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1.
Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart.
Singh, RM, Waqar, T, Howarth, FC, Adeghate, E, Bidasee, K, Singh, J
Heart failure reviews. 2018;(1):37-54
Abstract
The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca2+]i or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure. Numerous studies have been performed to identify the cellular, subcellular, and molecular derangements in diabetes-induced cardiomyopathy (DCM), but the precise mechanism(s) is still unknown. This review focuses on the mechanism behind DCM, the onset of contractile dysfunction, and the associated changes with special emphasis on hyperglycemia, mitochondrial dysfunction in the diabetic heart. Further, management strategies, including treatment and emerging therapeutic modalities, are discussed.
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2.
Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery.
Castillero, E, Ali, ZA, Akashi, H, Giangreco, N, Wang, C, Stöhr, EJ, Ji, R, Zhang, X, Kheysin, N, Park, JS, et al
American journal of physiology. Heart and circulatory physiology. 2018;(5):H1463-H1476
Abstract
Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.
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3.
Clinical Impact of Left Ventricular Diastolic Dysfunction in Chronic Kidney Disease.
Ogawa, T, Nitta, K
Contributions to nephrology. 2018;:81-91
Abstract
Left ventricular diastolic dysfunction (LVDD) frequently occurs in chronic kidney disease (CKD) and is associated with heart failure and higher mortality. LVDD is observed in patients with early stages of CKD and is associated with cardiovascular events, in patients undergoing incident hemodialysis in the absence of systolic function. The pathogenesis of CKD includes abnormal ventricular filling in diastole and a higher LV filling pressure (LVFP) because of LV hypertrophy (LVH), in addition to myocardial interstitial fibrosis. Therefore, LV dysfunction tends to cause pulmonary congestion. In patients with CKD, the mechanism of LVDD is complicated and mainly involves LVH, which is a physiological response to pressure and volume overload. Other factors related to CKD, including LVH, neurohumoral alterations, inflammation, anemia, and mineral disorders, might cause the development of LVDD. Echocardiography is frequently used for noninvasive evaluation of diastolic function and for estimating LVFP. Echocardiographic quantification of LVFP is based on the E/e' ratio, where E is the early mitral flow velocity on transmitral Doppler and e' is the early mitral annulus velocity obtained from tissue Doppler. An E/e' ratio <8 is considered to be normal, whereas a ratio >15 is considered to mirror the increase in LVFP. The main strategy for treating LVDD is to minimize the large volume shift to control blood pressure and prevent myocardial interstitial fibrosis.
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4.
Changes in myocardial iron content following administration of intravenous iron (Myocardial-IRON): Study design.
Miñana, G, Cardells, I, Palau, P, Llàcer, P, Fácila, L, Almenar, L, López-Lereu, MP, Monmeneu, JV, Amiguet, M, González, J, et al
Clinical cardiology. 2018;(6):729-735
Abstract
Treatment with intravenous ferric carboxymaltose (FCM) has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency. However, the underlying mechanisms for these beneficial effects remain undetermined. The aim of this study is to quantify cardiac magnetic resonance changes in myocardial iron content after administration of intravenous FCM in patients with heart failure and iron deficiency and contrast them with parameters of heart failure severity. This is a multicenter, double-blind, randomized study. Fifty patients with stable symptomatic heart failure, left ventricular ejection fraction <50%, and iron deficiency will be randomly assigned 1:1 to receive intravenous FCM or placebo. Intramyocardial iron will be evaluated by T2* and T1 mapping cardiac magnetic resonance sequences before and at 7 and 30 days after FCM. After 30 days, patients assigned to placebo will receive intravenous FCM in case of persistent iron deficiency. The main endpoint will be changes from baseline in myocardial iron content at 7 and 30 days. Secondary endpoints will include the correlation of these changes with left ventricular ejection fraction, functional capacity, quality of life, and cardiac biomarkers. The results of this study will add important knowledge about the effects of intravenous FCM on myocardial tissue and cardiac function. We hypothesize that short-term (7 and 30 days) myocardial iron content changes after intravenous FCM, evaluated by cardiac magnetic resonance, will correlate with simultaneous changes in parameters of heart failure severity. The study is registered at http://www.clinicaltrials.gov (NCT03398681).
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5.
Distinct Myocardial Targets for Diabetes Therapy in Heart Failure With Preserved or Reduced Ejection Fraction.
Paulus, WJ, Dal Canto, E
JACC. Heart failure. 2018;(1):1-7
Abstract
Noncardiac comorbidities such as diabetes mellitus (DM) have different outcomes in heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). These different outcomes are the result of distinct myocardial effects of DM on HFpEF and HFrEF, which relate to different mechanisms driving myocardial remodeling in each heart failure phenotype. Myocardial remodeling is driven by microvascular endothelial inflammation in HFpEF and by cardiomyocyte cell death in HFrEF. Evidence consists of: different biomarker profiles, in which inflammatory markers are prominent in HFpEF and markers of myocardial injury or wall stress are prominent in HFrEF; reduced coronary flow reserve with microvascular rarefaction in HFpEF; and upregulation of free radical-producing enzymes in endothelial cells in HFpEF and in cardiomyocytes in HFrEF. As biopsies from patients with diabetic cardiomyopathy reveal, DM affects failing myocardium by phenotype-specific mechanisms. In HFpEF, DM mainly increases cardiomyocyte hypertrophy and stiffness, probably because of hyperinsulinemia and microvascular endothelial inflammation. In HFrEF, DM augments replacement fibrosis because of cardiomyocyte cell death induced by lipotoxicity or advanced glycation end products. Because DM exerts distinct effects on myocardial remodeling in HFpEF and HFrEF, the heart failure phenotype is important for DM therapy.
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6.
Assessment of Remote Myocardium Heterogeneity in Patients with Ventricular Tachycardia Using Texture Analysis of Late Iodine Enhancement (LIE) Cardiac Computed Tomography (cCT) Images.
Esposito, A, Palmisano, A, Antunes, S, Colantoni, C, Rancoita, PMV, Vignale, D, Baratto, F, Della Bella, P, Del Maschio, A, De Cobelli, F
Molecular imaging and biology. 2018;(5):816-825
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Abstract
PURPOSE Diffuse remodeling of myocardial extra-cellular matrix is largely responsible for left ventricle (LV) dysfunction and arrhythmias. Our hypothesis is that the texture analysis of late iodine enhancement (LIE) cardiac computed tomography (cCT) images may improve characterization of the diffuse extra-cellular matrix changes. Our aim was to extract volumetric extracellular volume (ECV) and LIE texture features of non-scarred (remote) myocardium from cCT of patients with recurrent ventricular tachycardia (rVT), and to compare these radiomic features with LV-function, LV-remodeling, and underlying cardiac disease. PROCEDURES Forty-eight patients suffering from rVT were prospectively enrolled: 5/48 with idiopathic VT (IVT), 23/48 with post-ischemic dilated cardiomyopathy (ICM), 9/48 with idiopathic dilated cardiomyopathy (IDCM), and 11/48 with scars from a previous healed myocarditis (MYO). All patients underwent echocardiography to assess LV systolic and diastolic function and cCT with pre-contrast, angiographic, and LIE scan to obtain end-diastolic volume (EDV), ECV, and first-order texture parameters of Hounsfield Unit (HU) of remote myocardium in LIE [energy, entropy, HU-mean, HU-median, standard deviation (SD), and mean absolute deviation (MAD)]. RESULTS Energy, HU mean, and HU median by cCT texture analysis correlated with ECV (rho = 0.5650, rho = 0.5741, rho = 0.5068; p < 0.0005). cCT-derived ECV, HU-mean, HU-median, SD, and MAD correlated directly to EDV by cCT and inversely to ejection fraction by echocardiography (p < 0.05). SD and MAD correlated with diastolic function by echocardiography (rho = 0.3837, p = 0.0071; rho = 0.3330, p = 0.0208). MYO and IVT patients were characterized by significantly lower values of SD and MAD when compared with ICM and IDCM patients, independently of LV-volume systolic and diastolic function. CONCLUSIONS Texture analysis of LIE may expand cCT capability of myocardial characterization. Myocardial heterogeneity (SD and MAD) was associated with LV dilatation, systolic and diastolic function, and is able to potentially identify the different patterns of structural remodeling characterizing patients with rVT of different etiology.
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Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses.
García-Conesa, MT, Chambers, K, Combet, E, Pinto, P, Garcia-Aloy, M, Andrés-Lacueva, C, de Pascual-Teresa, S, Mena, P, Konic Ristic, A, Hollands, WJ, et al
International journal of molecular sciences. 2018;(3)
Abstract
Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation.
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8.
Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SIP in human ageing hearts.
Piotrowska, Ż, Niezgoda, M, Łebkowski, W, Filipek, A, Domian, N, Kasacka, I
Biology of sex differences. 2018;(1):50
Abstract
BACKGROUND Women live about 4 years longer due to lower prevalence of cardiovascular complication with ageing. However, the mechanisms involved in the preservation of heart functionality in women have not been fully elucidated. The endocannabinoid system fulfils a significant role in the regulation of cardiovascular system functioning. Cannabinoids, acting through specific receptors (CB1 and CB2), influence on blood pressure, heart rate and myocardial contractility. The function of cardiac muscle cells is strictly dependent on calcium ions. Calcium homeostasis in cardiomyocytes is subjected to complex regulation via calcium-binding proteins. Among them, increasing attention has been paid to the recently discovered S100A6 and CacyBP/SIP. In order to better understand sex differences in the regulation of cardiomyocyte function during ageing, we undertook the present research aimed at immunohistochemical identification and comparative evaluation of cannabinoid receptors, S100A6 and CacyBP/SIP, in the myocardium of ageing men and women. METHODS The study was conducted on the hearts of 12 men and 10 women (organ donors) without a history of cardiovascular disease. The subjects were divided into two age groups: subjects older than 50 years and subjects under 50 years old. Paraffin heart sections were processed by immunohistochemistry for detection of cannabinoids receptors, S100A6 and CacyBP/SIP. In the heart samples from each study, participant's expression of genes coding for CB1, CB2, S100A6 and CacyBP/SIP using real-time PCR method was measured. RESULTS CB1 and CB2 immunoreactivity in the cytoplasm of cardiomyocytes in the heart of subjects over 50 was weaker than in younger individuals. In the heart of younger men, CB1-immunoreactivity was weaker and CB2-immunoreaction was stronger compared to women. In the hearts of older men, the CB1-immunostaining was more intense and CB2-immunoreactivity was weaker than in women. Immunodetection of CB1 shoved the presence of receptor in the intercalated discs, but only in the hearts of individuals over the 50 years old. In the hearts of older individuals, stronger immunolabelling was observed for S100A6 and CacyBP/SIP. Male hearts had greater S100A6-immunoreactivity (both age groups) but less CacyBP/SIP immunostaining (individuals over 50 years) compared to the age-matched women. The expression of genes coding CB1, CB2, S100A6 and CacyBP/SIP in the human heart was sex and age-dependent. Observed changes between men and women as well as between subject under and over 50 years were consistent with immunohistochemically stated changes in peptide content. CONCLUSION Together, the data presented here indicate a close interaction between ageing and sex on the distribution and levels of cannabinoid receptors (CB1, CB2), S100A6 and CacyBP/SIP in the human heart.
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Lack of modulatory effect of the SCN5A R1193Q polymorphism on cardiac fast Na+ current at body temperature.
Abe, M, Kinoshita, K, Matsuoka, K, Nakada, T, Miura, K, Hata, Y, Nishida, N, Tabata, T
PloS one. 2018;(11):e0207437
Abstract
SCN5A encodes the main subunit of the NaV1.5 channel, which mediates the fast Na+ current responsible for generating cardiac action potentials. The single nucleotide polymorphism SCN5A(R1193Q), which results in an amino acid replacement in the subunit, is common in East Asia. SCN5A(R1193Q) is often identified in patients with type 3 long QT syndrome and Brugada syndrome. However, its linkage to arrhythmic disorders is under debate. Previous electrophysiological studies performed at room temperature inconsistently reported the gain- or loss-of-function effect of SCN5A(R1193Q) on the NaV1.5 channel. More recently, it was theoretically predicted that SCN5A(R1193Q) would exert a loss-of-function effect at body temperature. Here, we experimentally assessed whether SCN5A(R1193Q) modulates the NaV1.5 channel at various temperatures including normal and febrile body temperatures. We compared voltage-gated Na+ currents in SCN5A(R1193Q)-transfected and wild-type SCN5A-transfected HEK293T cells using a whole-cell voltage-clamp technique. First, we made comparisons at constant temperatures of 25°C, 36.5°C, and 38°C, and found no difference in the conductance density, voltage dependence of gating, or time dependence of gating. This suggested that SCN5A(R1193Q) does not modulate the NaV1.5 channel regardless of temperature. Second, we made comparisons while varying the temperature from 38°C to 26°C in 3 min, and again observed no difference in the time course of the amplitude or time dependence of gating during the temperature change. This also indicated that SCN5A(R1193Q) does not modulate the NaV1.5 channel in response to an acute body temperature change. Therefore, SCN5A(R1193Q) may not be a monogenic factor that triggers arrhythmic disorders.
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10.
Late sodium current inhibitors to treat exercise-induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium.
Ferrantini, C, Pioner, JM, Mazzoni, L, Gentile, F, Tosi, B, Rossi, A, Belardinelli, L, Tesi, C, Palandri, C, Matucci, R, et al
British journal of pharmacology. 2018;(13):2635-2652
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Abstract
BACKGROUND AND PURPOSE In 30-40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left ventricular (LV) outflow gradients develop only during exercise due to catecholamine-induced LV hypercontractility (inducible obstruction). Negative inotropic pharmacological options are limited to β-blockers or disopyramide, with low efficacy and tolerability. We assessed the potential of late sodium current (INaL )-inhibitors to treat inducible obstruction in HCM. EXPERIMENTAL APPROACH The electrophysiological and mechanical responses to β-adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of INaL -inhibitors (ranolazine and GS-967) in HCM samples were investigated under conditions simulating rest and exercise. KEY RESULTS In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective INaL -inhibitor GS-967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca2+ ] and shortened action potentials, matching the effects of ranolazine (10μM). Mechanical responses to isoprenaline (inotropic and lusitropic) were comparable in HCM and control myocardium. However, isoprenaline prolonged action potentials in HCM myocardium, while it shortened them in controls. Unlike disopyramide, neither GS-967 nor ranolazine reduced force at rest. However, in the presence of isoprenaline, they reduced Ca2+ -transient amplitude and twitch tension, while the acceleration of relaxation was maintained. INaL -inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, INaL -inhibitors abolished arrhythmias induced by isoprenaline. CONCLUSIONS AND IMPLICATIONS Ranolazine and GS-967 reduced septal myocardium tension during simulated exercise in vitro and therefore have the potential to ameliorate symptoms caused by inducible obstruction in HCM patients, with some advantages over disopyramide and β-blockers.