High-intensity interval training improves cardiomyocyte contractile function and myofilament sensitivity to intracellular Ca2+ in obese rats.

High-intensity interval training (HIIT) has shown significant results in addressing adiposity and risk factors associated with obesity. However, there are no studies that investigate the effects of HIIT on contractility and intracellular Ca2+ handling. The purpose of this study was to explore the impact of HIIT on cardiomyocyte contractile function and intracellular Ca2+ handling in rats in which obesity was induced by a saturated high-fat diet (HFD). Male Wistar rats were initially randomized into a standard diet and a HFD group. The experimental protocol spanned 23 weeks, comprising the induction and maintenance of obesity (15 weeks) followed by HIIT treatment (8 weeks). Performance was assessed using the maximum oxygen consumption test ( V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Evaluation encompassed cardiac, adipose and skeletal muscle histology, as well as contractility and intracellular Ca2+ handling. HIIT resulted in a reduction in visceral area, an increase in V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ , and an augmentation of gastrocnemius fibre diameter in obese subjects. Additionally, HIIT led to a decrease in collagen fraction, an increase in percentage shortening, and a reduction in systolic Ca2+/percentage shortening and systolic Ca2+/maximum shortening rates. HIIT induces physiological cardiac remodelling, enhancing the contractile function of cardiomyocytes and improving myofilament sensitivity to Ca2+ in the context of obesity. This approach not only enhances cardiorespiratory and physical performance but also reduces visceral area and prevents interstitial fibrosis.

Heart failure management with ß-blockers: can we do better?

Heart failure (HF) is associated with disabling symptoms, poor quality of life, and a poor prognosis with substantial excess mortality in the years following diagnosis. Overactivation of the sympathetic nervous system is a key feature of the pathophysiology of HF and is an important driver of the process of adverse remodelling of the left ventricular wall that contributes to cardiac failure. Drugs which suppress the activity of the renin-angiotensin-aldosterone system, including ß-blockers, are foundation therapies for the management of heart failure with reduced ejection fraction (HFrEF) and despite a lack of specific outcomes trials, are also widely used by cardiologist in patients with HF with preserved ejection fraction (HFpEF). Today, expert opinion has moved away from recommending that treatment for HF should be guided solely by the LVEF and interventions should rather address signs and symptoms of HF (e.g. oedema and tachycardia), the severity of HF, and concomitant conditions. ß-blockers improve HF symptoms and functional status in HF and these agents have demonstrated improved survival, as well as a reduced risk of other important clinical outcomes such as hospitalisation for heart failure, in randomised, placebo-controlled outcomes trials. In HFpEF, ß-blockers are anti-ischemic and lower blood pressure and heart rate. Moreover, ß-blockers also reduce mortality in the setting of HF occurring alongside common comorbid conditions, such as diabetes, CKD (of any severity), and COPD. Higher doses of ß-blockers are associated with better clinical outcomes in populations with HF, so that ensuring adequate titration of therapy to their maximal (or maximally tolerated) doses is important for ensuring optimal outcomes for people with HF. In principle, a patient with HF could have combined treatment with a ß-blocker, renin-angiotensin-aldosterone system inhibitor/neprilysin inhibitor, mineralocorticoid receptor antagonist, and a SGLT2 inhibitor, according to tolerability.

Effect of chronic exposure to fine particulate matter on cardiac tissue of NZBWF1 mice.

Epidemiological and toxicological studies have shown that inhalation of particulate matter (PM) is associated with development of cardiovascular diseases. Long-term exposure to PM may increase the risk of cardiovascular events and reduce life expectancy. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, autoimmune in nature, that is characterized by the production of autoantibodies that affects several organs, including the heart. Air pollution - which can be caused by several different factors - may be one of the most important points both at the onset and the natural history of SLE. Therefore this study aims to investigate whether exposure to air pollution promotes increased inflammation and cardiac remodelling in animals predisposed to SLE. Female NZBWF1 mice were exposed to an environmental particle concentrator. Aspects related to cardiac remodelling, inflammation and apoptosis were analysed in the myocardium. Body weight gain, cardiac trophism by heart/body weight ratio, relative area of cardiomyocytes and the fibrotic area of cardiac tissue were evaluated during the exposure period. Animals exposed to PM2.5 showed increased area of cardiomyocytes, and area of fibrosis; in addition, we observed an increase in IL-1 and C3 in the cardiac tissue, demonstrating increased inflammation. We suggest that air pollution is capable of promoting cardiac remodelling and increased inflammation in animals predisposed to SLE.

The Role of Extracellular Matrix in the Experimental Acute Aortic Regurgitation Model in Rats.

BACKGROUND: Mechanisms involved in cardiac remodelling by aortic regurgitation (AR) and the moment when cardiac dysfunction begins are largely unknown. This study aimed to investigate cardiac morphology and function after 1, 4, 8, and 12 weeks of experimental AR in Wistar rats. Extracellular matrix was also investigated as the potential mechanism that underlies the AR remodelling process. METHODS: Male Wistar rats underwent surgical acute AR (AR group, n=51) or a sham surgery (sham group, n=32). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 12 weeks. Morphometry of cardiac tissue and the activities of metalloproteinase 2 (MMP-2) and tissue metalloproteinase inhibitor-1 (TIMP-1) were analysed. Statistical analysis was performed by two-way ANOVA. Significance level was 5%. RESULTS: The AR group presented an increase in the sphericity index (week 1); an increase in the left atrium, left ventricular mass index, TIMP-1 and MMP-2 activities, and collagen fraction (week 4); an increase in myocyte area (week 8); and a reduction in fraction shortening (week 12). First, the chamber became more spherical; second, MMP-2 and TIMP-1 were activated and this may have contributed to hypertrophy and atrial enlargement, until systolic dysfunction occurred. CONCLUSIONS: This study showed a sequence of abnormalities that preceded myocardial dysfunction in an experimental model of AR. First, haemodynamic volume overload led to a more spherical left ventricle chamber. Second, MMP-2 and TIMP-1 transitorily increased and may have contributed to atrial enlargement, eccentric hypertrophy, and systolic dysfunction.

The role of glucose metabolism and insulin resistance in cardiac remodelling induced by cigarette smoke exposure.

The aim of this study is to evaluate whether the alterations in glucose metabolism and insulin resistance are mechanisms presented in cardiac remodelling induced by the toxicity of cigarette smoke. Male Wistar rats were assigned to the control group (C; n = 12) and the cigarette smoke-exposed group (exposed to cigarette smoke over 2 months) (CS; n = 12). Transthoracic echocardiography, blood pressure assessment, serum biochemical analyses for catecholamines and cotinine, energy metabolism enzymes activities assay; HOMA index (homeostatic model assessment); immunohistochemistry; and Western blot for proteins involved in energy metabolism were performed. The CS group presented concentric hypertrophy, systolic and diastolic dysfunction, and higher oxidative stress. It was observed changes in energy metabolism, characterized by a higher HOMA index, lower concentration of GLUT4 (glucose transporter 4) and lower 3-hydroxyl-CoA dehydrogenase activity, suggesting the presence of insulin resistance. Yet, the cardiac glycogen was depleted, phosphofructokinase (PFK) and lactate dehydrogenase (LDH) increased, with normal pyruvate dehydrogenase (PDH) activity. The activity of citrate synthase, mitochondrial complexes and ATP synthase (adenosine triphosphate synthase) decreased and the expression of Sirtuin 1 (SIRT1) increased. In conclusion, exposure to cigarette smoke induces cardiac remodelling and dysfunction. The mitochondrial dysfunction and heart damage induced by cigarette smoke exposure are associated with insulin resistance and glucose metabolism changes.

Myocardial fibrosis in chagas disease and molecules related to fibrosis.

Chronic Chagas cardiomyopathy (CCC) is responsible for the disease's greater morbidity and poor prognosis. Although understanding the pathophysiology of CCC and the fundamentals of its clinical management derives from research related to other cardiomyopathies, there are peculiarities that distinguish CCC from the others. CCC is the most fibrous heart disease, and its myocardial involvement is important as it disorganizes or disrupts the extracellular matrix, creating an environment conducive to the formation of arrhythmogenic foci. It is also considered the most arrhythmogenic of the known heart diseases, giving rise to complex arrhythmias, usually associated with varying degrees of stimulus conduction disorders. The central proposal of this review is to describe a possible association between the distribution and degree of myocardial fibrosis and cardiac arrhythmogenicity in patients with Chagas cardiomyopathy, drawing attention to the importance of noninvasive biomarkers for the quantification of myocardial fibrosis.

Prospective Echocardiographic Evaluation of the Right Ventricle and Pulmonary Arterial Pressure in Hyperthyroid Patients.

BACKGROUND: Pulmonary arterial hypertension (PAH) occurs in 35% to 65% of hyperthyroid patients. Despite this high frequency, only a few authors have examined the effects of hyperthyroidism treatment on PAH and the right ventricle. We evaluated the effects of hyperthyroidism and its reversal on cardiovascular structure and function using Doppler echocardiography. METHODS: We prospectively evaluated 32 patients (42.5±11.9years old) with thyrotoxicosis. Exclusion criteria included previous cardiovascular disease. An echocardiogram was performed at the time of hyperthyroidism diagnosis and after normalisation of free thyroxine (T4) levels. Patients were divided into two groups according to the presence or absence of PAH at the diagnosis, or at two moments, before and after T4 normalisation. RESULTS: Graves' disease was the most frequent aetiology (75%) of hyperthyroidism. Pulmonary arterial hypertension was observed in 43.8% of patients. Free T4 concentration was higher in PAH than non-PAH patients. Free T4 normalised after 5 (2.0-10.5; median and percentiles) months of treatment. Cardiac chamber sizes and cardiac output were higher in PAH. Right ventricular (RV) systolic function was impaired in PAH. Cardiac output and free T4 (r=0.42; p<0.05) correlated with pulmonary artery systolic pressure (PASP). Cardiac chamber size, cardiac output, left ventricular ejection fraction, and PASP (34.0±8.6 to 21.7±4.5mmHg) reduced after treatment. Right ventricular myocardial performance index and fractional area change improved after T4 normalisation. CONCLUSIONS: Pulmonary arterial hypertension is highly prevalent in hyperthyroid patients and is combined with increased cardiac chambers size and cardiac output, and impaired RV function. Cardiovascular changes are reversible after T4 normalisation in patients without cardiovascular disease.

Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats.

We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS-Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS-Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS-Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS-Ex than Sham; however, myocyte diameter was higher in AS-Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS-Ex than Sham and glutathione peroxidase was lower in AS-Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS-Ex than AS. The MAPK JNK was higher in AS-Ex than Sham and AS groups. Phosphorylated P38 was lower in AS-Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy.

Potential adverse cardiac remodelling in highly trained athletes: still unknown clinical significance.

Moderate endurance exercise has long been considered an essential element to maintain cardiovascular health, and sedentary behaviour in the general population has been related to a significant increase in all-causes of mortality, cardiovascular disease mortality and cardiovascular disease incidence. However, a growing group of people performs an intense exercise that leads to multiple heart adaptive changes that are collectively called "athlete's heart". In this review, we discussed the evidence of cardiac remodelling process secondary to repetitive and strenuous exercise in some predisposed athletes that produces intense and probably deleterious changes in cardiac morphology and function with no clear clinical significance in long-term follow-up. Moreover, we also discussed the individual biological response to exercise assessed by myocardial damage, inflammation, oxidative stress, fibrosis and ventricular hypertrophy biomarkers showing different intensities with equivalent exertion.

Spondias mombin supplementation attenuated cardiac remodelling process induced by tobacco smoke.

The objective of this study was to investigate the influence of Spondias mombin (SM) supplementation on the cardiac remodelling process induced by exposure to tobacco smoke (ETS) in rats. Male Wistar rats were divided into 4 groups: group C (control, n = 20) comprised animals not exposed to cigarette smoke and received standard chow; group ETS (n = 20) comprised animals exposed to cigarette smoke and received standard chow; group ETS100 (n = 20) received standard chow supplemented with 100 mg/kg body weight/d of SM; and group ETS250 (n = 20) received standard chow supplemented with 250 mg/kg body weight/d of SM. The observation period was 2 months. The ETS animals had higher values of left cardiac chamber diameters and of left ventricular mass index. SM supplementation attenuated these changes. In addition, the myocyte cross-sectional area (CSA) was lower in group C compared with the ETS groups; however, the ETS250 group had lower values of CSA compared with the ETS group. The ETS group also showed higher cardiac levels of lipid hydroperoxide (LH) compared with group C; and, groups ETS100 and ETS250 had lower concentrations of LH compared with the ETS group. Regarding energy metabolism, SM supplementation decreased glycolysis and increased the ß-oxidation and the oxidative phosphorylation. There were no differences in the expression of Nrf-2, SIRT-1, NF-κB, interferon-gamma and interleukin 10. In conclusion, our results suggest that ETS induced the cardiac remodelling process. In addition, SM supplementation attenuated this process, along with oxidative stress reduction and energy metabolism modulation.

Estrategias de tratamiento del paciente con hipertensión arterial esencial: Perfil neurohormonal y geometría ventricular izquierda

La geometría ventricular izquierda, determinada por ecocardiografía bidimensional, proporciona de manera indirecta información sobre el perfil hemodinámico y neurohormonal del paciente hipertenso. En dos estudios pilotos, llevados a cabo en el Instituto de Investigaciones Cardiovasculares de la Universidad de Los Andes hemos utilizado al patrón geométrico como guía para orientar el tratamiento farmacológico del paciente hipertenso. La correspondencia de la estrategia farmacológica con el mecanismo neurohormonal, responsable de la hipertensión arterial, permite un control de la presión arterial con menor número de medicamentos y reduce la incidencia de efectos colaterales y complicaciones. Más aún, el proceso de remodelación cardiaca puede ser influenciado favorable o desfavorablemente, si la estrategia terapéutica empleada se corresponde o no con el mecanismo neurohormonal subyacente. El proceso de remodelación cardiaca, en la transición hacia los dos fenotipos de insuficiencia cardiaca congestiva, se caracteriza por modificaciones opuestas de la geometría y función ventricular. Los pacientes que evolucionan hacia la insuficiencia cardiaca sistólica experimentan una progresiva dilatación de las cavidades cardiacas izquierdas y disminución de la función sistólica. Por el contrario, en los pacientes que evolucionan hacia la insuficiencia cardiaca diastólica, el tamaño de las cavidades cardiacas se reduce y la relajación ventricular se altera.

The neurohormonal and hemodynamic profiles, of uncomplicated hypertensive patients, can be inferred from the left ventricular geometric pattern. We have used the left ventricular geometric pattern to guide the pharmacological treatment of hypertensive patients. Blood pressure control can be achieved with less medications and complications and adverse effects are reduced with a therapeutic strategy aimed at the underlying neurohormonal and hemodynamic profiles. On the contrary, cardiac remodelling is unfavorably influenced by a therapeutic strategy unmatched to the underlying responsable mechanisms. During transition to the two phenotypes of congestive heart failure, cardiac remodelling evolves in opposite directions. Thus, patients with systolic heart failure undergo progressive ventricular dilatation with thinning of its walls, where as, diastolic heart failure patients are characterized by shrinking of their left ventricular cavities with increasing relative wall thickness.