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.

Prognostic Value of RV Abnormalities on CMR in Patients With Known or Suspected Cardiac Sarcoidosis.

BACKGROUND: Left ventricular abnormalities in cardiac sarcoidosis (CS) are associated with adverse cardiovascular events, whereas the prognostic value of right ventricular (RV) involvement found on cardiac magnetic resonance is unclear. OBJECTIVES: This study aimed to systematically assess the prognostic value of right ventricular ejection fraction (RVEF) and RV late gadolinium enhancement (LGE) in known or suspected CS. METHODS: This study was prospectively registered in PROSPERO (CRD42022302579). PubMed, Embase, and Web of Science were searched to identify studies that evaluated the association between RVEF or RV LGE on clinical outcomes in CS. A composite endpoint of all-cause death, cardiovascular events, or sudden cardiac death (SCD) was used. A meta-analysis was performed to determine the pooled risk ratio (RR) for these adverse events. The calculated sensitivity, specificity, and area under the curve with 95% CIs were weighted and summarized. RESULTS: Eight studies including a total of 899 patients with a mean follow-up duration of 3.2 ± 0.7 years were included. The pooled RR of RV systolic dysfunction was 3.1 (95% CI: 1.7-5.5; P < 0.01) for composite events and 3.0 (95% CI: 1.3-7.0; P < 0.01) for SCD events. In addition, CS patients with RV LGE had a significant risk for composite events (RR: 4.8 [95% CI: 2.4-9.6]; P < 0.01) and a higher risk for SCD (RR: 9.5 [95% CI: 4.4-20.5]; P < 0.01) than patients without RV LGE. Furthermore, the pooled area under the curve, sensitivity, and specificity of RV LGE for identifying patients with CS who were at highest SCD risk were 0.8 (95% CI: 0.8-0.9), 69% (95% CI: 50%-84%), and 90% (95% CI: 70%-97%), respectively. CONCLUSIONS: In patients with known or suspected CS, RVEF and RV LGE were both associated with adverse events. Furthermore, RV LGE shows good discrimination in identifying CS patients at high risk of SCD.

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.

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).

Research priorities in advanced heart failure: James Lind alliance priority setting partnership.

OBJECTIVE: To determine research priorities in advanced heart failure (HF) for patients, carers and healthcare professionals. METHODS: Priority setting partnership using the systematic James Lind Alliance method for ranking and setting research priorities. An initial open survey of patients, carers and healthcare professionals identified respondents' questions, which were categorised to produce a list of summary research questions; questions already answered in existing literature were removed. In a second survey of patients, carers and healthcare professionals, respondents ranked the summary research questions in order of priority. The top 25 unanswered research priorities were then considered at a face-to-face workshop using nominal group technique to agree on a 'top 10'. RESULTS: 192 respondents submitted 489 responses each containing one or more research uncertainty. Out-of-scope questions (35) were removed, and collating the responses produced 80 summary questions. Questions already answered in the literature (15) were removed. In the second survey, 65 questions were ranked by 128 respondents. The top 10 priorities were developed at a consensus meeting of stakeholders and included a focus on quality of life, psychological support, the impact on carers, role of the charity sector and managing prognostic uncertainty. Ranked priorities by physicians and patients were remarkably divergent. CONCLUSIONS: Engaging stakeholders in setting research priorities led to a novel set of research questions that might not have otherwise been considered. These priorities can be used by researchers and funders to direct future research towards the areas which matter most to people living with advanced HF.

Prevalence of 18F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS AND RESULTS: We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ±â€¯13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. CONCLUSION: In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

Diagnostic accuracy and prognostic value of simultaneous hybrid 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in cardiac sarcoidosis.

Aims: Cardiac death is the leading cause of mortality in patients with sarcoidosis, yet cardiac involvement often remains undetected. Cardiovascular magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) have been used to diagnose cardiac sarcoidosis (CS) yet never simultaneously in a cohort. This study sought to assess the diagnostic and prognostic utility of simultaneous hybrid cardiac PET/MR. Methods and results: Fifty-one consecutive patients with suspected CS (age 50 ± 13 years, 31 males) underwent simultaneous PET/MR following a high-fat/low-carbohydrate diet and 12-h fast. Blinded image analysis of FDG uptake and late gadolinium enhancement (LGE) was performed using the American Heart Association (AHA) 16-segment model. The sensitivity and specificity of PET/MR for diagnosing CS was estimated using the Japanese Ministry of Health and Welfare guidelines. The primary endpoint was a composite of death, aborted sudden cardiac death, sustained ventricular arrhythmia, complete heart block, and hospital admission with decompensated heart failure. The secondary endpoints were a fall in left ventricular ejection fraction (LVEF) >10%, non-sustained ventricular tachycardia and other cardiac-related hospital admission. The prevalence of CS was 65% (n = 33). The sensitivity of PET and CMR alone for detecting CS was 0.85 and 0.82, respectively. Hybrid PET/MR was superior for detecting CS with sensitivity, specificity, positive, and negative predictive values of 0.94, 0.44, 0.76, and 0.80, respectively. There was poor inter-modality agreement for the location of cardiac abnormalities (k = 0.02). Over the median follow-up of 2.2 years, there were 18 (35%) adverse events. Cardiac RV PET abnormalities and presence of LGE were independent predictors of adverse events. Abnormalities found on both PET and magnetic resonance imaging was the strongest predictor of major adverse cardiac events. Conclusion: Simultaneous PET/MR is an accurate method for diagnosing CS. FDG-PET and CMR combined offers complementary information on disease pathophysiology. The presence of LGE and FDG uptake on PET/MR identifies patients at higher risk of adverse events. PET and CMR should therefore be considered in the assessment of disease presence, stage, and prognosis in CS.

Heart failure - what the general physician needs to know.

The British Society of Heart Failure (BSH) meetings highlight the latest advancements within the field of heart failure (HF) and provide education for training and revalidation for cardiologists and general physicians. This article reviews take-home messages from the 7th BSH HF revalidation and training meeting. It emphasises what every physician needs to know about the latest acute HF guidelines, diagnostics in HF, management strategies (including pharmacotherapeutics and device therapy), and when to consider referring to a transplant centre for mechanical circulatory support or transplantation. It describes the practical challenges faced and provides clinicians with a framework to assist with service development and commissioning of resources to deliver optimal, integrated services that meet the ever-advancing needs of our HF communities.

A high frequency of viral agents yet absence of Borrelia burgdorferi is seen within the myocardium of subjects with normal left ventricular systolic function: an electron microscopy study.

A wide range of viral agents is associated with the development of acute myocarditis and its possible chronic sequela, dilated cardiomyopathy (DCM). There is also increasing evidence that Borrelia burgdorferi (Bb) is associated with DCM in endemic regions for Bb infection. This study sought to use electron microscopy to prospectively analyze the presence of viruses and Bb within the myocardium of 40 subjects with preserved left ventricular (LV) ejection fraction and 40 patients with new-onset unexplained DCM during the same time period. Virus particles were found within the myocardium of 23 subjects (58%) of both cohorts studied, yet there was no statistically significant difference in virus family presence between those with DCM versus those with preserved LV systolic function. In contrast, Bb was detected only in those subjects with DCM (0 versus 5 subjects; p ˂ 0.05). Polymerase chain reaction was performed on samples from patients who were positive for Bb according to electron microscopy, and Bb was confirmed in 4 out of 5 individuals. Our results demonstrate that the prevalence of viral particles does not differ between subjects with preserved LV systolic function versus those with DCM and therefore suggests that the mere presence of a viral agent within the myocardium is not sufficient to establish a clear link with the development of DCM. In contrast, the presence of Bb was found only within myocardial samples of patients with DCM; this finding supports the idea of a causal relationship between Bb infection and DCM development.

Improving the diagnostic accuracy for detecting cardiac sarcoidosis.

Cardiac sarcoid is a potentially fatal condition that presents with a wide range of clinical manifestations including conduction abnormalities, tachyarrhythmias, congestive heart failure, cardiomyopathy and sudden cardiac death. Small observational registries and non-comparative studies have described clinical evidence of cardiac involvement in 5% of patients with systemic sarcoid, yet autopsy studies suggest prevalence as high as 79%. This suggests that cardiac sarcoidosis (CS) is underdiagnosed in everyday clinical practice. The scarcity of data and lack of consensus on the most appropriate methods for detecting, monitoring and treating CS presents a significant diagnostic and therapeutic challenge. This review explores the potential impact of novel strategies, including multimodality imaging, on the diagnostic accuracy for detecting CS and treatment.

Atlas of the clinical genetics of human dilated cardiomyopathy.

AIM: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSION: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

Application of current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy in every day clinical practice.

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac muscle disease associated with sudden cardiac death, ventricular arrhythmias and cardiac failure. It is primarily a disease of the desmosome, with mutations in desmosomal protein genes identified in approximately 50% of affected individuals. Mutations result in fibrofatty replacement of cardiomyocytes, aneurysm formation and dilatation of the right and often the left ventricle. The clinical diagnosis of ARVC is based upon complex criteria that consider pathology, genetics and clinical presentation. This review describes the application of the revised criteria for ARVC in everyday practice and illustrates the requirement for continued modification to improve their sensitivity and specificity.