Adverse Left Ventricle Remodeling Research Articles

Mitral regurgitation increases systolic strains in remote zone and worsens left ventricular dyssynchrony in a swine model of ischemic cardiomyopathy.

Ischemic mitral regurgitation (IMR) imposes volume overload on the left ventricle (LV), accelerating adverse LV remodeling. In this study, we sought to investigate the impact of volume overload due to IMR on regional myocardial contractile mechanics. Ten Yorkshire swine were induced with myocardial infarction (MI) by occluding the left circumflex coronary artery (LCx). Cardiac MRI was performed at baseline (BL) and 2.5 months (2.5M) post-MI. IMR was quantified with epicardial echocardiography 3 months post-MI. The animals were then assigned to 2 groups: no/mild MR (nmMR, n = 4) and moderate/severe MR (msMR, n = 6). MRI images were analyzed to assess infarction size, end-diastolic and end-systolic volume (EDV and ESV, respectively), ejection fraction (EF), longitudinal strain (LS), circumferential strain (CS), and systolic dyssynchrony index (SDI). The myocardial region was divided into infarction, border, and remote zones based on the LCx-supplied region. There was no difference in the infarction size. Group-wise comparison of LS and CS between BL and 2.5M demonstrated that LS and CS in the infarction zone and the border zone decreased at 2.5M in both groups. However, LS and CS in the remote zone were elevated only in the msMR group (LS: -9.81 ± 3.96 vs. -12.58 ± 5.07, p < 0.01; CS; -12.78 ± 3.81 vs. -16.09 ± 3.33, p < 0.01) at 2.5M compared to BL. The SDI of CS was significantly elevated in the msMR group (0.1255 vs. 0.0974, p = 0.015) at 2.5M compared to BL. Elevated LS and CS in the remote zone were observed in moderate/severe MR and ventricular dyssynchrony. These elevated cardiac strains, coupled with ventricular dyssynchrony, may contribute to the progression of MR, thereby accelerating heart failure.

Combined physical training protects the left ventricle from structural and functional damages in experimental pulmonary arterial hypertension

BackgroundUnder the adverse remodeling of the right ventricle and interventricular septum in pulmonary arterial hypertension (PAH) the left ventricle (LV) dynamics is impaired. Despite the benefits of combined aerobic and resistance physical trainings to individuals with PAH, its impact on the LV is not fully understood.ObjectiveTo test whether moderate-intensity combined physical training performed during the development of PAH induced by MCT in rats is beneficial to the LV’s structure and function.MethodsMale Wistar rats were divided into two groups: Sedentary Hypertensive Survival (SHS, n = 7); and Exercise Hypertensive Survival (EHS, n = 7) to test survival. To investigate the effects of combined physical training, another group of rats were divided into three groups: Sedentary Control (SC, n = 7); Sedentary Hypertensive (SH, n = 7); and Exercise Hypertensive (EH, n = 7). PAH was induced through an intraperitoneal injection of MCT (60 mg/kg). Echocardiographic evaluations were conducted on the 22nd day after MCT administration. Animals in the EHS and EH groups participated in a combined physical training program, alternating aerobic (treadmill running: 50 min, 60% maximum running speed) and resistance (ladder climbing: 15 climbs with 1 min interval, 60% maximum carrying load) exercises, one session/day, 5 days/week for approximately 4 weeks.ResultsThe physical training increased survival and tolerance to aerobic (i.e., maximum running speed) and resistance (i.e., maximum carrying load) exertions and prevented reductions in ejection fraction and fractional shortening. In addition, the physical training mitigated oxidative stress (i.e., CAT, SOD and MDA) and inhibited adverse LV remodeling (i.e., Collagen, extracellular matrix, and cell dimensions). Moreover, the physical training preserved the amplitude and velocity of contraction and hindered the reductions in the amplitude and velocity of the intracellular Ca2+ transient in LV single myocytes.ConclusionModerate-intensity combined physical training performed during the development of MCT-induced PAH in rats protects their LV from damages to its structure and function and hence increases their tolerance to physical exertion and prolongs their survival.

Association of Mild-to-Moderate Aortic Regurgitation With Outcomes in Heart Failure With Preserved Ejection Fraction

ObjectiveTo assess aortic regurgitation (AR) prevalence, its hemodynamic effect, and long-term prognostic implications in patients admitted with de novo or worsened heart failure with preserved ejection fraction (HFpEF). MethodsConsecutive patients hospitalized with de novo or worsened HFpEF between 2014 and 2020 were enrolled. Patients with more than moderate aortic and/or mitral valve disease were excluded. Based on the presence and degree of AR, patients were divided into those without AR, those with mild, and those with moderate AR. Data on cardiovascular death, heart failure (HF) rehospitalization, and their composite (major adverse cardiovascular events) were collected. ResultsThe final study population consisted of 458 HFpEF patients: 156 (34.1%) with mild-AR, 153 (33.4%) with moderate-AR, and the remaining 149 (32.5%) with no AR. Mild-to-moderate AR patients were older, with larger left atrium–left ventricle (LV) volumes, greater LV mass index, higher filling pressure, and prevalence of diastolic dysfunction compared with the no-AR group (all P<.05). During 5-year follow-up, 113 patients died of cardiovascular causes, 124 patients were rehospitalized for HF, whereas 196 experienced the composite endpoint. Mild-to-moderate AR was identified as an independent predictor of all-cause death (HR, 1.62; 95% CI, 1.14 to 1.58; P=.04) and major adverse cardiovascular event occurrence (HR, 1.48; 95% CI, 1.05 to 2.09; P=.02). A total of 126 (35.5%) of 355 patients showed progression of AR at follow-up echocardiography. ConclusionMild-to-moderate AR is common among patients hospitalized for HFpEF. It is associated with adverse LV remodeling and worse long-term outcomes. These findings warrant further prospective studies addressing the importance of AR in prognostic stratification and exploring therapeutic strategies to mitigate its hemodynamic effect on HF.

Serum levels of GM-CSF, CCL11, CCL22 and TRAIL in patients with primary ST-segment elevation myocardial infarction and post-infarction heart remodeling

Aim: To study serum values of GM-GSF, CCL22, CCL11 and TRAIL in patients with primary ST-segment elevation myocardial infarction (STEMI) in early and late post-MI period and their relationship with heart remodeling in 12 months after acute myocardial infarction (MI) diagnosis.Materials and Methods. Eighty four patients with new-onset STEMI were enrolled in the study. Echocardiography was done on day 1 and in 12 months MI. Serum levels of GM-GSF, CCL22, CCL11, TRAIL and C-reactive protein (CRP), NT-pro-NP, troponin I, CK-MV were assessed on days 1 (T1), 7 (T2), in 6 (T3) and 12 months (T4). Patients with adverse left ventricle (LV) remodeling were classified as group 1, and patients with adaptive LV remodeling were classified as group 2 in 12 month of follow-up.Results. 64 patients underwent a 12-month follow-up, of which adverse LV remodeling developed in. Patients from group 1 showed significantly higher levels of markers of myocardial necrosis (CPK MB, troponin I) on the first day of MI and NT-proBNP at all points of the investigation than in patients from 2nd group, p &lt; 0.05. Analysis of the chemokines revealed, that the serum concentration of GM-CSF at the points Т2, Т3, T4 and TRAIL at points T1, T4 were significantly higher, and CCL22 at all of the study and CCL11 at T1, T2, T3 significantly lower than patients from group 2, p &lt; 0,05. According of multiple linear regression predictors of LV dilatation by the 12th month of MI were the serum levels of GM-CSF (p = 0,004), NT-pro-BNP (p = 0,009) on the 7th day of MI and the age of patients (p = 0,005).Conclusions. In patients with adverse LV remodeling have higher levels of circulating GM-GSF, TRAIL and lower levels CCL11, CCL22 in early and late post-MI period. Among the studied inflammatory biomarkers, only the level of GM-CSF on the 7th day of STEMI showed an independent relationship with late adverse LV remodeling.

THE ROLE OF BIOMARKER MACROPHAGE MIGRATION INHIBITORY FACTOR IN CARDIAC REMODELING PREDICTION IN PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION.

The aim: To estimate the role of macrophage migration inhibitory factor and soluble ST2 in predicting the left ventricle remodeling six months after ST-segment elevation myocardial infarction. Materials and methods: The study involved 134 ST-segment elevation myocardial infarction patients. Occurrence of post-percutaneous coronary (PCI) intervention epicardial blood flow of TIMI <3 or myocardial blush grade 0-1 along with ST resolution <70% within 2 hours after PCI was qualified as the no-reflow condition. Left ventricle remodeling was defined after 6-months as an increase in left ventricle end-diastolic volume and/or end-systolic volume by more than 10%. Results: A logistic regression formula was evaluated. Included biomarkers were macrophage migration inhibitory factor and sST2, left ventricle ejection fraction: Y=exp(-39.06+0.82EF+0.096ST2+0.0028MIF) / (1+exp(-39.06+0.82EF+0.096ST2+0.0028MIF)). The estimated range is from 0 to 1 point. Less than 0.5 determines an adverse outcome, and more than 0.5 is a good prognosis. This equation, with sensitivity of 77 % and specificity of 85%, could predict the development of adverse left ventricle remodeling six months after a coronary event (AUC=0.864, CI 0.673 to 0.966, p<0.05). Conclusions: A combination of biomarkers gives a significant predicting result in the formation of adverse left ventricular remodeling after ST-segment elevation myocardial infarction.

Exercise training after myocardial infarction increases survival but does not prevent adverse left ventricle remodeling and dysfunction in high-fat diet fed mice

AimsAerobic exercise is an important component of rehabilitation after cardiovascular injuries including myocardial infarction (MI). In human studies, the beneficial effects of exercise after an MI are blunted in patients who are obese or glucose intolerant. Here, we investigated the effects of exercise on MI-induced cardiac dysfunction and remodeling in mice chronically fed a high-fat diet (HFD). Main methods: C57Bl/6 male mice were fed either a standard (Chow; 21% kcal/fat) or HFD (60% kcal/fat) for 36 weeks. After 24 weeks of diet, the HFD mice were randomly subjected to an MI (MI) or a sham surgery (Sham). Following the MI or sham surgery, a subset of mice were subjected to treadmill exercise. Key findingsHFD resulted in obesity and glucose intolerance, and this was not altered by exercise or MI. MI resulted in decreased ejection fraction, increased left ventricle mass, increased end systolic and diastolic diameters, increased cardiac fibrosis, and increased expression of genes involved in cardiac hypertrophy and heart failure in the MI-Sed and MI-Exe mice. Exercise prevented HFD-induced cardiac fibrosis in Sham mice (Sham-Exe) but not in MI-Exe mice. Exercise did, however, reduce post-MI mortality. SignificanceThese data indicate that exercise significantly increased survival after MI in a model of diet-induced obesity independent of effects on cardiac function. These data have important translational ramifications because they demonstrate that environmental interventions, including diet, need to be carefully evaluated and taken into consideration to support the effects of exercise in the cardiac rehabilitation of patients who are obese.

Unfavorable left ventricular remodeling due to experience of chronic sleep restriction after myocardial infarction: The role of matrix metalloproteinases & oxidative stress

Disturbed sleep or sleep loss due to vocational or lifestyle changes following MI is a common problem that may affect many physiological processes involved in left ventricle (LV) remodeling. Herein, we proposed that experience of sleep disruption and/or restriction after myocardial infarction (MI) may aggravate cardiac extracellular matrix remodeling and induce apoptosis in the cardiomyocytes. MI was induced in adult male rats by permanent ligation of the left anterior descending coronary artery. Twenty-four hours after surgery, some animals experienced chronic sleep restriction (CSR) for 6 days. Serum levels of CK-MB, PAB, and TNF-α were evaluated at days 1, 8, and 21 postsurgery. Twenty-one days after surgery, hemodynamic parameters and expression of MMP-2, MMP-9, TIMP-1, and TNF-α, as well as myocardial fibrosis and apoptosis in the noninfarcted area of the LV were assessed. Our results showed a clear decrease in serum concentrations of CK-MB, PAB and TNF-α at day 21 postsurgery in the MI group as compared to MI+SR animals in which these markers remained at high levels. CSR following MI deteriorated LV hemodynamic indexes and also impaired the balance between MMPs and TIMP-1. Further, it yielded an increase in oxidant and inflammatory state which caused deleterious fibrotic and apoptotic effects on cardiomycytes. Our data suggest post-MI sleep loss may cause adverse LV remodeling due to increased inflammatory reactions as well as oxidative burden and/or anti-oxidative insufficiency that in turn impede the balance between MMPs and their inhibitors.

487 Increased CT Angiography-Derived Extracellular Volume Fraction Predicts Less Benefit In Left Ventricular Remodeling And Ejection Fraction After Transcatheter Edge To Edge Repair For Severe Mitral Regurgitation

Introduction: Mitral regurgitation (MR) leads to adverse structural remodeling of the left ventricle (LV), which may be reversed with timely transcatheter mitral valve edge to edge repair (TMR). Extracellular volume fraction (ECV), a marker of myocardial fibrosis, is associated with adverse LV remodeling and can be measured on cardiac computed tomography angiography (CTA). We evaluated the association between CTA-derived ECV and echocardiographic LV remodeling in patients with severe MR undergoing TMR.

CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells.

Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2+ monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation. We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects. We demonstrated that CCL17 is expressed in CCR2+ macrophages and cluster of differentiation 11b+ conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17+ macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling. These findings identify CCL17 as a proinflammatory mediator of CCR2+ macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.

Ischemic Mitral Regurgitation: A Multifaceted Syndrome with Evolving Therapies.

Dysfunction of the left ventricle (LV) with impaired contractility following chronic ischemia or acute myocardial infarction (AMI) is the main cause of ischemic mitral regurgitation (IMR), leading to moderate and moderate-to-severe mitral regurgitation (MR). The site of AMI exerts a specific influence determining different patterns of adverse LV remodeling. In general, inferior-posterior AMI is more frequently associated with regional structural changes than the anterolateral one, which is associated with global adverse LV remodeling, ultimately leading to different phenotypes of IMR. In this narrative review, starting from the aforementioned categorization, we proceed to describe current knowledge regarding surgical approaches in the management of IMR.

Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.

BackgroundWe determined if the sodium glucose co‐transporter 2 inhibitor empagliflozin attenuates pressure overload‐induced heart failure in non‐diabetic mellitus mice by direct cardiac effects and the mechanisms involved.Methods and ResultsMale C57BL/6J mice (4–6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction‐induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate‐activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway.ConclusionsOur study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate‐activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure‐overload in non‐diabetic mellitus mice.

Peculiarities of cardiac remodeling and myocardial dysfunction in metabolic syndrome

Introduction. In 2016, updated recommendations for echocardiographic diagnosis of diastolic dysfunction were developed. It requires a review of the degree of metabolic syndrome (MS) influence on the heart and blood vessels remodeling and the development of left ventricle (LV) diastolic dysfunction (DD).Purpose. Assessment of the MScontribution to the heart and blood vessels remodeling, as well as to the development of LVDD with an analysis of the LV remodeling types and the degree of LVDD.Materials and methods. The main group: 130 patients with MS (62 (47,7%) — men, 68 (52,3%) — women; average age — 59,8±9,5 years) who underwent in-patient examination and treatment in the cardiology department for arterial hypertension (AH) in 2015-2017. The control group included 36 patients with AH (18 (50%) — men, 18 (50%) — women; average age — 56,0±12,7 years) without abdominal obesity, not meeting the criteria of MS International Diabetes Federation.Results. MS is associated with increased prevalence of adverse LV remodeling and DD. In MS group concentric LV hypertrophy was detected significantly commoner than in group without MS, in which concentric remodeling was the most frequent structural abnormality. Eccentric LV hypertrophy was diagnosed only in pts with so-called complete MS. Moreover DD was detected in all pts with complete MS. Type 2 DD was present predominantly in subgroup with complete MS, reflecting relationship between the degree of LV DD and severity of MS in AH pts.Conclusions. Obtained results confirm adverse influence of central obesity and MS on LV myocardial structure and function.

Abstract 13320: Direct Cardiac Actions of Empagliflozin Improve Mitochondrial Oxidative Phosphorylation and Attenuate Pressure-overload Heart Failure

Introduction: The underlying mechanisms by which empagliflozin (EMPA) and other sodium glucose co-transporter 2 (SGLT2) inhibitors attenuate heart failure (HF) are still poorly understood. However, this protection does not appear to be fully explained by their antihyperglycemic or diuretic effects. Hypothesis: EMPA attenuates HF by direct effects on the heart to improve its metabolism and function. Methods: C57BL/6J mice (4-6 months) were subjected to transverse aortic constriction (TAC) or sham surgeries. Two weeks after TAC, EMPA (10 mg/kg/day) or vehicle was administered daily for 4 additional weeks. Cardiac function was assessed by echocardiography and cardiac substrate metabolism measured in isolated perfused hearts. Transmission electron microscopy was used to evaluate mitochondrial morphology and molecular docking analysis to predict potential cardiac targets of EMPA. Results: EMPA increased survival and attenuated adverse left ventricle remodeling and cardiac fibrosis after TAC. EMPA also attenuated left ventricular systolic dysfunction (ejection fraction 51.6 vs. 40.2% p&lt;0.05; fraction shortening 28.8 vs 18.4% p&lt;0.05). EMPA rescued impaired glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. Molecular docking analysis and isolated perfused heart experiments indicated that EMPA can directly bind glucose transporters in the heart to reduce glycolysis, and enhance AMP-activated protein kinase. EMPA treatment enhanced mitochondrial biogenesis, restored mitochondria cristae integrity, increased expression of endogenous antioxidants, and reduced cellular apoptosis caused by leakage of cytochrome C from mitochondria into the cytosol. These beneficial cardiac effects of EMPA occurred despite no alterations in fasting blood glucose, body weight, or daily urine volume. Conclusions. Our study demonstrated that EMPA may directly bind glucose transporters and reduce excessive glycolysis in failing hearts. EMPA enhanced mitochondrial biogenesis, improved mitochondrial oxidative phosphorylation, and reduced mitochondria-mediated apoptosis, thereby attenuating cardiac dysfunction and progression of HF.

Impact of global longitudinal strain on left ventricular remodeling and clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI).

Predicting left ventricle (LV) remodeling is important for outcome prediction in patients with ST-segment elevation myocardial infarction (STEMI). Novel echocardiographic techniques may be beneficial for those patients. We hypothesized that the semiautomated calculation of baseline global longitudinal strain (GLS) can predict LV remodeling and 6-month clinical outcomes in these patients. During the period from March to December 2018, 130 patients with successful reperfusion of STEMI were prospectively included. Within 48hours, patients underwent a baseline GLS study with follow-up study at 6months. Patients were divided into two groups: group I: patients who showed adverse LV remodeling and group II: patients who did not. The endpoint was a composite of cardiovascular mortality, readmission due to heart failure, and urgent revascularization. The mean baseline GLS changed from -13.1±3.5% for group I and -16.8±3.1% for group II, to -10.2±4.7% and -12.6±3.1%, respectively, at 6-month follow-up. ROC analysis demonstrated a cutoff value of baseline GLS>-12.5% predicted LV remodeling with 64.5% sensitivity and 89% specificity (AUC 0.797, 95% CI 0.690-0.904). Multivariate logistic regression analysis model using 6-month MACEs occurrence as a dependent factor showed baseline GLS value> -12.5% to be the only significant independent predictor MACEs occurrence (OR 0.704, 95% CI 0.597-0.829, P<.001). Linear regression analysis showed that for every point estimate deterioration of baseline GLS, there was a significant corresponding 2.55mL increase in LVEDV at 6-month follow-up (CI -4.501 to -0.612, P=.01). GLS measurement can predict remodeling and adverse clinical events in STEMI patients.

On the simulation of mitral valve function in health, disease, and treatment.

The mitral valve (MV) is the heart valve that regulates blood ?ow between the left atrium and left ventricle (LV). In situations where the MV fails to fully cover the left atrioventricular ori?ce during systole, the resulting regurgitation causes pulmonary congestion, leading to heart failure and/or stroke. The causes of MV insuf?ciency can be either primary (e.g. myxomatous degeneration) where the valvular tissue is organically diseased, or secondary (typically inducded by ischemic cardiomyopathy) termed ischemic mitral regurgitation (IMR), is brought on by adverse LV remodeling. IMR is present in up to 40% of patients and more than doubles the probability of cardiovascular morbidity after 3.5 years. There is now agreement that adjunctive procedures are required to treat IMR caused by lea?et tethering. However, there is no consensus regarding the best procedure. Multicenter registries and randomized trials would be necessary to prove which procedure is superior. Given the number of proposed procedures and the complexity and duration of such studies, it is highly unlikely that IMR procedure optimization will be achieved by prospective clinical trials. There is thus an urgent need for cell and tissue physiologically based quantitative assessments of MV function to better design surgical solutions and associated therapies. Novel computational approaches directed towards optimized surgical repair procedures can substantially reduce the need for such trial-and-error approaches. We present the details of our MV modeling techniques, with an emphasis on what is known and investigated at various length scales.

In This Issue

HomeCirculation ResearchVol. 122, No. 3In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published2 Feb 2018https://doi.org/10.1161/RES.0000000000000197Circulation Research. 2018;122:385Open Software to Quantify Cardiac Contraction (p e5)Sala et al create MUSCLEMOTION, an open-source software for quantifying contractions in both heart muscle cells and tissues.Download figureDownload PowerPointMeasurement and analysis of cardiac contractility are of high importance in studying muscle function, assessing disease phenotypes, and evaluating drug toxicity. Unlike electrophysiological measurements, for which there are well-established and standardized techniques applicable to a range of samples, the techniques for measuring myocardial contractions tend to be sample-specific, not easily comparable, and require specialized expertise. Sala and colleagues have now developed a novel software that can quantify contractions in movies of specimens as diverse as single heart cells, cultured cardiac myocytes, 3D cardiac organoids, and even living Zebrafish hearts. They tested the ability of their software, called MUSCLEMOTION, to detect drug-induced and disease-related contraction differences in a variety of samples and showed that the performance of the software was comparable to various gold-standard techniques tailored to those specific samples. By making MUSCLEMOTION user-friendly and freely accessible, the authors hope to facilitate comparisons of contraction data, not just between samples, but between laboratories as well, thereby facilitating data replication and reproducibility.64 Novel Genetic Loci for Coronary Artery Disease (p 433)Van der Harst and Verweij provide evidence for an omnigenic model of coronary artery disease.Download figureDownload PowerPointCoronary artery disease (CAD) is a multifactorial condition with contributions from both genetic and environmental factors. It has been associated with a number of genetic loci, yet linking these to potential pathological pathways remains difficult. Van der Harst and Verweij have now carried out the largest GWAS (genome-wide association study) to date. Examining nearly 8 million single nucleotide polymorphisms (SNPs) in a total of 122 733 CAD patient samples, they identified 64 novel CAD-associated loci. These candidate genes, however, are involved in such broad biological functions and expressed in such diverse tissues that the contribution of genetic factors appears to be even more complicated than first thought, as many loci have no obvious link to CAD. Based on these findings, the authors suggest that the model of CAD as a polygenic disease—one caused by multiple genes affecting a handful of key pathways—may be incorrect. Instead, they surmise that the results point to an omnigenic model—whereby the link between many SNPs and CAD may be one of interconnectedness of gene-regulatory mechanisms. If so, determining cell-specific networks of gene expression may be the best route to understanding CAD pathology.Long-Term MRI Follow-Up of MVO After Cell Therapy (p 479)Traverse et al report the final 2-year results of the stem cell TIME trial.Download figureDownload PowerPointStem cell therapies are under investigation for their potential to promote cardiac tissue repair after myocardial infarction (MI). Because changes to the myocardium following reperfusion could influence cell engraftment and survival, the timing of cell delivery was examined in the TIME trial (Timing In Myocardial Infarction Evaluation), which compared delivery of cells on day 3 with day 7 following MI in 120 patients. At 6 months, the results indicated that cells delivered at either time point offered no benefits to patients. And 2 years later, these results remain the same. However, the study has also provided one of the largest MRI datasets of patients following MI. By analyzing these data, Traverse and colleagues show that patients who had microvascular obstructions at baseline have poorer outcomes—larger infarct size, more adverse left ventricle remodeling, reduced recovery of ventricle function, and greater likelihood of requiring an implantation device. From these findings, the team suggests that the presence of microvascular obstruction may be a powerful predictor of subsequent left ventricle failure, and that microvascular dysfunction identifies the most at-risk patients. Previous Back to top Next FiguresReferencesRelatedDetails February 2, 2018Vol 122, Issue 3 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000197 Originally publishedFebruary 2, 2018 PDF download Advertisement

Pim1 Overexpression Prevents Apoptosis in Cardiomyocytes After Exposure to Hypoxia and Oxidative Stress via Upregulating Cell Autophagy

Background/Aims: Microvascular obstruction (MVO), an undesirable complication of percutaneous coronary intervention, is independently associated with adverse left ventricle remodeling and poor prognosis after acute myocardial infarction. Hypoxia and oxidative stress major roles in the pathophysiology of MVO. Pim1 serves an important protective role in the ischemic myocardium, but the underlying mechanisms remain poorly defined. Autophagy in early hypoxia or during moderate oxidative stress has been demonstrated to protect the myocardium. In this study, we investigated the association between the protective effect of Pim1 and autophagy after hypoxia and oxidative stress. Methods: Ventricular myocytes from neonatal rat heart (NRVMs) were isolated. NRVMs were exposed to hypoxia and H2O2. Rapamycin and 3-methyladenine (3-MA) were used as an activator and inhibitor of autophagy, respectively. pHBAd-Pim1 was transfected into NRVMs. We assessed cardiomyocyte apoptosis by Annexin V-FITC/PI flow cytometry. Autophagy was evaluated by mRFP-GFP-LC3 adenovirus infection by confocal microscopy. Western blotting was used to quantify apoptosis or autophagy protein (caspase-3, LC3, P62, AMPK, mTOR, ATG5) concentrations. Results: Autophagy and apoptosis in NRVMs significantly increased and peaked at 3 h and 6 h, respectively, after exposure to hypoxia and H2O2. The mTOR inhibitor rapamycin induced autophagy and decreased cardiomyocyte apoptosis, but the autophagy inhibitor 3-MA decreased autophagy and increased apoptosis at 3 h after exposure to hypoxia and H2O2. Pim1 levels in NRVMs increased at 3 h and decreased gradually after exposure to hypoxia and H2O2. Pim1 overexpression enhanced autophagy and decreased apoptosis. Pim1-induced promotion of autophagy is partly the result of activation of the AMPK/mTOR/ATG5 pathway after exposure to hypoxia and H2O2. Conclusion: Our results revealed that Pim1 overexpression prevented NRVMs from apoptosis via upregulating autophagy after exposure to hypoxia and oxidative stress, partly through activation of the AMPK/mTOR/ATG5 autophagy pathway.

Low-dose of relaxin protects against arrhythmias and adverse left ventricle remodeling

Low-dose of relaxin protects against arrhythmias and adverse left ventricle remodeling

Adverse Remodeling and Reverse Remodeling After Myocardial Infarction.

The purpose of this review it to summarize the current literature on remodeling after myocardial infarction, inclusive of pathophysiological considerations, imaging modalities, treatment strategies, and future directions. As patients continue to live longer after myocardial infarction (MI), the prevalence of post-MI heart failure continues to rise. Changes in the left ventricle (LV) after MI involve complex interactions between cellular and extracellular components, under neurohormonal regulation. Treatments to prevent adverse LV remodeling and promote reverse remodeling in the post-MI setting include early revascularization, pharmacotherapy aimed at neurohormonal blockade, and device-based therapies that address ventricular dyssynchrony. Despite varying definitions of adverse LV remodeling examined across multiple imaging modalities, the presence of an enlarged LV cavity and/or reduced ejection fraction is consistently associated with poor clinical outcomes. Advances in our knowledge of the neurohormonal regulation of adverse cardiac remodeling have been instrumental in generating therapies aimed at arresting adverse remodeling and promoting reserve remodeling. Further investigation into other specific mechanisms of adverse LV remodeling and pathways to disrupt these mechanisms is ongoing and may provide incremental benefit to current evidence-based therapies.

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling.

This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1-/- ) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1-/- mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.