Cardiac Stiffness Research Articles

Evaluation of the relationship between left atrial stiffness, left ventricular stiffness, and left atrioventricular coupling index in type 2 diabetes patients: a speckle tracking echocardiography study.

Cardiovascular complications are a leading cause of mortality and disability in individuals with diabetes mellitus (DM). Moreover, DM can directly impact the structure and function of cardiac muscle. We conducted a study to evaluate cardiac stiffness in DM patients in both the left atrium (LA) and left ventricle (LV), as well as to assess the impact of DM on the synchronization of the LA and LV, particularly within the Vietnamese population, utilizing speckle tracking echocardiography (STE). We studied 111 research subjects divided into two groups comprising 52 patients with DM and 59 healthy individuals. All the subjects provided relevant clinical information, and echocardiography was performed to assess the indices of LA stiffness, LV stiffness, and left atrioventricular coupling index (LACI). Our study indicated that DM patients exhibited greater LA and LV stiffness than control patients. The LACI (%) in the DM group was also greater than that in the control group (17.12% ± 6.72% vs. 12.28% ± 3.96%, respectively; p < 0.001). The LACI was positively correlated with the LA and LV stiffness indices. Decreased levels of LV GLS, adjusted for age, sex, blood pressure, and BMI, have emerged as identified risk factors for DM. LA stiffness, LV stiffness, and the LACI are greater in DM patients than in normal individuals.

Abstract 15259: The Novel Antisense Oligonucleotide CDR132L Improves Cardiac Function in Heart Failure Across Different Species

Introduction: The chronic progressive condition of heart failure (HF) is, to date, largely irreversible and continues to impose global morbidity. MicroRNAs exert substantial roles in HF progression by orchestrating pathological genes and pathways. Medications directly tackling the roots of the disease are rare, but inhibition of miR-132, a microRNA that was shown to be upregulated upon cardiac remodeling and HF, is a promising approach. Thus, CDR132L, a clinical-stage synthetic antisense oligonucleotide miR-132 inhibitor, can be an innovative therapy for patients with HF. Hypothesis: To examine the effect of CDR132L, different studies were conducted, including in mice and pigs and in a first-inhuman phase 1b safety and tolerability study that revealed preclinical and exploratory efficacy data. Results: MiR-132 transgenic mice developed reduced left-ventricular ejection fraction (LVEF) and cardiac dilatation. CDR132L treatment significantly improved LVEF and reversed cardiac dilatation. The results were confirmed in a porcine transverse aortic constriction model, where the LVEF was significantly improved in the CDR132L treatment group compared to control animals (48.9% vs. 36.1%). In post-MI HF pigs subjected to different treatment and dosing regimens, resulted in a significant and dose-dependent improvement of the cardiac function, illustrated by an up to 10.4% improvement in LVEF to the placebo group at day 56. During a monthly treatment, 87.5% of the animals treated 5x 5 mg/kg with CDR132L showed a ΔLVEF of &gt;7% compared to the placebo group. Additionally, CDR132L improved contractility and the diastolic function by reducing cardiac stiffness. A successful translation of these preclinical results into humans was performed in a CDR132L safety and tolerability Phase 1b clinical trial in HF patients. In an exploratory analysis, the combined endpoint, consisting of patients with a decrease in NT-proBNP levels and/or an absolute increase in LVEF, was significantly met by 79% of the patients in the pharmacodynamically active CDR132L group. Conclusion: Pharmacological miR-132 inhibition by CDR132L improved cardiac function in multi-species models of HF, highlighting the therapeutic potential for clinical use in HF patients.

Conductive electrospun polymer improves stem cell-derived cardiomyocyte function and maturation

Despite numerous efforts to generate mature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), cells often remain immature, electrically isolated, and may not reflect adult biology. Conductive polymers are attractive candidates to facilitate electrical communication between hPSC-CMs, especially at sub-confluent cell densities or diseased cells lacking cell-cell junctions. Here we electrospun conductive polymers to create a conductive fiber mesh and assess if electrical signal propagation is improved in hPSC-CMs seeded on the mesh network. Matrix characterization indicated fiber structure remained stable over weeks in buffer, scaffold stiffness remained near in vivo cardiac stiffness, and electrical conductivity scaled with conductive polymer concentration. Cells remained adherent and viable on the scaffolds for at least 5 days. Transcriptomic profiling of hPSC-CMs cultured on conductive substrates for 3 days showed upregulation of cardiac and muscle-related genes versus non-conductive fibers. Structural proteins were more organized and calcium handling was improved on conductive substrates, even at sub-confluent cell densities; prolonged culture on conductive scaffolds improved membrane depolarization compared to non-conductive substrates. Taken together, these data suggest that blended, conductive scaffolds are stable, supportive of electrical coupling in hPSC-CMs, and promote maturation, which may improve our ability to model cardiac diseases and develop targeted therapies.

Continuous shear wave measurements for dynamic cardiac stiffness evaluation in pigs

Ultrasound-based shear wave elastography is a promising technique to non-invasively assess the dynamic stiffness variations of the heart. The technique is based on tracking the propagation of acoustically induced shear waves in the myocardium of which the propagation speed is linked to tissue stiffness. This measurement is repeated multiple times across the cardiac cycle to assess the natural variations in wave propagation speed. The interpretation of these measurements remains however complex, as factors such as loading and contractility affect wave propagation. We therefore applied transthoracic shear wave elastography in 13 pigs to investigate the dependencies of wave speed on pressure–volume derived indices of loading, myocardial stiffness, and contractility, while altering loading and inducing myocardial ischemia/reperfusion injury. Our results show that diastolic wave speed correlates to a pressure–volume derived index of operational myocardial stiffness (R = 0.75, p < 0.001), suggesting that both loading and intrinsic properties can affect diastolic wave speed. Additionally, the wave speed ratio, i.e. the ratio of systolic and diastolic speed, correlates to a pressure–volume derived index of contractility, i.e. preload-recruitable stroke work (R = 0.67, p < 0.001). Measuring wave speed ratio might thus provide a non-invasive index of contractility during ischemia/reperfusion injury.

A numerical study of a left ventricular expander for heart failure with preserved ejection fraction.

Increased cardiac stiffness hinders proper left ventricular (LV) expansion, resulting in decreased volume and diastolic dysfunction. LV expanders are spring-like devices designed to improve diastolic function by facilitating mechanical outward expansion. Implantations in animals and humans have shown promising results, yet further evaluation is needed to assess a range of functions and the risk of use. In this computational study, the effectiveness and potential use of a generic LV expander were assessed by using previously generated finite-element models of induced heart failure with preserved ejection fraction (HFpEF). Following implantation, the treated models were compared to the corresponding untreated and healthy pre-induction models. The influence of device orientation and its material properties was also examined. Our results demonstrated a reduction in LV pressure and a volumetric improvement. Computed LV stresses have shown no gross irregularities. The device contributed to stress elevation during diastole while having a minor effect during systole, supporting a basic safety profile. This is the first study to use numerical analysis to assess LV expanders' performance on different HFpEF phenotypes. Improvement in heart function was demonstrated in both subjects, suggesting its potential use in various HFpEF manifestations, yet customization and optimal deployment are essential to improve heart performance.

Mechanical Control of Relaxation using Intact Cardiac Trabeculae.

Diastolic dysfunction is a common phenotype across cardiovascular disease presentations. In addition to elevated cardiac stiffness (elevated left ventricular end-diastolic pressure), impaired cardiac relaxation is a key diagnostic indicator of diastolic dysfunction. While relaxation requires the removal of cytosolic calcium and deactivation of sarcomeric thin filaments, targeting such mechanisms has yet to provide effective treatments. Mechanical mechanisms, such as blood pressure (i.e., afterload), have been theorized to modify relaxation. Recently, we showed that modifying the strain rate of a stretch, not afterload, was both necessary and sufficient to modify the subsequent relaxation rate of myocardial tissue. The strain rate dependence of relaxation, called the mechanical control of relaxation (MCR), can be assessed using intact cardiac trabeculae. This protocol describes the preparation of a small animal model, experimental system and chamber, isolation of the heart and subsequent isolation of a trabecula, preparation of the experimental chamber, and experimental and analysis protocols. Evidence for lengthening strains in the intact heart suggests that MCR might provide new arenas for better characterization of pharmacological treatments, along with a method to assess myofilament kinetics in intact muscles. Therefore, studying the MCR may elucidate a path to novel approaches and new frontiers in the treatment of heart failure.

A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young’s Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key ‘linker’ sites in this schema that may represent potential therapeutic targets.

A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is characterized by structural and functional abnormalities in the myocardium affecting people with diabetes. Treatment of DCM focuses on glucose control, blood pressure management, lipid-lowering, and lifestyle changes. Due to limited therapeutic options, DCM remains a significant cause of morbidity and mortality in patients with diabetes, thus emphasizing the need to develop new therapeutic strategies. Ongoing research is aimed at understanding the underlying molecular mechanism(s) involved in the development and progression of DCM, including oxidative stress, inflammation, and metabolic dysregulation. The goal is to develope innovative pharmaceutical therapeutics, offering significant improvements in the clinical management of DCM. Some of these approaches include the effective targeting of impaired insulin signaling, cardiac stiffness, glucotoxicity, lipotoxicity, inflammation, oxidative stress, cardiac hypertrophy, and fibrosis. This review focuses on the latest developments in understanding the underlying causes of DCM and the therapeutic landscape of DCM treatment.

Comparing Myocardial Shear Wave Propagation Velocity Estimation Methods Based on Tissue Displacement, Velocity and Acceleration Data.

Shear wave elastography (SWE) is a promising technique used to assess cardiac function through the evaluation of cardiac stiffness non-invasively. However, in the literature, SWE varies in terms of tissue motion data (displacement, velocity or acceleration); method used to characterize mechanical wave propagation (time domain [TD] vs. frequency domain [FD]); and the metric reported (wave speed [WS], shear or Young's modulus). This variety of reported methodologies complicates comparison of reported findings and sheds doubt on which methodology better approximates the true myocardial properties. We therefore conducted a simulation study to investigate the accuracy of various SWE data analysis approaches while varying cardiac geometry and stiffness. Lower WS values were obtained by the TD method compared with the FD method. Acceleration-based WS estimates in the TD were systematically larger than those based on velocity (∼10% difference). These observations were confirmed by TD analysis of 32 in vivo SWE mechanical wave measurements. In vivo data quality is typically too low for accurate FD analysis. Therefore, our study suggests using acceleration-based TD analysis for in vivo SWE to minimize underestimation of the true WS and, thus, to maximize the sensitivity of SWE to detect stiffness changes resulting from pathology.

414-P: Effects of Obesity and Type 2 Diabetes on Cardiac Structure and Arterial Stiffness

T2D is a global epidemic leading to excess cardiovascular (CV) mortality including heart failure (HF) . Strategies are emerging to prevent HF progression, so early detection is needed. We have identified preclinical cardiac dysfunction associated with central arterial stiffness and decreased cardiorespiratory fitness. We hypothesized that cardiac magnetic resonance (CMR) would identify changes in diabetes. Methods: Age and BMI-similar premenopausal women and men with (n=24) and without (n=30) uncomplicated T2D were studied. CMR for cardiac function, regionally resolved pulse wave velocity (PWV) via 2D phase-contrast MRI assessed proximal arterial stiffness, and carotid to femoral applanation tonometry PWV (C-F PWV) using SphygmoCor assessed global arterial stiffness. The vascular territories covered by SphygmoCor does not include the ascending aorta. Results: CMR showed significant changes consistent with cardiac dysfunction in T2D (Table 1) . PWV was significantly greater with T2D in the ascending and proximal descending aorta (p&amp;lt;0.05) . Subclinical diastolic cardiac dysfunction (EDVi) correlated with proximal PWV in T2D (p=0.046, r2=0.24) . C-F PWV did not differ between groups. Conclusions: CMR detects early arterial stiffening in people with uncomplicated T2D and mild cardiac dysfunction. These findings support the use of CMR for detecting central arterial stiffness and incipient CV complications. Disclosure D.Enge: None. M.O.Whipple: None. K.S.Hunter: None. K.J.Nadeau: None. J.G.Regensteiner: None. A.J.Barker: None. J.Reusch: Advisory Panel; Medtronic. M.Schäfer: None. T.Fujiwara: None. E.Clark: None. E.Englund: None. R.L.Scalzo: None. D.Rafferty: None. I.E.Schauer: None. L.Abushamat: None. Funding National Institutes of Health (CX001532) University of Colorado Denver (NCT03419195) National Institutes of Health (R01-DK-124344) National Institutes of Health (K25HL119608)

Immune correlates of cardiovascular co-morbidity in HIV infected participants from South India

BackgroundUnderstanding the immune correlates of cardiovascular disease (CVD) risk in HIV infection is an important area of investigation in the current era of aging with HIV infection. Less is known about CVD risk and HIV infection in developing nations where additional risk factors may be playing a role in the CVD development. In this study, we assessed the effects of systemic inflammation, microbial translocation (MT), T cell immune activation (IA), and nadir CD4 counts on cardiac function and arterial stiffness as markers of subclinical atherosclerosis in HIV-infected individuals. MethodsPeople with HIV (PWH) who were ART naïve (n = 102) or virally suppressed on ART (n = 172) were stratified on nadir CD4 counts and compared to HIV-uninfected controls (n = 64). Determination was made of cardiac function via radial pulse wave and carotid intima thickness (C-IMT) measurements. Plasma biomarkers of inflammation and MT by ELISA or multiplex assays, and immune activation (IA) of T cells based HLA-DR and CD38 expression were investigated by flow cytometry. T-test, Mann–Whitney U test, and Spearman correlation were used to analyze study parameters.ResultsReduction in cardiac function with lower cardiac ejection time (p < 0.001), stroke volume (p < 0.001), cardiac output (p = 0.007), higher arterial stiffness (p < 0.05) were identified in ART-naïve participants, compared to PWH on ART (p < 0.05). No significant difference in C-IMT values were noted. Higher inflammatory and MT markers were found in the ART-naïve group compared to treated group who were comparable to uninfected participants, except for having higher TNF-α (p < 0.001) and sCD14 (p < 0.001). Immune activation of CD4 and CD8 T-cells was greater in ART-naïve participants compared to ART-treated and uninfected controls (p < 0.05). Lower nadir CD4 counts, higher inflammation, and higher MT predicted poor cardiac measures in the ART-naïve with nadir CD4 < 200cells/mm3 manifesting the highest arterial stiffness, and lowest cardiac function, whereas ART-treated, even with nadir < 200 cells/mm3 were similar to uninfected in these measures.ConclusionsIn HIV-infected individuals, initiation of ART even at nadir of < 200 cells/mm3 may prevent or reverse cardiovascular disease outcomes that are easily measurable in low income countries.

Endothelial Dysfunction and Diabetic Cardiomyopathy.

The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca2+ mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.

Relationship of arterial and cardiac stiffness in rotating shift workers in the Arctic

Objective . To investigate factors associated with arterial hypertension (HTN), evaluate their interrelationship in rotational shift workers in the Arctic. Design and methods . In the polar settlement of Yamburg (68 N), on the basis of Health Service LLC “Gazprom Dobycha Yamburg” medical unit, 183 out of 213 subjects were enrolled in the study: 100 males (M) aged 48,8 ± 8,4 years, 83 females (F) aged 49,7 ± 7,1 years (p = 0,443), comparable in te duration of rotational shift work: 16,5 ± 8,6 and 16,3 ± 8,9 years, respectively. Patients were divided into 2 groups according to the level of blood pressure (BP): Group 1 (Gr. 1) included 86 individuals with HTN1, 2 stages (BP &gt; 140/90 mm Hg); Group 2 (Gr. 2) comprised 97 individuals with BP &lt; 140/90 mm Hg. Ultrasound examination of carotid arteries was performed, and the indicators of local arterial stiffness (Peterson’s elastic modulus (Ep), β -stiffness) were assessed. The following diagnostic procedures were performed: ambulatory BP monitoring; cardio-ankle vascular index (CAVI) and pulse wave velocity (PWV) assessment; echocardiography with the assessment of probability for heart failure with preserved ejection fraction (HFpEF) by the H2FPEF score (Heavy; Hypertensive; Atrial Fibrillation; Pulmonary Hypertension; Elder; Filling Pressure); biochemical blood tests with the evaluation of homocysteine, high-sensitivity C-reactive protein (hs-CRP), pro-brain natriuretic peptide (pro-BNP). Results . In Gr. 1 vs Gr. 2, elevated levels of left CAVI (p = 0,022) and right CAVI ( р = 0,045) were registered; PWV in Gr. 1 was significantly higher than in Gr. 2 [right (p &lt; 0,001) and left (p &lt; 0,001)], and homocysteine (p = 0,025) level was higher in HTN group. Probability of HFpEF by the H2FPEF score was higher in Gr. 1 than in Gr. 2 ( р &lt; 0,001). According to logistic regression analysis, there was a relationship between HTN and PWV (odds ratio (OR) = 1,44; 95% confidence interval (CI) 1,22–1,75), 24-hour diastolic BP variability (DBPV24) (OR = 1,16; 95% CI 1,01–1,38), with the probability of HFpEF (OR = 1,67; 95% CI 1,23–2,33). Peterson’s elastic modulus (Ep) correlated with left ventricular myocardial mass (LVMM) (r = 0,39, p &lt; 0,01), left ventricular myocardial mass index (LVMMI) (r = 0,39, p &lt; 0,01), HFpEF probability (r = 0,27, p &lt; 0,01); while β -stiffness index of common carotid arteries correlated with LVMM (r = 0,25, p &lt; 0,01). Conclusions . According to logistic regression analysis results, relationship between PWV, DBPV24 and signs of HFpEF by the H2FPEF score and HTN was registered in rotational shift workers in the Arctic region. Obtained data defined HTN as a risk factor for HFpEF even in asymptomatic patients and might be taken into account for cardiovascular prevention in terms of rotational shift work. The associations of arterial stiffness with LVMM and LVMMI, signs of HFpEF by the H2FPEF score may indicate simultaneous interconnected processes of arterial and cardiac stiffness formation.

Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.

Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Altered Expression of ORAI and STIM Isoforms in Activated Human Cardiac Fibroblasts.

Cardiac fibrotization is a well-known process characteristic of many cardiac pathological conditions. The key element is excessive activation of cardiac fibroblasts, their transdifferentiation into myofibroblasts, increased production, and accumulation of extracellular matrix proteins, resulting in cardiac stiffness. The exact cellular mechanisms and molecular components involved in the process are not fully elucidated, but the SOCE mechanism could play an important role. Its key molecules are the molecular sensor of calcium in ER/SR - STIM and the highly selective calcium channels Orai located in the plasma membrane. This study aims to evaluate selected SOCE-associated genes in the activation of HCF cell culture by several known substances (phenylephrine, isoprenaline) that represent cardiovascular overload. After cell cultivation, cell medium was collected to measure the soluble collagen content. From the harvested cells, qRT-PCR was performed to determine the mRNA levels of the corresponding genes. The activation of cells was based on changes in the relative expression of collagen genes as well as the collagen content in the medium of the cell culture. We detected an increase in the expression of the Orai2 isoform, a change in the Orai1/Orai3 ratio and also an increase in the expression of the STIM2 isoform. These results suggest an increased activation of the SOCE mechanism under stress conditions of fibroblasts, which supports the hypothesis of fibroblast activation in pathological processes by altering calcium homeostasis through the SOCE mechanism.

Association of pre-pregnancy subclinical insulin resistance with cardiac dysfunction in healthy nulliparous women.

To investigate the association between pre-pregnancy subclinical insulin resistance and cardiovascular dysfunction in healthy nulliparous women, and with hypertension in subsequent pregnancy. Secondary analysis of a single center prospective observational study conducted November 2011-June 2014. Healthy nulliparous women underwent detailed cardiovascular and metabolic assessment. Insulin resistance was determined by homeostasis model assessment (HOMA-IR). Associations of HOMA-IR with metabolic and cardiovascular measurements were assessed with Spearman correlations. Charts were reviewed in women who conceived singleton pregnancies. Metabolic measurements included serum glucose, insulin, creatinine, CRP, and lipids. HOMA-IR was calculated using fasting serum insulin and glucose. Indices of cardiovascular stiffness were determined from pulse wave velocity and response to volume challenge. Pregnancy outcomes included delivery mode and gestational age, birthweight, and hypertension. HOMA-IR was positively associated with BMI (r=0.462, p<0.001), body fat percentile (r=0.463, p<0.001), CRP (r=0.364, p=0.003), and negatively associated with serum HDL (r=-0.38, p=0.002) and creatinine (r=-0.242, p=0.049). HOMA-IR was positively associated with blood pressure (r=0.347, p=0.004), resting heart rate (r=0.433, p = <0.001), response to volume challenge (r=0.325, p<0.01). Increased HOMA-IR was associated with a faster cardiac ejection time in response to volume challenge (r=-0.415, p<0.001), which is a marker of decreased cardiac compliance to volume increase, or cardiac stiffness. HOMA-IR is associated with pre-pregnancy cardiac stiffness. Cholesterol was not associated with cardiovascular dysfunction. A non-significant trend was observed between HOMA-IR and hypertension in subsequent pregnancy.

Resveratrol against Cardiac Fibrosis: Research Progress in Experimental Animal Models.

Cardiac fibrosis is a heterogeneous disease, which is characterized by abundant proliferation of interstitial collagen, disordered arrangement, collagen network reconstruction, increased cardiac stiffness, and decreased systolic and diastolic functions, consequently developing into cardiac insufficiency. With several factors participating in and regulating the occurrence and development of cardiac fibrosis, a complex molecular mechanism underlies the disease. Moreover, cardiac fibrosis is closely related to hypertension, myocardial infarction, viral myocarditis, atherosclerosis, and diabetes, which can lead to serious complications such as heart failure, arrhythmia, and sudden cardiac death, thus seriously threatening human life and health. Resveratrol, with the chemical name 3,5,4′-trihydroxy-trans-stilbene, is a polyphenol abundantly present in grapes and red wine. It is known to prevent the occurrence and development of cardiovascular diseases. In addition, it may resist cardiac fibrosis through a variety of growth factors, cytokines, and several cell signaling pathways, thus exerting a protective effect on the heart.

Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure

Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity, and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed. Dahl salt-sensitive rats fed a high-salt diet, with echocardiographically verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt-sensitive rats receiving low salt diet served as controls. Protein and phosphorylated Ser, Thr, and Tyr residues from left ventricular tissue were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared with control. Of those, 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β, and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests that PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment. Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.

Arterial stiffness and the risk of heart failure formation in rotational shift workers in the arctic

Abstract Aim To investigate factors associated with arterial hypertension (AH) development, evaluate arterial stiffness (AS) and the risk of heart failure formation in rotational shift workers in the Arctic. Methods Within 6 days of September 2019, in the polar settlement of Yamburg (68 N), on the basis of Yamburggazdobycha LLC medical unit, 183 individuals (48.7±8.3 years), working rotating shifts (16.9±8.7 years) were enrolled via medical examination. Patients were divided into 2 groups according to the level of blood pressure (BP): Group 1 (Gr. 1) included 86 individuals with AH of 1,2 stages; Group 2 (Gr. 2) comprised 97 individuals with BP &amp;lt;140/90 mm Hg. Ultrasound examination of carotid arteries (CA) was performed, Peterson's elastic modulus (Ep), β-stiffness index, cardio-ankle vascular index (CAVI), pulse wave velocity (PWV) were determined; ABPM was performed; EchoCG was conducted using calculation of probability for heart failure with preserved ejection fraction (HFpEF) by the H2FPEF score (Heavy; Hypertensive; Atrial Fibrillation; Pulmonary Hypertension; Elder; Filling Pressure); blood lipid spectrum, inflammatory markers, brain natriuretic peptide were determined. Results In Gr.1 vs Gr.2, elevated levels of left CAVI (7.9 vs 7.4) (p=0.022) and right CAVI (7.9 vs 7.5) (p=0.045) were registered; PWV: 13.8 m/s vs 12.6 m/s (right), (p&amp;lt;0.001) and 13.9 m/s vs 12.6 m/s (left), (p&amp;lt;0.001); triglycerides, (p=0.03); very low density lipoprotein cholesterol, (p=0.054); homocysteine, (p=0.025). Probability of HFpEF by the H2FPEF score was higher in Gr.1 than Gr.2 (p&amp;lt;0.001). According to logistic regression analysis, data of odds ratio (OR) determined the risk of AH developing with increasing of PWV (OR=1.444); 24-hour diastolic blood pressure variability (DBPV24) (OR = 1.164); probability of HFpEF by the H2FPEF score (OR = 1.677). Relationships of Peterson's elastic modulus (Ep) of common carotid artery (CCA) with left ventricular myocardial mass (LVMM) (r=0.39), (p&amp;lt;0.01), LVMMI (r=0.39), (p&amp;lt;0.01), probability HFpEF by H2EPEF score (r=0.27), (p&amp;lt;0.01); β-stiffness index of CCA with LVMM (r=0.25), (p&amp;lt;0.01) were found. Conclusion Interrelation of AH with PWV (OR=1.444), DBPV24 (OR=1.677), probability of HFpEF by the H2FPEF score (OR = 1.677) should be considered for prognostication of the risk of AH with HFpEF formation in rotational shift workers in the Arctic. Associations of AS with LVMM and LVMMI, HFpEF signs may indicate processes of simultaneous interconnected formation of arterial and cardiac stiffness. Funding Acknowledgement Type of funding sources: None.

Reverse remodeling in diabetic cardiomyopathy: the role of extracellular matrix.

Diabetic patients are prone to suffer from cardiovascular disease, specifically from ischemic heart disease and diabetic cardiomyopathy, which have a huge impact on morbidity and mortality worldwide. Cardiac fibrosis due to alteration of the extracellular matrix (ECM) remodeling is often observed in diabetes and myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. At single-cell level, the ECM govern, metabolism, motility, orientation, and proliferation. However, in pathological condition such as diabetes, changes in ECM lead to fibrosis and subsequently cardiac stiffness and cardiomyocytes dysfunction. Antidiabetic drugs, particularly sodium-glucose cotransporter-2 (SGLT2) inhibitors have antifibrotic effects and may promote ECM reverse remodeling. In this review, the mechanisms, and the role of ECM remodeling and reverse remodeling as a potential therapeutic target for diabetic cardiomyopathy are discussed.