Effects Of Pde Type 5 Inhibitors On Left Ventricular Diastolic Dysfunction In Resistant Hypertension.

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

Changes in cardiac heparan sulfate proteoglycan expression and streptozotocin-induced diastolic dysfunction in rats

Background: Changes in the proteoglycans glypican and syndecan-4 have been reported in several pathological conditions, but little is known about their expression in the heart during diabetes. The aim of this study was to investigate in vivo heart function changes and alterations in mRNA expression and protein levels of glypican-1 and syndecan-4 in cardiac and skeletal muscles during streptozotocin (STZ)-induced diabetes. Methods: Diabetes was induced in male Wistar rats by STZ administration. The rats were assigned to one of the following groups: control (sham injection), after 24 hours, 10 days, or 30 days of STZ administration. Echocardiography was performed in the control and STZ 10-day groups. Western and Northern blots were used to quantify protein and mRNA levels in all groups. Immunohistochemistry was performed in the control and 30-day groups to correlate the observed mRNA changes to the protein expression. Results: In vivo cardiac functional analysis performed using echocardiography in the 10-day group showed diastolic dysfunction with alterations in the peak velocity of early (E) diastolic filling and isovolumic relaxation time (IVRT) indices. These functional alterations observed in the STZ 10-day group correlated with the concomitant increase in syndecan-4 and glypican-1 protein expression. Cardiac glypican-1 mRNA and skeletal syndecan-4 mRNA and protein levels increased in the STZ 30-day group. On the other hand, the amount of glypican in skeletal muscle was lower than that in the control group. The same results were obtained from immunohistochemistry analysis. Conclusion: Our data suggest that membrane proteoglycans participate in the sequence of events triggered by diabetes and inflicted on cardiac and skeletal muscles.

Baroreflex Sensitivity Impairment Is Associated With Cardiac Diastolic Dysfunction in Rats

Background: Studies have shown that the autonomic dysfunction accompanied by impaired baroreflex sensitivity was associated with higher mortality. However, the influence of decreased baroreflex sensitivity on cardiac function, especially in diastolic function, is not well understood. This study evaluated the morpho-functional changes associated with baroreflex impairment induced by chronic sinoaortic denervation (SAD). Methods and Results: Animals were divided into sinoaortic denervation (SAD) and control (C) groups. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses, induced by vasoactive drugs. Cardiac function was studied by echocardiography and by left ventricle (LV) catheterization. LV collagen content and the expression of regulatory proteins involved in intracellular Ca(2+) homeostasis were quantified. Results showed higher LV mass in SAD versus C animals. Furthermore, an increase in deceleration time of E-wave in the SAD versus the C group (2.14 +/- 0.07 ms vs 1.78 +/- 0.03 ms) was observed. LV end-diastolic pressure was increased and the minimum dP/dt was decreased in the SAD versus the C group (12 +/- 1.5 mm Hg vs 5.3 +/- 0.2 mm Hg and 7,422 +/- 201 vs 4,999 +/- 345 mm Hg/s, respectively). SERCA/NCX ratio was lower in SAD than in control rats. The same was verified in SERCA/PLB ratio. Conclusions: The results suggest that baroreflex dysfunction is associated with cardiac diastolic dysfunction independently of the presence of other risk factors. (J Cardiac Fail 2011;17:519-525)

Right ventricular diastolic dysfunction in the postoperative period of tetralogy of Fallot

OBJECTIVE: To assess right ventricular diastolic function in the intermediate postoperative period of repair of tetralogy of Fallot. METHODS: We carried out a case-control study with 60 patients divided into 2 groups as follows: 1) group I - 30 patients who had undergone repair of tetralogy of Fallot and 2) group II - 30 healthy children. The 2 groups were paired for age, sex, and body surface. The flows in the pulmonary and tricuspid valves were analyzed with Doppler echocardiography. The presence of anterograde flow at the end of diastole in the pulmonary artery defined restrictive right ventricular physiology. Surgical, radiological, electrocardiographic, and echocardiographic variables were analized in the group I. RESULTS: The velocity of the A wave and the E/A ratio for the tricuspid valve showed significant differences between the groups. Cases with E/A < 1.30 predominated in inspiration (group I - 19/30, and group II - 5/30). The duration of the QRS complex on the electrocardiogram was significantly increased in patients with E/A <1.30. Nineteen (63.3%) patients had restrictive right ventricular physiology, which had a longer postoperative period, longer duration of the QRS complex, and a lower E/A ratio in inspiration. The surgical and radiological variables showed no statistical difference. CONCLUSION: Restrictive right ventricular physiology was detected on the intermediate follow-up of most patients undergoing repair of tetralogy of Fallot. The postoperative period and QRS duration were increased in patients with impairment in diastolic function.

Effects of PDE type 5 inhibitors on Left Ventricular Diastolic Dysfunction in Resistant Hypertension

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

Myocardial fibrosis rather than hypertrophy induces diastolic dysfunction in renovascular hypertensive rats

The aim of the present study was to evaluate the-effect of interstitial fibrosis alone or associated with hypertrophy. on diastolic myocardial function in renovascular hypertensive rats. Myocardial function was evaluated in isolated papillary muscle from renovascular hypertensive Wistar rats (RHT, n = 14), renovascular hypertensive rats treated with the angiotensin converting enzyme inhibitor (ACEI) ramipril, 20 mg.kg(-1).day(-1) (RHT RAM, n = 14), and age-matched unoperated and untreated Wistar rats (CONT, n = 12). The ACEI treatment for 3 weeks allowed the regression of myocyte mass and the maintenance of interstitial fibrosis. Myocardial passive stiffness was analyzed by the resting tension - length relationship. The myocardial fibrosis was evaluated by measuring myocardial hydroxyproline (Hyp) concentration and by histological studies of the myocardium stained with hematoxylin and eosin or picrosirius red. Left ventricular weight was significantly higher in RHT (0.97 +/- 0.12 g) compared with CONT (0.66 +/- 0.06 g) and RHT RAM (0.69 +/- 0.14 g). The Hyp levels were 2.9 +/- 0.4, 3.4 +/- 0.3, and 3.8 +/- 0.4 mu g/mg of dry tissue for the CONT, RHT, and RHT RAM, respectively. Perivascular and interstitial fibrosis were observed in RHT and RHT RAM groups. There were lymphomononuclear inflammatory exudate and edema around arteries, involving adjacent myocytes in the RHT group. There was an increased passive stiffness in RHT and RHT RAM groups compared with the CONT group. In conclusion, our results indicate that the Impaired diastolic function in the renovascular hypertensive rats is related to interstitial fibrosis rather than to myocardial hypertrophy.

Association between left ventricular diastolic dysfunction and severity of chronic obstructive pulmonary disease

OBJECTIVES: ,,,,,The prevalence of electrocardiographic and echocardiographic abnormalities in chronic obstructive pulmonary disease according to disease severity has not yet been established. The aim of this study was to assess the prevalence of electrocardiographic and echocardiographic abnormalities in chronic obstructive pulmonary disease patients according to disease severity. ,,,, ,,,, ,,,,,METHODS: ,,,,,The study included 25 mild/moderate chronic obstructive pulmonary disease patients and 25 severe/very severe chronic obstructive pulmonary disease patients. All participants underwent clinical evaluation, spirometry and electrocardiography/echocardiography. ,,,, ,,,, ,,,,,RESULTS: ,,,,,Electrocardiography and echocardiography showed Q-wave alterations and segmental contractility in five (10%) patients. The most frequent echocardiographic finding was mild left diastolic dysfunction (88%), independent of chronic obstructive pulmonary disease stage. The proportion of right ventricular overload (p<0.05) and blockage of the anterosuperior division of the left bundle branch were higher in patients with greater obstruction. In an echocardiographic analysis, mild/moderate chronic obstructive pulmonary disease patients showed more abnormalities in segmental contractility (p<0.05), whereas severe/very severe chronic obstructive pulmonary disease patients showed a higher prevalence of right ventricular overload (p<0.05), increased right cardiac chamber (p<0.05) and higher values of E-wave deceleration time (p<0.05). Age, sex, systemic arterial hypertension, C-reactive protein and disease were included as independent variables in a multiple linear regression; only disease severity was predictive of the E-wave deceleration time [r2 = 0.26, p = 0.01]. ,,,, ,,,, ,,,,,CONCLUSION: ,,,,,Chronic obstructive pulmonary disease patients have a high prevalence of left ventricular diastolic dysfunction, which is associated with disease severity. Because of this association, it is important to exclude decompensated heart failure during chronic obstructive pulmonary disease exacerbation.

Pamidronate attenuates diastolic dysfunction induced by myocardial infarction associated with changes in geometric patterning

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Exercise training prevents diastolic dysfunction induced by metabolic syndrome in rats

OBJECTIVE: High fructose consumption contributes to the incidence of metabolic syndrome and, consequently, to cardiovascular outcomes. We investigated whether exercise training prevents high fructose diet-induced metabolic and cardiac morphofunctional alterations. METHODS: Wistar rats receiving fructose overload (F) in drinking water (100 g/l) were concomitantly trained on a treadmill (FT) for 10 weeks or kept sedentary. These rats were compared with a control group (C). Obesity was evaluated by the Lee index, and glycemia and insulin tolerance tests constituted the metabolic evaluation. Blood pressure was measured directly (Windaq, 2 kHz), and echocardiography was performed to determine left ventricular morphology and function. Statistical significance was determined by one-way ANOVA, with significance set at p<0.05. RESULTS: Fructose overload induced a metabolic syndrome state, as confirmed by insulin resistance (F: 3.6 +/- 0.2 vs. C: 4.5 +/- 0.2 mg/dl/min), hypertension (mean blood pressure, F: 118 +/- 3 vs. C: 104 +/- 4 mmHg) and obesity (F: 0.31 +/- 0.001 vs. C: 0.29 +/- 0.001 g/mm). Interestingly, fructose overload rats also exhibited diastolic dysfunction. Exercise training performed during the period of high fructose intake eliminated all of these derangements. The improvements in metabolic parameters were correlated with the maintenance of diastolic function. CONCLUSION: The role of exercise training in the prevention of metabolic and hemodynamic parameter alterations is of great importance in decreasing the cardiac morbidity and mortality related to metabolic syndrome.

Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression

Previous studies demonstrated that impaired left ventricular (LV) relaxation in cardiac allografts limits exercise tolerance post-transplant despite preserved systolic ejection fraction (EF). This study tested in human cardiac allografts whether the isovolumic relaxation time (IVRT), which provides the basis for most of diastolic LV filling, relates with gene expression of regulatory proteins of calcium homeostasis or cardiac matrix proteins. Gene expression was studied in 31 heart transplant recipients (25 male, 6 female) 13-83 months post-transplant with LVEF >50%, LV end-diastolic pressure <20 mmHg, normal LV mass index and without allograft rejection or significant cardiac pathology. IVRT related with the other diastolic parameters e-wave velocity (r = -0.46; p = 0.01), e/a-wave ratio (r = -0.5; p < 0.01) but not with heart frequency (r = -0.16; p = 0.4). No relation of IVRT was observed for immunosuppression, mean rejection grade or other medication. IVRT was not related with gene expression of desmin, collagen I, phospholamban, the Na+-Ca2+ exchanger, the ryanodine receptor or interstitial fibrosis but correlated inversely with SERCA2a (r = -0.48; p = 0.02). Prolonged IVRT is associated with decreased SERCA2a expression in cardiac allografts without significant other pathology. Similar observations in non-transplanted patients with diastolic failure suggest that decreased SERCA2a expression is an important common pathomechanism.

Persistent diastolic dysfunction late after valve replacement in severe aortic regurgitation

BACKGROUND: Regression of left ventricular (LV) hypertrophy with normalization of diastolic function has been reported in patients with aortic stenosis late after aortic valve replacement (AVR). The purpose of the present study was to evaluate the effect of AVR on LV function and structure in chronic aortic regurgitation early and late after AVR. METHODS AND RESULTS: Twenty-six patients were included in the present analysis. Eleven patients with severe aortic regurgitation were studied before, early (21 months) and late (89 months) after AVR through the use of LV biplane angiograms, high-fidelity pressure measurements, and LV endomyocardial biopsies. Fifteen healthy subjects were used as controls. LV systolic function was determined from biplane ejection fraction and midwall fractional shortening. LV diastolic function was calculated from the time constant of LV relaxation, peak filling rates, and myocardial stiffness constant. LV structure was assessed from muscle fiber diameter, interstitial fibrosis, and fibrous content. LV muscle mass decreased significantly by 38% early and 55% late after surgery. Ejection fraction was significantly reduced preoperatively and did not change after AVR (P=NS). LV relaxation was significantly prolonged before surgery (89+/-28 ms) but was normalized late after AVR (42+/-14 ms). Early and late peak filling rates were increased preoperatively but normalized postoperatively. Diastolic stiffness constant was increased before surgery (22+/-6 versus 9+/-3 in control subjects; P=0.0003) and remained elevated early and late after AVR (23+/-4; P=0.002). Muscle fiber diameter decreased significantly after AVR but remained increased at late follow-up. Interstitial fibrosis was increased preoperatively and increased even further early but decreased late after AVR. Fibrosis was positively linearly correlated to myocardial stiffness and inversely correlated to LV ejection fraction. CONCLUSIONS: Patients with aortic regurgitation show normalization of macroscopic LV hypertrophy late after AVR, although fiber hypertrophy persists. These changes in LV myocardial structure late after AVR are accompanied by a change in passive elastic properties with persistent diastolic dysfunction.

Diastolic dysfunction of the cardiac allograft and maximal exercise capacity

BACKGROUND: Peak oxygen uptake (peak Vo(2)) is an established integrative measurement of maximal exercise capacity in cardiovascular disease. After heart transplantation (HTx) peak Vo(2) remains reduced despite normal systolic left ventricular function, which highlights the relevance of diastolic function. In this study we aim to characterize the predictive significance of cardiac allograft diastolic function for peak Vo(2). METHODS: Peak Vo(2) was measured using a ramp protocol on a bicycle ergometer. Left ventricular (LV) diastolic function was assessed with tissue Doppler imaging sizing the velocity of the early (Ea) and late (Aa) apical movement of the mitral annulus, and conventional Doppler measuring early (E) and late (A) diastolic transmitral flow propagation. Correlation coefficients were calculated and linear regression models fitted. RESULTS: The post-transplant time interval of the 39 HTxs ranged from 0.4 to 20.1 years. The mean age of the recipients was 55 +/- 14 years and body mass index (BMI) was 25.4 +/- 3.9 kg/m(2). Mean LV ejection fraction was 62 +/- 4%, mean LV mass index 108 +/- 22 g/m(2) and mean peak Vo(2) 20.1 +/- 6.3 ml/kg/min. Peak Vo(2) was reduced in patients with more severe diastolic dysfunction (pseudonormal or restrictive transmitral inflow pattern), or when E/Ea was > or =10. Peak Vo(2) correlated with recipient age (r = -0.643, p < 0.001), peak heart rate (r = 0.616, p < 0.001) and BMI (r = -0.417, p = 0.008). Of all echocardiographic measurements, Ea (r = 0.561, p < 0.001) and Ea/Aa (r = 0.495, p = 0.002) correlated best. Multivariate analysis identified age, heart rate, BMI and Ea/Aa as independent predictors of peak Vo(2). CONCLUSIONS: Diastolic dysfunction is relevant for the limitation of maximal exercise capacity after HTx.