Polycystic ovarian syndrome increases prevalence of concentric hypertrophy in normotensive obese women.

BACKGROUND: It remains unclear as to whether polycystic ovary syndrome (PCOS) is an additional risk factor in the development of left ventricular (LV) hypertrophy in obese women. In the current study, we provide clarity on this issue by rigorously analysing patient LV geometry beyond the basic clinical measures currently used. Importantly, the cohort contained only normotensive patients that would normally be deemed low risk with no further intervention required. METHODS: The study comprised 24 obese women with PCOS and 29 obese Control women. Transthoracic echocardiography was used to evaluate LV structure/function. Basic clinical and metabolic data were collected for each participant consisting of age, BMI, blood pressure, fasting glucose, LDL-C, HLD-C, cholesterol and triglyceride levels. Exclusion criteria; BMI < 30 g/m2, type 2 diabetes, hypertension. RESULTS: Both groups exhibited concentric remodelling of the LV posterior wall at a prevalence of ~20%, this associated with grade 1 diastolic dysfunction. Estimated LV mass/height2.7 was increased patients with PCOS (45 ± 2.2 vs 37 ± 1.6) with 33% exhibiting LV mass/height2.7 above ASE guidelines, compared to 7% in Controls. Furthermore, 25% of patients with PCOS were characterised with concentric hypertrophy, an alteration in LV geometry that was not observed in the Control group. CONCLUSIONS: To our knowledge, this is the first study to assess LV geometric patterns in obese women with PCOS. The results suggest that obese women with PCOS are at greater risk of concentric hypertrophy than obese only women and provide justification for additional cardiovascular risk assessment in normotensive obese/PCOS women.

Adeno-associated virus 9-mediated RNA interference targeting SOCS3 alleviates diastolic heart failure in rats.

OBJECTIVE: To explore the effect of adeno-associated virus 9-mediated RNA interference targeting SOCS3 (AAV9-SOCS3 siRNA) on the treatment of diastolic heart failure (DHF). METHOD: A rat DHF model was established, and cardiac function and hemodynamic changes were measured. HE, Sirius red and TUNEL staining were applied to observe the pathological changes in the myocardium. Immunoblotting and immunohistochemical staining were utilized to detect SOCS3 expression. The expression levels of various factors, including fibrosis-related factors (collagen I, collagen II, α-SMA and TGF-ß), inflammatory-related factors (IL-1ß, IL-6, TNF-α, p-p65 and ICAM-1) and factors related to the JAK/STAT signal pathway were analyzed by immunoblotting and/or qPCR. The serum levels of IL-1ß, IL-6, and TNF-α were measured using ELISA. RESULTS: SOCS3 expression was significantly downregulated in the DHF rat model by SOCS3 siRNA delivery. In the successfully established DHF rat model, cardiac function was clearly decreased, and cardiomyocyte apoptosis and myocardial fibrosis were significantly increased. These changes were ameliorated by treatment with AAV9-SOCS3 siRNA. The expression levels of p-JAK2 and p-STAT3 were significantly upregulated in the AAV9-SOCS3 siRNA group compared with the sham and AAV9-siRNA control groups, indicating that SOCS3 is a negative regulator of this signaling pathway. The expression levels of collagen I/III, α-SMA and TGF-ß were also decreased at both the mRNA and protein levels. In addition, the serum and myocardial tissue expression levels of inflammatory-related factors, such as IL-6, IL-1ß, and TNF-α, were also reduced by the administration of AAV9-SOCS3 siRNA compared with the AAV9-siRNA control. CONCLUSIONS: SOCS3 gene silencing by AAV9-SOCS3 siRNA administration in a DHF rat model significantly reduced myocardial fibrosis and the inflammatory response and improved heart function. Therefore, this treatment is a potential therapeutic method for treating DHF.

Females Are Protected From Iron-Overload Cardiomyopathy Independent of Iron Metabolism: Key Role of Oxidative Stress.

BACKGROUND: Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood. METHODS AND RESULTS: Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17ß-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury. CONCLUSIONS: Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17ß-estradiol therapy was protective in male iron-overloaded mice.

[Low calorie diet influence optimization on body composition at obese patients with secondary diastolic heart failure].

In open prospective monocentric study in 3 parallel groups we studied the effectiveness of correction of body composition using low calorie diet therapy with inclusion of specialized food products (SFP)--sources of polyphenols and iridoids made on the basis of the juice of Morinda citrifolia L. fruits. We studied 90 patients aged from 30 to 50 years old with grade III obesity and clinically expressed secondary diastolic heart failure. The duration of diet therapy was 42 days. It was shown that low-calorie diet has non-optimal effect on the body composition in morbidly obese patients with secondary diastolic heart failure, namely leading to the expressed loss of body fatless (7.2%, p=0.00008) and muscle mass (by 16.6%, p=0.00004); at the same time the reduction of total body weight is noted only by 2.3% (p=0.053), reduction of waist measurement by 1.3% (p=0.028) and reduction of hips measurement by 1.3% (p=0.09), accompanied by the reduction of body fat by 8.5% (p=0.000017) and of liquid by 7.3% (p=0.0018). The introduction of the SFP into the diet optimizes the effect of low calorie diet therapy on the anthropometric parameters and body composition. The most important effect of the SFP is the ability to prevent the excess loss of muscle mass in patients, and this effect is being dose-dependent. The loss of muscle mass in two groups of patients was 3.1-4.1% after 6 weeks of diet therapy, while in the control group it was 8.5% (p=0.0051). We have concluded that the inclusion of the SFP, manufactured on the basis Morinda citrifolia L. (noni) juice to the low calorie diet allows to initiate mainly the loss of the body fat with the simultaneous protection of active cellular mass, which is without doubt can be considered as the advantage compared to the standard low calorie diet.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition.

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure.

Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) mice underwent either saline (n = 12) or aldosterone (n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNγ (250 U/ml) and/or aldosterone (1 µM). Hypertension was less marked in IFNγKO-aldosterone mice than in WT-aldosterone mice (127 ± 5 vs. 136 ± 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 ± 0.1 vs. 4.3 ± 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 ± 0.1 vs. 2.8 ± 0.1). LV ejection fraction was no different between IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.

Cellular mechanisms for diastolic dysfunction in the human heart.

Left ventricular (LV) diastolic dysfunction is an important contributor to many different cardiovascular diseases. LV diastolic dysfunction can manifest itself as slow LV relaxation, slow LV filling or high diastolic LV stiffness. Diastolic abnormalities have been described in the senescent heart, in heart failure with preserved ejection fraction (HFPEF), in diabetic cardiomyopathy, in aortic valve stenosis (AVS), in hypertrophic cardiomyopathy (HCM), as well as in Fabry disease (FD), however, exact cellular and molecular alterations behind the diastolic deterioration in these diseases are not yet completely characterized. Several studies thoroughly investigated altered cardiomyocyte function, changes of contractile myofilaments, extracellular collagen deposition and advanced glycation end products (AGEs) cross-linking in the background of diastolic dysfunction. These clinical and experimental data suggest that underlying mechanisms of LV diastolic dysfunction are divergent in different cardiac pathologies, therefore the present review aims to summarize mechanisms at the cellular level of diastolic abnormalities in various cardiovascular diseases.

Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction.

OBJECTIVES: We attempted to correlate echocardiographic analysis of diastolic function with changes of myocardial collagen in middle-aged patients with heart failure (HF) despite normal ejection fraction (EF). BACKGROUND: Increased collagen deposition may contribute to the deterioration of the left ventricular compliance and diastolic dysfunction in HF. METHODS: We investigated 41 patients (median age 50 years [interquartile range: 41 to 57 years]) with normal EF (median 62% [interquartile range: 56% to 70%]) whose endomyocardial biopsies were taken previously. Assessment of diastolic function was performed by mitral-flow and tissue Doppler measurements. Sirius red and immunohistologic staining was performed to determine collagen volume fraction (CVF) and cross-linking, collagen types I and III expression, and lysyl-oxidase (LOX) expression. Expression of collagen messenger ribonucleic acid was determined by real-time polymerase chain reaction. RESULTS: Twenty-six patients with HFNEF with diastolic dysfunction showed a significant increase in total collagen and collagen I expression compared with that of 15 controls. This was accompanied with enhanced collagen cross-linking and LOX overexpression in HFNEF. Among all flow Doppler, only deceleration time of E was associated with CVF (R = 0.43), whereas tissue Doppler parameters correlated with CVF, collagen I at the protein and mRNA levels (E' [R = -0.58, -0.60, -0.45]; E'/A' [R = -0.32, -0.36, -0.31]), and left ventricular filling index (E/E' [R = 0.72, 0.68, 0.63]), respectively. No correlation with collagen III was found. The degree of collagen cross-linking and LOX expression was related to E' (R = -0.55 and -0.60) and E/E' (R = 0.72 and 0.71), respectively, but not to flow Doppler. Collagen overexpression correlated with reduced exercise capacity. CONCLUSIONS: Patients with HFNEF showed increased content of myocardial collagen type I, enhanced collagen cross-linking, and LOX expression, which were associated with impaired diastolic tissue Doppler parameters.

Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats.

AIMS: heart growth and function are angiogenesis-dependent, but little is known concerning the effects of key regulators of angiogenesis on diastolic heart failure. Here, we tested the hypothesis that local vascular endothelial growth factor-B (VEGF-B) gene therapy prevents left ventricular diastolic dysfunction. METHODS AND RESULTS: rats were subjected to pressure overload by infusing angiotensin II (33.3 microg/kg/h) for 2 weeks using osmotic minipumps. Intramyocardial delivery of adenoviral vector expressing VEGF-B(167A) improved the angiotensin II-induced diastolic dysfunction compared with LacZ control virus. Local VEGF-B gene transfer increased the mean capillary area in the left ventricle in control and angiotensin II-infused animals, whereas the density of capillaries was not affected. Interestingly, significant increases were noted in Ki67(+) proliferating cells, expression of interleukin1ß, and c-kit(+) cells in response to VEGF-B gene transfer. The increase in cardiac c-kit(+) cells was not associated with an induction of stromal cell-derived factor 1α, suggesting no mobilization of cells from bone marrow. Also, the phosphatidylinositol 3-kinase/Akt pathway was activated. CONCLUSION: VEGF-B gene transfer resulted in prevention of the angiotensin II-induced diastolic dysfunction associated with induction of the Akt pathway, increased proliferation and number of c-kit(+) cells, as well as an increase in the capillary area in the left ventricle. VEGF-B may offer novel therapeutic possibilities for the prevention of the transition from compensated to decompensated cardiac hypertrophy and thereby for the treatment of heart failure.

Prevalencia de la miocardiopatía cirrótica / Cirrhotic cardiomypathy prevalence

Las alteraciones en la función cardiovascular de los pacientes con cirrosis hepática (CH) han sido extensamente descritas durante las últimas décadas. Una de estas es la Miocardiopatía Cirrótica (MC) la cual se define a través de: Un incremento en el gasto cardíaco con una respuesta ventricular enlentecida, Disfunción sistólica y/o diastólica, Ausencia de falla ventricular en reposo, Anormalidades electrofisiológicas como un intervalo Q-T prolongado e incompetencia cronotrópica. La repercusión clínica de la MC suele ser latente o subclínica, sin embargo, ante procedimientos quirúrgicos, hemorragias digestivas, infecciones, etc, podrían desencadenar descompensaciones hemodinámicas letales. El objetivo de este estudio fue conocer la prevalencia de la MC en base a la presencia de alteraciones ecocardiográficas y electrocardiográficas en pacientes con diferentes estadios de disfunción hepática, e independientemente de la causa de la misma. Este trabajo fue una investigación de tipo descriptiva, prospectiva- transversal, que incluyó un total de 30 pacientes cirróticos pertenecientes a la consulta de hepatología. Los hallazgos ecocardiográficos mostraron una función sistólica conservada en 100% de los pacientes; con disfunción diastólica leve en 60 % de los mismos. Entre los hallazgos electrocardiográficos, se comprobó que 20 de los 30 pacientes presentaban prolongación del intervalo QT. La mayoría de los pacientes con evidencia de daño cardíaco se clasificaron como Child C. Se concluye que la MC es un trastorno cardiovascular estructural y funcional leve que se presenta en más de la mitad de los pacientes con diagnóstico de CH de cualquier etiología...

Cardiovascular function disorders in patients with liver cirrhosis (LC) have been comprehensively described in last decades. Cirrhotic cardiomyopathy (CM) is one of them and is defi ned through the increase of the cardiac output with slow ventricular response, systolic and/or diastolic dysfunction, absence of ventricular failure in repose, electrophysiological abnormalities such as long QT interval and chronotropic incompetence. CM’s clinical repercussion uses to be latent or subclinical, however could trigger lethal hemodynamic decompensations in case of surgical procedures, digestive hemorrhages, infections, et cetera. This study was aimed to know the CM prevalence based on the presence of echocardiographic and electrocardiographic disorders in patients with different-staging hepatic dysfunction, regardless its cause. This work was a prospective-cross-sectioned descriptive research that included a total of 30 cirrhotic patients coming from the hepathology consult. Echocardiographic findings showed a patients’ preserved systolic function in 100%, and a light diastolic dysfunction in 60%. The electrocardiographic findings allowed to proving that 20 out 30 patients presented long QT interval. Most of patients evidencing heart damage were classified as Child C. The conclusion is that CM is a light structural and functional cardiovascular disorder which is found in over half of patients with a LC diagnosis regardless its etiology...

Usefulness of left atrial volume for the diagnosis of diastolic heart failure: an echocardiographic-catheterization study.

The present study attempted to determine the accuracy of left atrial volume (LAVi) by transthoracic echocardiography in the diagnosis of diastolic heart failure (DHF) in patients presenting with chronic, isolated dyspnea. We included 28 consecutive patients with a left ventricular ejection fraction >50% without prior history of heart failure. DHF was authenticated in 20 patients by invasive left ventricular end-diastolic pressure >16 mmHg. By logistic regression analysis, LAVi was predictive of DHF (p=0.015). LAVi>38 ml/m(2) was a useful predictor of DHF (area under the ROC curve of 0.84 [0.65-0.95], p<0.001, sensitivity 60%, specificity 100%). The standard cut-off value of 34 ml/m(2) was 70% sensitive and 88% specific.

Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats.

The Ca2+ channel blocker nifedipine has been reported to reduce the rate of new overt heart failure. We investigated the effects of nifedipine on left ventricular remodeling, oxidative stress, and gene expression in the failing heart of Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet from 7 weeks of age were treated with a non-antihypertensive (1 mg/kg per day, Nif-L) or mild-antihypertensive dose of nifedipine (3 mg/kg per day, Nif-H) or with vehicle (Vehicle) from 12 to 19 weeks. Marked left ventricular hypertrophy and fibrosis were apparent and the ratio of collagen type I to type III mRNA levels and the activity of matrix metalloproteinase (MMP)-2 and its mRNA expression in the myocardium were increased in Vehicle at 19 weeks in comparison with Control. Load-induced left ventricular hypertrophy was reduced in Nif-H, but not in Nif-L, relative to that in Vehicle. Treatment with either dose of nifedipine reduced the extent of fibrosis, the collagen type I to type III mRNA ratio, and MMP-2 activity and its mRNA expression compared with those in Vehicle. The decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in the left ventricle of Vehicle were also inhibited by nifedipine at both doses. Nifedipine thus inhibited the development of left ventricular fibrosis and diastolic heart failure in DS rats, independently of its antihypertensive effect. The overall protective action of nifedipine is likely attributable to its antioxidant effect as well as to its antihypertensive action.