Determinants of subclinical diabetic heart disease

Aims/hypothesis: Subclinical left ventricular (LV) dysfunction has been shown by tissue Doppler and strain imaging in diabetic patients in the absence of coronary disease or LV hypertrophy, but the prevalence and aetiology of this finding remain unclear. This study sought to identify the prevalence and the determinants of subclinical diabetic heart disease. Methods: A group of 219 unselected patients with type 2 diabetes without known cardiac disease underwent resting and stress echocardiography. After exclusion of coronary artery disease or LV hypertrophy, the remaining 120 patients ( age 57 +/- 10 years, 73 male) were studied with tissue Doppler imaging. Peak systolic strain of each wall and systolic (Sm) and diastolic ( Em) velocity of each basal segment were measured from the three apical views and averaged for each patient. Significant subclinical LV dysfunction was identified according to Sm and Em normal ranges adjusted by age and sex. Strain and Em were correlated with clinical, therapeutic, echocardiographic and biochemical variables, and significant independent associations were sought using a multiple linear regressionmodel. Results: Significant subclinical LV dysfunction was present in 27% diabetic patients. Myocardial systolic dysfunction by peak strain was independently associated with glycosylated haemoglobin level ( p< 0.001) and lack of angiotensin- converting enzyme inhibitor treatment ( p= 0.003). Myocardial diastolic function ( Em) was independently predicted by age ( p= 0.013), hypertension ( p= 0.001), insulin ( p= 0.008) and metformin ( p= 0.01) treatment. Conclusions/ interpretation: In patients with diabetes mellitus, subclinical LV dysfunction is common and associated with poor diabetic control, advancing age, hypertension and metformin treatment; ACE inhibitor and insulin therapies appear to be protective.

Screening for heart disease in diabetic subjects

Background The prevalence of left ventricular hypertrophy (LVH), coronary artery disease, and subclinical cardiomyopathy in diabetic patients without known cardiac disease is unclear. We sought the frequency of these findings to determine whether plasma brain natriuretic peptide (BNP) could be used as an alternative screening tool to identify subclinical LV dysfunction. Methods Asymptomatic patients with diabetes mellitus without known cardiac disease (n = 10 1) underwent clinical evaluation, measurement of BNP, exercise stress testing, and detailed echocardiographic assessment. After exclusion of overt dysfunction or ischemia, subclinical myocardial function was sought on the basis of myocardial systolic (Sm) and diastolic velocity (Em). Association was. sought between subclinical dysfunction and clinical, biochemical, exercise, and echocardiographic variables. Results Of 101 patients, 22 had LVH and 16 had ischemia evidenced by exercise-induced wall motion abnormalities. Only 4 patients had abnormal BNP levels; BNP was significantly increased in patients with LVH. After exclusion of LVH and coronary artery disease, subclinical cardiomyopathy was identified in 24 of 66 patients: Subclinical disease could not be predicted by BNP. Conclusions Even after exclusion of asymptomatic ischemia and hypertrophy, subclinical systolic and diastolic dysfunction occurs in a significant number of patients with type 2 diabetes. However, screening approaches, including BNP, do not appear to be sufficiently sensitive to identify subclinical dysfunction, which requires sophisticated echocardiographic analysis.

Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II

1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human ( 14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 mu M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P < 0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P > 0.1). FK506 had no effect on contractile force (P = 0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P = 0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC epsilon compared to samples incubated without PKCe. 6 Endogenous cardiostimulants which activate G alpha q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Aims - Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3 and 9 of GSK-3 respectively, required for inactivation by upstream kinases. Methods and results - Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion - Expression of inactivation-resistant GSK-3/does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3/, may enable a sustained cardiac response to chronic-agonist stimulation while preventing pathological remodelling. © 2010 The Author.

Involvement of NADPH oxidases in cardiac remodelling and heart failure

Cardiac remodelling occurs in response to stress, such as chronic hypertension or myocardial infarction, and forms the substrate for subsequent development of heart failure. Key pathophysiological features include ventricular hypertrophy, interstitial fibrosis, contractile dysfunction, and chamber dilatation. Although the molecular mechanisms are complex and not fully defined, substantial evidence now implicates increased oxidative stress as being important. The NADPH oxidase ('Nox') enzymes are a particularly important source of reactive oxygen species that are implicated in redox signalling. This article reviews the evidence for an involvement of NADPH oxidases in different aspects of adverse cardiac remodelling. A better understanding of the roles of this complex enzyme family may define novel therapeutic targets for the prevention of heart failure. Copyright © 2007 S. Karger AG.

NADPH oxidase and heart failure

Reactive oxygen species play important roles in the pathophysiology of chronic heart failure secondary to chronic left ventricular hypertrophy or myocardial infarction. Reactive oxygen species influence several components of the phenotype of the failing heart, including contractile function, interstitial fibrosis, endothelial dysfunction and myocyte hypertrophy. Recent studies implicate the production of reactive oxygen species by a family of NADPH oxidases in these effects. NADPH oxidases are activated in an isoform-specific manner by many pathophysiological stimuli and exert distinct downstream effects. Understanding NADPH oxidase activation and regulation, and their downstream effectors, could help to develop novel therapeutic targets.

NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure

Markers of increased oxidative stress are known to be elevated following acute myocardial infarction and in the context of chronic left ventricular hypertrophy or heart failure, and their levels may correlate with the degree of contractile dysfunction or cardiac deficit. An obvious pathological mechanism that may account for this correlation is the potential deleterious effects of increased oxidative stress through the induction of cellular dysfunction, energetic deficit or cell death. However, reactive oxygen species have several much more subtle effects in the remodelling or failing heart that involve specific redox-regulated modulation of signalling pathways and gene expression. Such redox-sensitive regulation appears to play important roles in the development of several components of the phenotype of the failing heart, for example cardiomyocyte hypertrophy, interstitial fibrosis and chamber remodelling. In this article, we review the evidence supporting the involvement of reactive oxygen species and redox signalling pathways in the development of cardiac hypertrophy and heart failure, with a particular focus on the NADPH oxidase family of superoxide-generating enzymes which appear to be especially important in redox signalling.

Epigenetic Therapy for the Treatment of Hypertension-Induced Cardiac Hypertrophy and Fibrosis

BACKGROUND: The development of heart failure is associated with changes in the size, shape, and structure of the heart that has a negative impact on cardiac function. These pathological changes involve excessive extracellular matrix deposition within the myocardial interstitium and myocyte hypertrophy. Alterations in fibroblast phenotype and myocyte activity are associated with reprogramming of gene transcriptional profiles that likely requires epigenetic alterations in chromatin structure. The aim of our work was to investigate the potential of a currently licensed anticancer epigenetic modifier as a treatment option for cardiac diseases associated with hypertension-induced cardiac hypertrophy and fibrosis.

METHODS AND RESULTS: The effects of DNA methylation inhibition with 5-azacytidine (5-aza) were examined in a human primary fibroblast cell line and in a spontaneously hypertensive rat (SHR) model. The results from this work allude to novel in vivo antifibrotic and antihypertrophic actions of 5-aza. Administration of the DNA methylation inhibitor significantly improved several echocardiographic parameters associated with hypertrophy and diastolic dysfunction. Myocardial collagen levels and myocyte size were reduced in 5-aza-treated SHRs. These findings are supported by beneficial in vitro effects in cardiac fibroblasts. Collagen I, collagen III, and α-smooth muscle actin were reduced in a human ventricular cardiac fibroblast cell line treated with 5-aza.

CONCLUSION: These findings suggest a role for epigenetic modifications in contributing to the profibrotic and hypertrophic changes evident during disease progression. Therapeutic intervention with 5-aza demonstrated favorable effects highlighting the potential use of this epigenetic modifier as a treatment option for cardiac pathologies associated with hypertrophy and fibrosis.

Tadalafil-induced Improvement In Left Ventricular Diastolic Function In Resistant Hypertension.

Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes. We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels. No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo. The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.

Cardioprotective Mechanism Of S-nitroso-n-acetylcysteine Via S-nitrosated Betadrenoceptor-2 In The Ldlr-/- Mice.

Previous studies from our group have demonstrated the protective effect of S-nitroso-N-acetylcysteine (SNAC) on the cardiovascular system in dyslipidemic LDLr-/- mice that develop atheroma and left ventricular hypertrophy after 15 days on a high fat diet. We have shown that SNAC treatment attenuates plaque development via the suppression of vascular oxidative stress and protects the heart from structural and functional myocardial alterations, such as heart arrhythmia, by reducing cardiomyocyte sensitivity to catecholamines. Here we investigate the ability of SNAC to modulate oxidative stress and cell survival in cardiomyocytes during remodeling and correlation with β₂-AR signaling in mediating this protection. Ventricular superoxide (O₂⁻) and hydrogen peroxide (H₂O₂) generation was measured by HPLC methods to allow quantification of dihydroethidium (DHE) products. Ventricular histological sections were stained using terminal dUTP nick-end labeling (TUNEL) to identify nuclei with DNA degradation (apoptosis) and this was confirmed by Western blot for cleaved caspase-3 and caspase-7 protein expression. The findings show that O₂⁻ and H₂O₂ production and also cell apoptosis were increased during left ventricular hypertrophy (LVH). SNAC treatment reduced oxidative stress during on cardiac remodeling, measured by decreased H₂O₂ and O₂⁻ production (65% and 52%, respectively), and a decrease in the ratio of p-Ser1177 eNOS/total eNOS. Left ventricle (LV) from SNAC-treated mice revealed a 4-fold increase in β₂-AR expression associated with coupling change to Gi; β₂-ARs-S-nitrosation (β₂-AR-SNO) increased 61%, while apoptosis decreased by 70%. These results suggest that the cardio-protective effect of SNAC treatment is primarily through its anti-oxidant role and is associated with β₂-ARs overexpression and β₂-AR-SNO via an anti-apoptotic pathway.

Chasing Cardiac Physiology And Pathology Down The Camkii Cascade.

Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca(2+) in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca(2+) signaling explains the subtle and critical control of important events of ECC and relaxation, such Ca(2+) influx and SR Ca(2+) release and uptake. The multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation, but also in cell death, transcriptional activation of hypertrophy, inflammation and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca(2+) levels. This activity can be sustained, creating molecular memory after the decline in Ca(2+) concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca(2+) regulation and dysregulation in cardiac health and disease.

Electrocardiogram, Heart Movement And Heart Rate In The Awake Gecko (hemidactylus Mabouia).

The electrocardiogram (ECG) is the simplest and most effective non-invasive method to assess the electrical activity of the heart and to obtain information on the heart rate (HR) and rhythm. Because information on the HR of very small reptiles (body mass <10 g) is still scarce in the literature, in the present work we describe a procedure for recording the ECG in non-anesthetized geckos (Hemidactylus mabouia, Moreau de Jonnès, 1818) under different conditions, namely manual restraint (MR), spontaneous tonic immobility (TI), and in the non-restrained condition (NR). In the gecko ECG, the P, QRS and T waves were clearly distinguishable. The HR was 2.83 ± 0.02 Hz under MR, which was significantly greater (p < 0.001) than the HR under the TI (1.65 ± 0.09 Hz) and NR (1.60 ± 0.10 Hz) conditions. Spontaneously beating isolated gecko hearts contracted at 0.84 ± 0.03 Hz. The in vitro beating rate was affected in a concentration-dependent fashion by adrenoceptor stimulation with noradrenaline, as well as by the muscarinic cholinergic agonist carbachol, which produced significant positive and negative chronotropic effects, respectively (p < 0.001). To our knowledge, this is the first report on the ECG morphology and HR values in geckos, particularly under TI. The methodology and instrumentation developed here are useful for non-invasive in vivo physiological and pharmacological studies in small reptiles without the need of physical restraint or anesthesia.

Respostas cardiopulmonares agudas de mulheres no treinamento de força

OBJETIVE: Investigate the cardiopulmonary responses of one strength training session in young women. METHOD: Twenty-three women aged between 18 and 29 years participated in this study. All the volunteers were submitted to the following tests: cardiopulmonary and one-repetition maximum (1-RM). The strength training protocol had emphasis on muscular hypertrophy, three sets from eight to twelve repetitions under 70% of 1-RM, with a one minute thirty-second break between sets. During the training session, the cardiopulmonary variables were measured with a metabolic gas analyzer and a telemetry module. RESULTS: The results of the oxygen consumption in the training session were from 8.43 + 1.76 ml/kg/min and of the heart rate of 108.08 + 15.26 bpm. The results of the oxygen consumption and of the heart rate in the training were lower (p < 0.01) than in the ventilatory threshold and of the oxygen consumption and the heart rate reserves. CONCLUSION: The obtained data show that the present protocol of strength training provided low overload to the cardiopulmonary system of young women.

Variabilidade da frequência cardíaca após treinamento concorrente : comparação entre homens e mulheres de meia-idade = Heart rate variability after concurrent training : comparison between middle-aged men and women

Universidade Estadual de Campinas . Faculdade de Educação Física

New Guidelines Of Cerebral Cardiopulmonary Resuscitation By The American Heart Association (2005 - 2006) [novas Diretrizes De Reanimação Cardiorrespiratória Cerebral Da Sociedade Americana De Cardiologia (2005 - 2006)]

No abstract available