Concurrent Resistance and Cardiorespiratory Training in Patients with Hypertrophic Cardiomyopathy: A Pilot Study.

Background: Exercise training in patients with HCM has evidenced benefits on functional capacity, cardiac function, and a reversion of adverse cardiac remodeling. The objective of this study was to assess the effect of a concurrent resistance and cardiorespiratory training program on functional capacity, biochemical parameters, and echocardiographic variables in a pilot group. Methods: Two HCM patients were evaluated before and after 12 weeks of individualized concurrent training with two sessions/week. Pre- and post-training data were compared for each patient. Evaluations included a cardiopulmonary exercise test (CPET), body composition, echocardiography, electrocardiography, and blood analysis. Results: Training promoted an increase in functional capacity (+4 mL·kg-1·min-1), ventilatory thresholds, and other CPET-derived variables associated with a better prognosis and long-term survival. Muscular mass was augmented (0.8 and 1.2 kg), along with a mean increase of 62% in upper and lower body strength. Echocardiographic features demonstrated the maintenance of cardiac function with signs of positive left ventricular remodeling and an improvement in diastolic function. Blood analyses, including cardiac troponins and NT-proBNP, displayed uneven changes in each patient, but the values fell into normal ranges in both cases. Conclusions: The available data suggest a positive effect of concurrent resistance and cardiorespiratory training on patients' functional capacity and cardiac function that may improve their functional class, quality of life, and long-term prognosis. The replication of this protocol in a larger cohort of patients is warranted to confirm these preliminary results.

Current therapies for hypertrophic cardiomyopathy: a systematic review and meta-analysis of the literature.

AIMS: The aim of this study was to synthesize the evidence on the effect of the current therapies over the pathophysiological and clinical characteristics of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: A systematic review and meta-analysis of 41 studies identified from 1383 retrieved from PubMed, Web of Science, and Cochrane was conducted. Therapies were grouped in pharmacological, invasive and physical exercise. Pharmacological agents had no effect on functional capacity measured by VO2max (1.11 mL/kg/min; 95% CI: -0.04, 2.25, P < 0.05). Invasive septal reduction therapies increased VO2max (+3.2 mL/kg/min; 95% CI: 1.78, 4.60, P < 0.05). Structured physical exercise programmes did not report contraindications and evidenced the highest increases on functional capacity (VO2max + 4.33 mL/kg/min; 95% CI: 0.20, 8.45, P < 0.05). Patients with left ventricular outflow tract (LVOT) obstruction at rest improved their VO2max to a greater extent compared with those without resting LVOT obstruction (2.82 mL/kg/min; 95% CI: 1.97, 3.67 vs. 1.18; 95% CI: 0.62, 1.74, P < 0.05). Peak LVOT gradient was reduced with the three treatment options with the highest reduction observed for invasive therapies. Left ventricular ejection fraction was reduced in pharmacological and invasive procedures. No effect was observed after physical exercise. Symptomatic status improved with the three options and to a greater extent with invasive procedures. CONCLUSIONS: Invasive septal reduction therapies increase VO2max, improve symptomatic status, and reduce resting and peak LVOT gradient, thus might be considered in obstructive patients. Physical exercise emerges as a coadjuvant therapy, which is safe and associated with benefits on functional capacity. Pharmacological agents improve reported NYHA class, but not functional capacity.

Humanized HO-1 BAC transgenic mice: a new model for the study of HO-1 gene regulation.

Heme oxygenase-1 (HO-1) is a ubiquitous inducible stress-response enzyme that plays a central role in tissue homeostasis, in protection against oxidative stress, and in the pathogenesis of disease. Kim et al. report a novel transgenic mouse that lacks the endogenous HO-1 gene but contains the human HO-1 gene with all its regulatory elements. These transgenic animals overexpress HO-1 in basal conditions but maintain HO-1 inducibility, protecting the kidney against glycerol- and cisplatin-induced nephrotoxicity.

Impact of dietary soy isoflavones in pregnancy on fetal programming of endothelial function in offspring.

Epidemiological evidence suggests that soy-based diets containing phytoestrogens (isoflavones) afford protection against cardiovascular diseases (CVDs); however, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which the isoflavones genistein, daidzein, and equol afford protection against oxidative stress remain to be investigated in large scale clinical trials. Isoflavones are transferred across the placenta in both rodents and humans, yet there is limited information on their actions in pregnancy and the developmental origins of disease. Our studies established that feeding a soy isoflavone-rich diet during pregnancy, weaning, and postweaning affords cardiovascular protection in aged male rats. Notably, rats exposed to a soy isoflavone-deficient diet throughout pregnancy and adult life exhibited increased oxidative stress, diminished antioxidant enzyme and eNOS levels, endothelial dysfunction, and elevated blood pressure in vivo. The beneficial effects of refeeding isoflavones to isoflavone-deficient rats include an increased production of nitric oxide and EDHF, an upregulation of antioxidant defense enzymes and lowering of blood pressure in vivo. This review focuses on the role that isoflavones in the fetal circulation may play during fetal development in affording protection against CVD in the offspring via their ability to activate eNOS, EDHF, and redox-sensitive gene expression.

Cardiopulmonary Exercise Test in Patients with Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with chronic diseases frequently adapt their lifestyles to their functional limitations. Functional capacity in Hypertrophic Cardiomyopathy (HCM) can be assessed by stress testing. We aim to review and analyze the available data from the literature on the value of Cardiopulmonary Exercise Test (CPET) in HCM. Objective measurements from CPET are used for evaluation of patient response to traditional and new developing therapeutic measurements. METHODS: A systematic review of the literature was conducted in PubMed, Web of Science and Cochrane in Mar-20. The original search yielded 2628 results. One hundred and two full texts were read after the first screening, of which, 69 were included for qualitative synthesis. Relevant variables to be included in the review were set and 17 were selected, including comorbidities, body mass index (BMI), cardiac-related symptoms, echocardiographic variables, medications and outcomes. RESULTS: Study sample consisted of 69 research articles, including 11,672 patients (48 ± 14 years old, 65.9%/34.1% men/women). Treadmill was the most common instrument employed (n = 37 studies), followed by upright cycle-ergometer (n = 16 studies). Mean maximal oxygen consumption (VO2max) was 22.3 ± 3.8 mL·kg-1·min-1. The highest average values were observed in supine and upright cycle-ergometer (25.3 ± 6.5 and 24.8 ± 9.1 mL·kg-1·min-1; respectively). Oxygen consumption in the anaerobic threshold (ATVO2) was reported in 18 publications. Left ventricular outflow tract gradient (LVOT) > 30 mmHg was present at baseline in 31.4% of cases. It increased to 49% during exercise. Proportion of abnormal blood pressure response (ABPRE) was higher in severe (>20 mm) vs. mild hypertrophy groups (17.9% vs. 13.6%, p < 0.001). Mean VO2max was not significantly different between severe vs. milder hypertrophy, or for obstructive vs. non-obstructive groups. Occurrence of arrhythmias during functional assessment was higher among younger adults (5.42% vs. 1.69% in older adults, p < 0.001). Twenty-three publications (9145 patients) evaluated the prognostic value of exercise capacity. There were 8.5% total deaths, 6.7% cardiovascular deaths, 3.0% sudden cardiac deaths (SCD), 1.2% heart failure death, 0.6% resuscitated cardiac arrests, 1.1% transplants, 2.6% implantable cardioverter defibrillator (ICD) therapies and 1.2 strokes (mean follow-up: 3.81 ± 2.77 years). VO2max, ATVO2, METs, % of age-gender predicted VO2max, % of age-gender predicted METs, ABPRE and ventricular arrhythmias were significantly associated with major outcomes individually. Mean VO2max was reduced in patients who reached the combined cardiovascular death outcome compared to those who survived (-6.20 mL·kg-1·min-1; CI 95%: -7.95, -4.46; p < 0.01). CONCLUSIONS: CPET is a valuable tool and can safely perform for assessment of physical functional capacity in patients with HCM. VO2max is the most common performance measurement evaluated in functional studies, showing higher values in those based on cycle-ergometer compared to treadmill. Subgroup analysis shows that exercise intolerance seems to be more related to age, medication and comorbidities than HCM phenotype itself. Lower VO2max is consistently seen in HCM patients at major cardiovascular risk.

Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones.

Cells have evolved highly regulated defense systems, including the redox sensitive Nrf2-Keap1 signaling pathway involved in the transcriptional activation of phase II defense and antioxidant genes in oxidative stress. Increased generation of reactive oxygen species (ROS) in cardiovascular disease (CVD) leads to impaired endothelial function and reduced nitric oxide (NO) bioavailability. Although epidemiological evidence suggests that diets containing plant-derived isoflavones (phytoestrogens) afford protection against CVDs, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which soy isoflavones (genistein, daidzein, and equol) afford protection against oxidative stress in CVD remain to be investigated in large-scale clinical trials. Studies in animal models and cultured vascular cells have established that isoflavones increase eNOS activity and expression and activate the Nrf2-Keap1 signaling pathway, leading to an upregulation of detoxifying and antioxidant defense genes. We review recent advances in the understanding of the signal transduction pathways involved in the activation of endothelial NO production and Nrf2-Keap1-mediated antioxidant gene expression by dietary isoflavones.

Effect of estrogen and angiotensin-converting enzyme inhibitor on vascular remodeling in ovariectomized spontaneously hypertensive rats.

OBJECTIVE: The present study evaluated whether estrogen influences the effect of angiotensin-converting enzyme inhibition in preventing the vascular remodeling induced by hypertension and also investigated the signal mechanism involved in that effect. DESIGN: Ten-week-old female spontaneously hypertensive rats were ovariectomized (OVX) and randomly assigned to the groups: untreated OVX and treated with 17beta-estradiol (estradiol, 1.5 mg) and/or captopril (5 mg/kg/day). Evolution of systolic blood pressure was determined until 18 weeks. At that time, the heart and mesentery were excised. Structural changes in coronary vessels were quantified by an image analyzer. Inmunoblotting was performed on mesenteric arteries for determination of phosphorylated (ERK1/2). RESULTS: Estradiol treatment enhanced the antihypertensive effect of captopril in OVX rats. Treatment with captopril slightly modified the media cross-sectional area and wall-to-lumen of myocardial arterioles from OVX spontaneously hypertensive rats, whereas coadministration of captopril and estradiol significantly reduced the media cross-sectional area, wall-to-lumen ratio, and perivascular fibrosis in OVX spontaneously hypertensive rats. Captopril alone did not significantly inhibit extracellular signal-regulated kinase 1/2 phosphorylation, whereas coadministration of captopril and estradiol significantly attenuated this parameter. CONCLUSIONS: These results indicate that estrogen may enhance the angiotensin-converting enzyme inhibition-mediated improvement of vascular remodeling in hypertension, which may be partly mediated via inhibition of extracellular signal-regulated kinase 1/2.

Fetal Val108/158Met catechol-O-methyltransferase (COMT) polymorphism and placental COMT activity are associated with the development of preeclampsia.

OBJECTIVE: To evaluate the association between fetal and maternal catechol-O-methyltransferase (COMT) Val158Met and methyl tetrahydrofolate reductase (MTHFR) C677T functional polymorphisms and preeclampsia, examining its influence on placental COMT and in maternal 2-methoxyestradiol (2-ME) plasma levels. DESIGN: Prospective case-control study. SETTING: University hospital. PATIENT(S): A total of 53 preeclamptic and 72 normal pregnant women. INTERVENTION(S): Maternal and cord blood samples and placental tissue samples were obtained. MAIN OUTCOME MEASURE(S): Maternal and fetal COMT and MTHFR polymorphisms were genotyped. Maternal plasma 2-ME and homocysteine levels, and expression and activity of placental COMT were measured. RESULT(S): The odds ratio for the risk of preeclampsia for fetal COMT Met/Met was 3.22, and it increased to 8.65 when associated with fetal MTHFR TT. Placental COMT activity and expression were influenced by genotype, but COMT activity in preeclamptic placentas did not differ from control pregnancies. There was no association between any genotypes and maternal 2-ME. Homocysteine levels were higher in women with preeclampsia than in normal pregnancies, and were inversely correlated with 2-ME plasma levels, indicating that its altered metabolism may lower COMT activity in vivo. CONCLUSION(S): Fetal Met-Met COMT genotype reduces COMT placental expression and activity in vitro and increases preeclampsia, risk but it does not explain the difference in maternal 2-ME levels between preeclamptic and normal pregnancies. However, the preeclamptic patients had elevated homocysteine levels that correlated inversely with 2-ME, indicating that an altered methionine-homocysteine metabolism may contribute to reduce COMT activity in vivo and explain the decreased levels of 2-ME in preeclamptic women.

17beta-estradiol exerts a beneficial effect on coronary vascular remodeling in the early stages of hypertension in spontaneously hypertensive rats.

OBJECTIVE: Estrogens may induce cardioprotective effects and prevent neointima formation in response to vascular injury in vivo. The present study evaluated the effect of 17beta-estradiol on myocardial arterial remodeling and on vascular mitogen-activated protein kinase expression in experimental hypertension. DESIGN: The experiments were performed in intact female spontaneously hypertensive rats (SHR), in SHR that were ovariectomized at 10 or 25 weeks of age, and in ovariectomized SHR that were supplemented with 17 beta-estradiol (OVX + E2, 1.5 mg every 8 weeks, subcutaneous pellets). RESULTS: At 18 weeks of age, in all myocardial arterioles and small arteries studied, we found significant increases in wall-to-lumen ratio in ovariectomized rats as compared with intact animals. 17beta-estradiol significantly reduced the wall-to-lumen ratio in OVX + E2 rats. Perivascular fibrosis of small coronary arteries was significantly increased by ovariectomy, and this effect was prevented by long-term treatment with 17beta-estradiol. Phosphorylated extracellular signal-regulated kinase 1/2 significantly increased in mesenteric arteries from ovariectomized animals and this effect was prevented by 17beta-estradiol. Wall-to lumen ratio and perivascular fibrosis were significantly higher in older intact animals at 33 weeks of age. However, neither ovariectomy nor estradiol replacement had any effect on long-term hypertension-induced vascular remodeling. CONCLUSIONS: These data suggest that estradiol may exert a beneficial effect by protecting the vasculature from hypertension-induced myocardial arterial remodeling in the early stages of hypertension, but not when chronic alterations are established after a long-term period of hypertension.

2-methoxyestradiol plasma levels are associated with clinical severity indices and biomarkers of preeclampsia.

We investigated whether clinical severity indices and biomarkers for preeclampsia (PE) are associated with low plasmatic 2-methoxyestradiol (2ME) in the third trimester of gestation. Blood was collected from 53 women with PE and 73 control pregnant women before parturition. The concentration of 2ME was significantly higher in controls than in patients with PE (2906.43 ± 200.69 pg/mL vs 1818.41 ± 189.25 pg/mL). The risk of PE decreased as 2ME levels increased. The 2ME values were negatively correlated with systolic peak arterial pressure and proteinuria in PE. Additionally, those women with PE with lower 2ME had a more serious clinical situation and needed a more aggressive therapy. Finally, 2ME levels (in patients with PE and total population) were significantly correlated with concentrations of soluble fms-like tyrosine kinase 1 and placental growth factor . Summarizing, patients with PE had lower 2ME levels that were correlated with different clinical indices and biomarkers of severity, indicating that 2ME could be taken into account for the clinical management of this syndrome.

Reactive oxygen and nitrogen species in the renal ischemia/reperfusion injury.

Renal ischemia is the most common cause of acute kidney injury (AKI) still associated with high mortality rates of about 50% in the intensive care unit. Postischemic AKI is characterized by decreased glomerular filtration rate and high renal vascular resistance with endothelial activation and dysfunction, a process of critical importance that is followed by a reduction in microvascular blood flow mainly affecting the renal outer medulla. The pathophysiology of postischemic AKI remains incompletely understood, although it seems to be a phenomenon of altered renal hemodynamics, linked critically to the production of high amounts of nitric oxide and free radicals. On the other hand, and depending on the severity of renal ischemia, tubular epithelial cells undergo a varying degree of necrosis or apoptosis with tubular obstruction followed by both, anatomical and functional recovery. The way in which vascular and tubular epithelium recover determines the final status of the renal function, ranging from full recovery to chronic renal failure and ultimately to end-stage renal disease. In this review we will revise the mechanisms responsible for these pathophysiologic alterations, including the role of heme oxygenase system and sex differences in the susceptibility to ischemic acute renal failure, and we will also review the pre- and postconditioning phenomena, in which brief episodes of ischemia before (pre-conditioning) or after (post-conditioning) the prolonged ischemia have a protective effect on AKI after reperfusion. Interestingly, these protective responses can be elicited by ischemizing distant tissues (remote conditioning). A better understanding of these mechanisms may help to improve the clinical outcome of those patients.

Sexual dimorphism in renal heme-heme oxygenase system in the streptozotocin diabetic rats.

Heme Oxygenase (HO) -1 and -2 exert antioxidant, cytoprotective and vascular actions in male diabetic rats. However, there is no information about the expression and functional significance of the renal HO system in diabetic females. The present study tested the hypothesis that the HO system is differentially regulated in the kidney of female Sprague Dawley diabetic rats, protecting it from nitrosative and glomerular functional damage. Two weeks after the administration of streptozotocin (STZ; 65 mg/kg. i.p), males (DM) and females (DF) showed hyperglycemia, polyuria and elevated kidney/body weight ratio, compared to their control males (CM) and females (CF). In conscious animals, creatinine clearance was higher (0.5 ± 00 vs. 0.3 ± 00; ml/min/100g BW; p<0.05) and urinary albumin excretion was lower (0.7 ± 0.3 vs 3.1 ± 0.7; mg/day) in DF compared to DM. Acute administration of a HO inhibitor stannous mesoporphyrin (SnMP 40 mol/kg, i.v.) induced a greater renal vasoconstrictor response in DF than in DM. Western blot analysis of renal tissue revealed higher renal cortex HO-1 protein levels in DF compared to all other groups; by immunohistochemistry this induction of HO-1 in DF was localized in tubular segments and glomeruli. Furthermore, renal cortical concentration of nitrosylated protein was higher in DM than in DF animals and inversely related with HO-1 levels in both renal cortex and medulla. These data demonstrate that the HO-1 protein is induced in females, associated with renal vasodilation, decreased renal nitrosative stress and reduced albuminuria, indicating that the HO system is protecting the kidney from diabetes-induced damage specifically in females.

Plasma levels of von Willebrand factor are increased in patients with hypertrophic cardiomyopathy.

UNLABELLED: Hypertrophic cardiomyopathy (HCM) is characterised by inappropriate hypertrophy, small-vessel coronary artery disease, myocyte disarray and increased interstitial fibrosis. Microvascular dysfunction is a common finding in HCM and its extent has been proposed as an important prognostic marker. Plasma von Willebrand factor (vWf) is an established marker of endothelial damage or dysfunction; however it has scarcely been studied in HCM. We hypothesised that vWf could be raised in patients with HCM and be related to different variables associated with severity of HCM. METHODS: We included 124 HCM patients, 93 males, aged 48+/-15 years, 59 healthy control subjects with similar age and sex and 20 patients with ischemic heart disease but clinical stability for the last 6 months. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, 24 hours ECG-Holter monitoring, and symptom limited treadmill exercise test. Risk factors for sudden death were evaluated. A blinded cardiac MRI was performed with late enhanced study with Gadolinium. Plasma vWf levels were assayed by commercial ELISA. RESULTS: Patients showed higher levels of vWf (140.0+/-65.0 UI/ml vs 105.0+/-51.0 UI/ml, p<0.001) even after adjusting for ABO blood group. vWf levels were found raised in patients with severe functional class (168.4+/-65.9 UI/mL vs 132.4+/-60.7 UI/mL, p=0.020), atrial fibrillation (175.8+/-69.4 UI/mL vs 133.0+/-59.0 UI/mL, p=0.005), hypertension (161.4+/-60.8 vs 128.9+/-60.5, p=0.010) obstruction (153.9+/-67.9 vs 128.2+/-57.4 UI/mL, p=0.046) and non sustained ventricular tachycardia (159.3+/-59.1 vs 133.0+/-63.0, p=0.049). vWf correlated with age (r:0.26; p=0.006) and obstruction (r:0.22; p=0.021). CONCLUSIONS: We show, for the first time, patients with HCM present significantly raised levels of vWf. These are associated with different conditions related to the severity of the disease.

Effects of oestrogen treatment and angiotensin-converting enzyme inhibition on the microvasculature of ovariectomized spontaneously hypertensive rats.

We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17beta-oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten-week-old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17beta-oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg(-1) day(-1) for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17beta-oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine-induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17beta-oestradiol and/or captopril. In addition, 17beta-oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine-induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17beta-oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17beta-oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.

17Beta-oestradiol enhances the acute hypotensive effect of captopril in female ovariectomized spontaneously hypertensive rats.

The objective of this study was to investigate whether the acute haemodynamic effects of angiotensin-converting enzyme inhibition with captopril could be enhanced by oestrogen administration, and then to evaluate the mechanisms involved in this enhancement. All experiments were performed in 18-week-old female spontaneously hypertensive rats arranged in three experimental groups: intact; ovariectomized (OVX); and ovariectomized plus treatment with 17beta-oestradiol (OVX + E2). These groups were used to evaluate the effects of captopril administration alone, or following bradykinin B2 receptor blockade or nitric oxide synthase inhibition, on a number of haemodynamic parameters (mean arterial pressure, cardiac index, vascular resistance and heart rate). The drop in mean arterial pressure and vascular resistance index in response to captopril was more pronounced in intact and ovariectomized rats treated with 17beta-oestradiol than in ovariectomized animals. Blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis attenuated the synergy between 17beta-oestradiol and captopril. It is concluded that ovariectomy blunted the blood pressure and vascular resistance index drop observed in intact rats in response to captopril. Treatment with 17beta-oestradiol prevented the blunted response to captopril in ovariectomized rats. Kinins and nitric oxide may be involved in the mechanisms of 17beta-oestradiol potentiation of the haemodynamic effects of captopril.