Right Heart Remodeling in Patients with End-Stage Alcoholic Liver Cirrhosis: Speckle Tracking Point of View

BACKGROUND: Data regarding cardiac remodeling in patients with alcoholic liver cirrhosis are scarce. We sought to investigate right atrial (RA) and right ventricular (RV) structure, function, and mechanics in patients with alcoholic liver cirrhosis. METHODS: This retrospective cross-sectional investigation included 67 end-stage cirrhotic patients, who were referred for evaluation for liver transplantation and 36 healthy controls. All participants underwent echocardiographic examination including strain analysis, which was performed offline. RESULTS: RV basal diameter and RV thickness were significantly higher in patients with cirrhosis. Conventional parameters of the RV systolic function were similar between the observed groups. Global, endocardial, and epicardial RV longitudinal strains were significantly lower in patients with cirrhosis. Active RA function was significantly higher in cirrhotic patients than in controls. The RA reservoir and conduit strains were significantly lower in cirrhotic patients, while there was no difference in the RA contractile strain. Early diastolic and systolic RA strain rates were significantly lower in cirrhotic patients than in controls, whereas there was no difference in the RA late diastolic strain rate between the two groups. Transaminases and bilirubin correlated negatively with RV global longitudinal strain and RV-free wall strain in patients with end-stage liver cirrhosis. The Model for End-stage Liver Disease (MELD) score, predictor of 3-month mortality, correlated with parameters of RV structure and systolic function, and RA active function in patients with end-stage liver cirrhosis. CONCLUSIONS: RA and RV remodeling is present in patients with end-stage liver cirrhosis even though RV systolic function is preserved. Liver enzymes, bilirubin, and the MELD score correlated with RV and RA remodeling

K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 μM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 μM; developed tension −9.8 ± 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 μM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 μM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca2+]e, K201 (0.3 μM) treatment significantly improved systolic function [developed tension +27 ± 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses fr symptomatic heart failure

AIMS: We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients. METHODS AND RESULTS: One hundred and sixty-four subjects with ejection fraction (EF) < 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3 +/- 6.7% vs. 29.8 +/- 7.8%), VO2,peak (14.1 +/- 3.0 vs. 13.6 +/- 2.7 mL/kg/min), and MLWHFQ (38.9 +/- 27.4 vs. 36.5 +/- 27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40 +/- 3.0 vs. 0.37 +/- 3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (-0.86 +/- 3.06 mL/kg/min) and increased in patients switched to active treatment (0.16 +/- 2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06 +/- 15.33 vs. -9.70 +/- 16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70 +/- 16.57), and decreased further in patients switched to active treatment (-0.70 +/- 15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P = 0.03 for each parameter). CONCLUSION: In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period

Periodontitis and Cardiovascular Diseases. Consensus Report

Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and Methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and Conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices

Periodontitis and Cardiovascular Diseases. Consensus Report.

Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and Methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and Conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices

Disease overarching mechanisms that explain and predict outcome of patients with high cardiovascular risk: rationale and design of the Berlin Long-term Observation of vascular events (BeLOVE) study

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of premature death worldwide. Effective and individualized treatment requires exact knowledge about both risk factors and risk estimation. Most evidence for risk prediction currently comes from population-based studies on first incident cardiovascular events. In contrast, little is known about the relevance of risk factors for the outcome of patients with established CVD or those who are at high risk of CVD, including patients with type 2 diabetes. In addition, most studies focus on individual diseases, whereas less is known about disease overarching risk factors and cross-over risk. AIM: The aim of BeLOVE is to improve short- and long-term prediction and mechanistic understanding of cardiovascular disease progression and outcomes in very high-risk patients, both in the acute as well as in the chronic phase, in order to provide the basis for improved, individualized management. STUDY DESIGN: BeLOVE is an observational prospective cohort study of patients of both sexes aged >18 in selected Berlin hospitals, who have a high risk of future cardiovascular events, including patients with a history of acute coronary syndrome (ACS), acute stroke (AS), acute heart failure (AHF), acute kidney injury (AKI) or type 2 diabetes with manifest target-organ damage. BeLOVE includes 2 subcohorts: The acute subcohort includes 6500 patients with ACS, AS, AHF, or AKI within 2-8 days after their qualifying event, who undergo a structured interview about medical history as well as blood sample collection. The chronic subcohort includes 6000 patients with ACS, AS, AHF, or AKI 90 days after event, and patients with type 2 diabetes (T2DM) and target-organ damage. These patients undergo a 6-8 hour deep phenotyping program, including detailed clinical phenotyping from a cardiological, neurological and metabolic perspective, questionnaires including patient-reported outcome measures (PROMs)as well as magnetic resonance imaging. Several biological samples are collected (i.e. blood, urine, saliva, stool) with blood samples collected in a fasting state, as well as after a metabolic challenge (either nutritional or cardiopulmonary exercise stress test). Ascertainment of major adverse cardiovascular events (MACE) will be performed in all patients using a combination of active and passive follow up procedures, such as on-site visits (if applicable), telephone interviews, review of medical charts, and links to local health authorities. Additional phenotyping visits are planned at 2, 5 and 10 years after inclusion into the chronic subcohort. FUTURE PERSPECTIVE: BeLOVE provides a unique opportunity to study both the short- and long-term disease course of patients at high cardiovascular risk through innovative and extensive deep phenotyping. Moreover, the unique study design provides opportunities for acute and post-acute inclusion and allows us to derive two non-nested yet overlapping sub-cohorts, tailored for upcoming research questions. Thereby, we aim to study disease overarching research questions, to understand crossover risk, and to find similarities and differences between clinical phenotypes of patients at high cardiovascular risk

A multi-vendor, multi-center study on reproducibility and comparability of fast strain-encoded cardiovascular magnetic resonance imaging

Myocardial strain is a convenient parameter to quantify left ventricular (LV) function. Fast strain-encoding (fSENC) enables the acquisition of cardiovascular magnetic resonance images for strain-measurement within a few heartbeats during free-breathing. It is necessary to analyze inter-vendor agreement of techniques to determine strain, such as fSENC, in order to compare existing studies and plan multi-center studies. Therefore, the aim of this study was to investigate inter-vendor agreement and test-retest reproducibility of fSENC for three major MRI-vendors. fSENC-images were acquired three times in the same group of 15 healthy volunteers using 3 Tesla scanners from three different vendors: at the German Heart Institute Berlin, the Charité University Medicine Berlin-Campus Buch and the Theresien-Hospital Mannheim. Volunteers were scanned using the same imaging protocol composed of two fSENC-acquisitions, a 15-min break and another two fSENC-acquisitions. LV global longitudinal and circumferential strain (GLS, GCS) were analyzed by a trained observer (Myostrain 5.0, Myocardial Solutions) and for nine volunteers repeatedly by another observer. Inter-vendor agreement was determined using Bland-Altman analysis. Test-retest reproducibility and intra- and inter-observer reproducibility were analyzed using intraclass correlation coefficient (ICC) and coefficients of variation (CoV). Inter-vendor agreement between all three sites was good for GLS and GCS, with biases of 0.01-1.88%. Test-retest reproducibility of scans before and after the break was high, shown by ICC- and CoV values of 0.63-0.97 and 3-9% for GLS and 0.69-0.82 and 4-7% for GCS, respectively. Intra- and inter-observer reproducibility were excellent for both parameters (ICC of 0.77-0.99, CoV of 2-5%). This trial demonstrates good inter-vendor agreement and test-retest reproducibility of GLS and GCS measurements, acquired at three different scanners from three different vendors using fSENC. The results indicate that it is necessary to account for a possible bias (< 2%) when comparing strain measurements of different scanners. Technical differences between scanners, which impact inter-vendor agreement, should be further analyzed and minimized.DRKS Registration Number: 00013253. Universal Trial Number (UTN): U1111-1207-5874

Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart

Heart failure (HF) is characterized by molecular and cellular defects which jointly contribute to decreased cardiac pump function. During the development of the initial cardiac damage which leads to HF, adaptive responses activate physiological countermeasures to overcome depressed cardiac function and to maintain blood supply to vital organs in demand of nutrients. However, during the chronic course of most HF syndromes, these compensatory mechanisms are sustained beyond months and contribute to progressive maladaptive remodeling of the heart which is associated with a worse outcome. Of pathophysiological significance are mechanisms which directly control cardiac contractile function including ion- and receptor-mediated intracellular signaling pathways. Importantly, signaling cascades of stress adaptation such as intracellular calcium (Ca2+) and 3′-5′-cyclic adenosine monophosphate (cAMP) become dysregulated in HF directly contributing to adverse cardiac remodeling and depression of systolic and diastolic function. Here, we provide an update about Ca2+ and cAMP dependent signaling changes in HF, how these changes affect cardiac function, and novel therapeutic strategies which directly address the signaling defects

Lipid metabolite biomarkers in cardiovascular disease: discovery and biomechanism translation from human studies

Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. Metabolomic studies in humans have supported previous findings into the pathomechanisms of CVD, namely atherosclerosis, apoptosis, inflammation, oxidative stress, and insulin resistance. The most widely studied classes of lipid metabolite biomarkers in CVD are phospholipids, sphingolipids/ceramides, glycolipids, cholesterol esters, fatty acids, and acylcarnitines. Technological advancements have enabled novel strategies to discover individual biomarkers or panels that may aid in the diagnosis and prognosis of CVD, with sphingolipids/ceramides as the most promising class of biomarkers thus far. In this review, application of metabolomic profiling for biomarker discovery to aid in the diagnosis and prognosis of CVD as well as metabolic abnormalities in CVD will be discussed with particular emphasis on lipid metabolites