the virus, its effects and to tailor treatment accordingly to prevent further casualties from this pandemic.