Design and rationale for a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy (OVOID) trial: study protocol for a randomized controlled trial

Background Dilated cardiomyopathy (DCMP) is characterized by ventricular chamber enlargement and systolic dysfunction which may cause heart failure. Patients with DCMP have overactivation of the renin-angiotensin-aldosterone systems, which can also adversely affect myocardial metabolism in heart failure. The impairment of myocardial metabolism can contribute to the progression of left ventricular remodeling and contractile dysfunction in heart failure. Although angiotensin II receptor blockers (ARBs) have been used to treat patients with DCMP, there has been no direct comparison of the efficacy of these agents. The objective of this study is to compare the effects of olmesartan and valsartan on myocardial metabolism in patients with DCMP. Methods/design The OVOID study (a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy) is designed as a non-blinded, open-label, parallel-group, prospective, randomized, controlled, multicenter clinical trial. A total of 40 DCMP patients aged between 20 and 85 years will be randomly allocated into the olmesartan or the valsartan group. 18F-fluoro-2-deoxyglucose (FDG) cardiac positron emission tomography (PET) will be performed at baseline and six months after receiving the study agent. The primary endpoint is myocardial glucose consumption per square meter, measured using 18F-FDG PET 6 months after receiving the study agent. Discussion The purpose of this trial is to compare the efficacy between olmesartan and valsartan in improving myocardial metabolism in DCMP patients. This will be the first randomized comparative study investigating the differential effects of ARBs on heart failure. Trial registration ClinicalTrials.govNCT04174456. Registered on 18 November 2019

Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a life-threatening form of heart disease that is typically characterized by progressive thinning of the ventricular walls, chamber dilation, and systolic dysfunction. Multiple mutations in the gene encoding filamin C (FLNC), an actin-binding cytoskeletal protein in cardiomyocytes, have been found in patients with DCM. However, the mechanisms that lead to contractile impairment and DCM in patients with FLNC variants are poorly understood. To determine how FLNC regulates systolic force transmission and DCM remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO) model to produce a rapid onset of DCM in adult mice. Loss of FLNC reduced systolic force development in single cardiomyocytes and isolated papillary muscles but did not affect twitch kinetics or calcium transients. Electron and immunofluorescence microscopy showed significant defects in Z-disk alignment in icKO mice and altered myofilament lattice geometry. Moreover, a loss of FLNC induces a softening myocyte cortex and structural adaptations at the subcellular level that contribute to disrupted longitudinal force production during contraction. Spatially explicit computational models showed that these structural defects could be explained by a loss of inter-myofibril elastic coupling at the Z-disk. Our work identifies FLNC as a key regulator of the multiscale ultrastructure of cardiomyocytes and therefore plays an important role in maintaining systolic mechanotransmission pathways, the dysfunction of which may be key in driving progressive DCM.

Role of open access echocardiography in detection of cardiac structural and functional abnormalities

PurposeTo evaluate the prevalence and incidence of significant structural heart disease in targeted patients with cardiac symptoms referred by general practitioners (GPs) using open access echocardiography, without prior clinical evaluation by a cardiologist.DesignData were derived from 488 subjects who underwent transthoracic echocardiography between January and April 2018. Patients were referred directly by GPs in East Berkshire, South England, through an online platform. Echocardiography was performed within 4–6 weeks of referral and all reports were assessed by a consultant cardiologist with expedited follow-up facilitated pro re nata. Results were analysed to determine the frequency of detection of structural abnormalities, particularly of the left ventricle and cardiac valves.ResultsEchocardiography was prospectively performed in consecutive subjects (50% male, mean (±SD) age 68.5±22 years; 50% female; mean (±SD) 64.6 (±19.1)). At least one abnormality likely to change management was found in 133 (27.3%) of all open access echocardiograms. Clinical heart failure with left ventricular systolic dysfunction (LVSD) and diastolic dysfunction was confirmed in 46 (9%) and 69 (14%), respectively. Of the 46 patients with LVSD, 33 were new diagnoses. Significant cardiac valve disease was found in 42 (8.6%) patients. 12 of these had known valvular disease or previous valvular surgery, and 30 were new diagnoses.ConclusionMajor structural and functional cardiac abnormalities are common in late middle-aged patients who present to GPs with cardiac symptoms and signs. Reported, unrestricted open access echocardiography enables early detection of significant cardiac pathology and timely intervention may improve cardiovascular outcomes.

PET Tracers for Imaging Cardiac Function in Cardio-oncology

Purpose of Review Successful treatment of cancer can be hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the injury to the heart is detected before the onset to irreversible cardiac impairment. The gold standard for cardiac imaging in cardio-oncology is echocardiography. Despite improvements in the application of this modality, it is not typically sensitive to sub-clinical or early-stage dysfunction. We identify in this review some emerging tracers for detecting incipient cardiotoxicity by positron emission tomography (PET). Recent Findings Vectors labeled with positron-emitting radionuclides (e.g., carbon-11, fluorine-18, gallium-68) are now available to study cardiac function, metabolism, and tissue repair in preclinical models. Many of these probes are highly sensitive to early damage, thereby potentially addressing the limitations of current imaging approaches, and show promise in preliminary clinical evaluations. Summary The overlapping pathophysiology between cardiotoxicity and heart failure significantly expands the number of imaging tools available to cardio-oncology. This is highlighted by the emergence of radiolabeled probes targeting fibroblast activation protein (FAP) for sensitive detection of dysregulated healing process that underpins adverse cardiac remodeling. The growth of PET scanner technology also creates an opportunity for a renaissance in metabolic imaging in cardio-oncology research.

Clinical Determinants and Prognosis of Left Ventricular Reverse Remodelling in Non-Ischemic Dilated Cardiomyopathy

Aims: Non-ischaemic dilated cardiomyopathy (NIDCM) is characterized by left ventricular (LV) chamber enlargement and systolic dysfunction in the absence of coronary artery disease. Left ventricular reverse remodelling (LVRR) is the ability of a dilated ventricle to restore its normal size, shape and function. We sought to determine the frequency, clinical predictors and prognostic implications of LVRR, in a cohort of heart failure (HF) patients with NIDCM. Methods: We conducted a multicentre observational, retrospective cohort study of patients with NIDCM, with prospective serial echocardiography evaluations. LVRR was defined as an increase of ≥15% in left ventricular ejection fraction (LVEF) or as a LVEF increase ≥ 10% plus reduction of LV end-systolic diameter index ≥ 20%. We used multivariable logistic regression analyses to identify the baseline clinical predictors of LVRR and evaluate the prognostic impact of LVRR. Results: LVRR was achieved in 42.5% of 527 patients with NIDCM during the first year of follow-up (median LVEF 49%, median change +22%), Alcoholic aetiology, HF duration, baseline LVEF and the absence of LBBB (plus NT-proBNP levels when in the model), were the strongest predictors of LVRR. During a median follow-up of 47 months, 134 patients died (25.4%) and 7 patients (1.3%) received a heart transplant. Patients with LVRR presented better outcomes, regardless of other clinical conditions. Conclusions: In patients with NIDCM, LVRR was frequent and was associated with improved prognosis. Major clinical predictors of LVRR were alcoholic cardiomyopathy, absence of LBBB, shorter HF duration, and lower baseline LVEF and NT-proBNP levels. Our study advocates for clinical phenotyping of non-ischaemic dilated cardiomyopathy and intense gold-standard treatment optimization of patients according to current guidelines and recommendations in specialized HF units.

Myocardial stunning in patients with coronary artery disease before and after treatment by method of coronary artery bypass grafting (own studies)

Aim of the study: Determination of quantitative radiological indicators of myocardial revascularization effectiveness in patients with coronary artery disease in the early postoperative period. Materials and methods of research: For the implementation of the clinical objectives, 62 patients with coronary artery disease, heart failure, with preserved systolic function and systolic dysfunction were examined in the early postoperative period (up to 7 days). The patients' age ranged from 40 to 79 years, the average age of the examined was 59.6 ± 8.2 years. 35 (56%) patients had HF with LV systolic dysfunction with EF of 49% or less. 27 (44%) patients had preserved systolic function - ejection fraction greater than or equal to 50%. Results: In the group before treatment, the average value ​​of MV was 69.4% CI 95% [65.3%; 73.5%], and after treatment the value of MV was 75.0% CI 95% (70.8%; 79.3%], p = 0.0000. Percentage of RFP inclusion in the anterior wall was 69.5% CI [66.2%; 72.8%] before treatment and significantly improved to 72.3% CI [69.1%; 75.4%] after treatment (p = 0.023). Lateral wall had a parameter value of 73.9% CI [70.7%; 77.1%] before treatment and improved perfusion up to 77.2% CI [74.3%; 80.2%] (p = 0.018). Parameter values for the intraventricular septum were 64.5% CI [60.7%; 68.3%] before treatment and 69% CI [65.2%; 72.8%] after treatment (p = 0.000034) and for the inferior wall those were 54.0% CI (49.7%; 58.3%] and 61.7% CI (57.9%); 65.6%] before and after treatment respectively (p = 0.000032). Conclusion: The determination of quantitative radiological parameters proposed as a result of this study is extremely important for the early postoperative period (7-10 days) for determination of stunned myocardial reserve and late stage of patients` management (1-1.5 years) for determination of hibernation reserve and final assessment of CABG effectiveness.

The role of central autonomic nervous system dysfunction in Takotsubo syndrome: a systematic review

Introduction Takotsubo syndrome (TTS), also known as stress cardiomyopathy or “broken heart” syndrome, is a mysterious condition that often mimics an acute myocardial infarction. Both are characterized by left ventricular systolic dysfunction. However, this dysfunction is reversible in the majority of TTS patients. Purpose Recent studies surprisingly demonstrated that TTS, initially perceived as a benign condition, has a long-term prognosis akin to myocardial infarction. Therefore, the health consequences and societal impact of TTS are not trivial. The pathophysiological mechanisms of TTS are not yet completely understood. In the last decade, attention has been increasingly focused on the putative role of the central nervous system in the pathogenesis of TTS. Conclusion In this review, we aim to summarize the state of the art in the field of the brain–heart axis, regional structural and functional brain abnormalities, and connectivity aberrancies in TTS.

Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload

Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

Electrocardiography Score for Left Ventricular Systolic Dysfunction in Non-ST Segment Elevation Acute Coronary Syndrome

Background: Few studies have characterized electrocardiography (ECG) patterns correlated with left ventricular (LV) systolic dysfunction in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS).Objectives: This study aims to develop ECG pattern-derived scores to predict LV systolic dysfunction in NSTE-ACS patients.Methods: A total of 466 patients with NSTE-ACS were retrospectively enrolled. LV ejection fraction (LVEF) was assessed by echocardiography within 72 h after the first triage ECG acquisition; there was no coronary intervention in between. ECG score was developed to predict LVEF < 40%. Performance of LVEF, the Global Registry of Acute Coronary Events (GRACE), Thrombolysis in Myocardial Infarction (TIMI) and ECG scores to predict 24-month all-cause mortality were analyzed. Subgroups with varying LVEF, GRACE and TIMI scores were stratified by ECG score to identify patients at high risk of mortality.Results: LVEF < 40% was present in 20% of patients. We developed the PQRST score by multivariate logistic regression, including poor R wave progression, QRS duration > 110 ms, heart rate > 100 beats per min, and ST-segment depression ≥ 1 mm in ≥ 2 contiguous leads, ranging from 0 to 6.5. The score had an area under the curve (AUC) of 0.824 in the derivation cohort and 0.899 in the validation cohort for discriminating LVEF < 40%. A PQRST score ≥ 3 could stratify high-risk patients with LVEF ≥ 40%, GRACE score > 140, or TIMI score ≥ 3 regarding 24-month all-cause mortality.Conclusions: The PQRST score could predict LVEF < 40% in NSTE-ACS patients and identify patients at high risk of mortality in the subgroups of patients with LVEF ≥ 40%, GRACE score > 140 or TIMI score ≥ 3.