Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Clinical, Demographic, and Imaging Correlates of Anemia in Heart Failure With Preserved Ejection Fraction (from the RELAX Trial).

Anemia is a commonly occurring comorbidity among patients of heart failure with preserved ejection fraction (HFpEF) but limited data exists on the cardiovascular phenotype of anemia in HFpEF. We sought to characterize the clinical features, exercise capacity, and outcomes in patients with HFpEF to elucidate the phenotype and pathophysiology of anemia in HFpEF. Post hoc analyses of participants enrolled in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial was performed. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Multivariate adjusted regression modeling was done to assess for differences in peak oxygen uptake. Adjusted hazard ratios were generated to assess difference in hospitalization events using a Cox proportional hazards model. Anemic HFpEF patients were more likely to be older, male, and have worse renal function (p <0.05 for all). N-terminal pro-B-type natriuretic peptide, troponin I, pro-collagen III N-terminal peptide, C-telopeptide for type I collagen, uric acid, cystatin-c, and galectin-3 (p <0.05 for all) levels were higher in anemic HFpEF patients. In adjusted models, anemic HFpEF patients had worse exercise capacity (peak oxygen uptake: 11.3 vs 12.1 mL/kg/min; p = 0.004). The hazard for cardiac or renal cause of hospitalization in those with anemia was 2.0 (95% confidence interval: 0.9 to 4.3). Anemic HFpEF patients have worse exercise capacity and are more likely to be hospitalized. A better understanding of the physiologic phenotypes of HFpEF patients may allow for greater personalization of treatment and prognostication in HFpEF patients.

Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

OBJECTIVES: To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF). DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Academic medical center, Winston-Salem, North Carolina. PARTICIPANTS: Older adults (N = 80, aged 71 ± 1; 80% female) with stable compensated HFpEF and controlled blood pressure (BP). MEASUREMENTS: Participants were randomized into a 9-month treatment of spironolactone 25 mg/d vs placebo. Assessments were peak exercise oxygen consumption (VO2 ), 6-minute walk test, Minnesota Living with Heart Failure Questionnaire (MLHFQ), cardiac magnetic resonance imaging, Doppler echocardiography, and vascular ultrasound. RESULTS: Seventy-one participants completed the trial: 37 in the spironolactone group and 34 in the placebo group. Adherence according to pill count was excellent (spironolactone 95%, placebo 97%). Mean spironolactone dose was 24.3 ± 2.9 mg/d and was well tolerated. Spironolactone significantly reduced systolic and diastolic BP at rest and peak exercise. At 9-month follow-up, baseline-adjusted peak VO2, the primary outcome, was 13.5 ± 0.3 mL/kg per minute in the spironolactone group versus 13.9 ± 0.3 mL/kg per minute in the placebo group (adjusted mean difference -0.4 mL/kg per minute; 95% confidence interval = -1.1-0.4 mL/kg per minute; P = .38). The 95% confidence intervals of spironolactone's effect on peak VO2 (-8.2% to 3.2%) excluded a clinically significant beneficial effect. There were also no significant differences in 6-minute walk distance, arterial stiffness, left ventricular (LV) mass, LV mass/end-diastolic volume, or MLHFQ score. CONCLUSION: In older adults with stable compensated HFpEF, 9 months of spironolactone 25 mg/d was well tolerated and reduced BP but did not improve exercise capacity, quality of life, LV mass, or arterial stiffness.

Canola oil rich in oleic acid improves diastolic heart function in diet-induced obese rats.

Obesity is a leading cause of cardiovascular disease. It directly affects heart structure and function and contributes to heart failure. Diet is a major factor involved in the development of obesity along with genetic factors. We examined the effects of monounsaturated and polyunsaturated fatty acid-rich oils on cardiac structure and function in the diet-induced rodent model of obesity (DIO). Obese prone (OP) rats were fed a high-fat diet (HF; 55% of kcal) for 12 weeks; Sprague-Dawley rats fed commercial chow served as control. Echocardiography was performed to assess the cardiac structure and function in all rats at 12 weeks. OP rats fed the HF diet showed significant impairment in diastolic function compared to control rats. The HF diet containing high oleic canola oil significantly improved diastolic function of OP rats compared to the HF diet with lard. In conclusion, canola oil rich in oleic acid, when incorporated into an HF diet, prevents the development of diastolic dysfunction in DIO rats.

[Effect of Kanli Granule on Myocardial Mechanics in Pressure Overload Induced Diastolic Heart Failure Rats].

OBJECTIVE: To observe the effect of Kanli Granule (KG) on myocardial mechanics in pressure overload induced diastolic heart failure (DHF) rats. METHODS: Totally 60 male Wistar rats were divided into the sham-operation group, the model group, the KG group, and the Valsartan group according to random digit table, 15 in each group. The pressure overload induced DHF model was established in all groups except the sham-operation group using abdominal aortic constriction surgery. Totally 7 rats died after modeling (with the mortality of 10. 67%) , and the rest 53 finished the following test. Rats in the KG group were administered with KG extract (calculated as 6. 75 g crude drug/kg) by gastrogavage. Rats in the Valsartan group were administered with Valsartan (7.2 µg/g) by gastrogavage. Equal volume of double distilled water was administered to rats in the model group and the sham-operation group by gastrogavage. All rats were intervened for 32 weeks. The response of isolated heart papillary muscle tonus to isoprenaline (ISO) and adenylate cyclase (Forskolin) was respectively observed. The enhancement phenomenon after resting development force (DF) of isolated heart papillary muscle tonus, and changes of DF in different Ca²âº concentrations were observed. RESULTS: (1) In the ISO response test: Compared with the sham-operation group, the amplifications of DF, ±df/dt, -df/dt were obviously elevated in the model group (P < 0.05). Compared with the model group, the amplifications of DF and ±df/dt were obviously lowered in the KG group (P < 0.01), and the amplification of ±df/dt was also reduced in the Valsartan group (P < 0.01). (2) In the Forskolin response test: Compared with the sham-operation group, the amplifications of DF and ±df/dt obviously increased in the model group (P < 0.05). Compared with the model group, the amplifications of DF and ±df/dt were obviously reduced in the KG group (P < 0.01), and the amplification of DF was also reduced in the Valsartan group (P < 0.05). (3) In post-resting DF enhancement test: Compared with the sham-operation group, the amplification of DF showed gradually decreasing tendency along with prolonged resting time in the model group, and they were obviously lowered at all time points (P < 0.05). Compared with the model group, the amplification of DF was gradually increasing along with prolonged resting time in the KG group. The amplification of DF at post-resting 240 s was obviously larger in the KG group than in the model group (P < 0.05). The amplification of post-resting DF still showed gradually decreasing tendency along with prolonged resting time in the Valsartan group, with increased amplifications of DF at post-resting 60 s and 120 s (P < 0. 05) (4) The amplifications of DF in different Ca²âº concentrations: Compared with the sham-operation group, the amplifications of DF were significantly elevated in different Ca²âº concentrations (1.75, 3.5, 7.0 mmol/L ) (P < 0.05, P < 0.01). Compared with the model group, there was no statistical difference in amplification of DF in different Ca²âº concentrations in the KG group (P > 0.05). The amplifications of DF in different Ca²âº concentrations were significantly reduced in the Valsartan group (P < 0.05). CONCLUSIONS: The ISO response and the Forskolin response were enhanced in isolated heart papillary muscle tonus of pressure overload induced DHF rats; enhanced post-resting DF was reduced; DF in different supra-physiologic levels of Ca²âº was still enhanced. KG could significantly improve excessive enhancement of pressure overload induced DHF rats in ISO response and Forskolin response, and improve enhancement of post-resting myocardium.

Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure).

OBJECTIVES: This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. BACKGROUND: Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. METHODS: Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. RESULTS: Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). CONCLUSIONS: In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.

Effects of PDE type 5 inhibitors on Left Ventricular Diastolic Dysfunction in Resistant Hypertension / Efeitos dos Inibidores da PDE do Tipo 5 sobre a Disfunção Diastólica Ventricular Esquerda na Hipertensão Arterial Resistente

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.

Resveratrol treatment of mice with pressure-overload-induced heart failure improves diastolic function and cardiac energy metabolism.

BACKGROUND: Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload-induced HF and identified physiological and molecular mechanisms contributing to this. METHODS AND RESULTS: C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment. CONCLUSIONS: Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism.

Myocardial energetics and ubiquinol in diastolic heart failure.

Diastolic heart failure, or heart failure with preserved ejection fraction, is a leading cause of morbidity and mortality. There are no current therapies effective in improving outcomes for these patients. The aim of this article is to review the literature and examine the role of coenzyme Q10 in heart failure with preserved ejection fraction related to mitochondrial synthesis of adenosine triphosphate and reactive oxygen species production. The study results reflect that myocardial energetics alters in diastolic heart failure and that there is defective energy metabolism and increased oxidative stress. Studies are emerging to evaluate coenzyme Q10 , particularly ubiquinol, as a supplemental treatment for heart-failure patients. In diastolic heart-failure patients, clinicians are beginning to use supplemental therapies to improve patient outcomes, and one promising complementary treatment to improve left ventricular diastolic function is ubiquinol. Additional studies are needed using large-scale randomized models to confirm if ubiquinol would be beneficial. Since ubiquinol is an antioxidant and is required for adenosine triphosphate production, clinicians and health scientists should be aware of the potential role of this supplement in the treatment of diastolic heart failure.

Pharmacology at work for cardio-oncology: ranolazine to treat early cardiotoxicity induced by antitumor drugs.

Antitumor drugs may cause asymptomatic diastolic dysfunction that introduces a lifetime risk of heart failure or myocardial infarction. Cardio-oncology is the discipline committed to the cardiac surveillance and management of cancer patients and survivors; however, cardio-oncology teams do not always attempt to treat early diastolic dysfunction. Common cardiovascular drugs, such as ß blockers or angiotensin-converting enzyme inhibitors or others, would be of uncertain efficacy in diastolic dysfunction. This perspective describes the potential value of ranolazine, an antianginal drug that improves myocardial perfusion by relieving diastolic wall tension and dysfunction. Ranolazine acts by inhibiting the late inward sodium current, and pharmacological reasonings anticipate that antitumor anthracyclines and nonanthracycline chemotherapeutics might well induce anomalous activation of this current. These notions formed the rationale for a clinical study of the efficacy and safety of ranolazine in cancer patients. This study was not designed to demonstrate that ranolazine reduced the lifetime risk of cardiac events; it was designed as a short term proof-of-concept study that probed the following hypotheses: 1) asymptomatic diastolic dysfunction could be detected a few days after patients completed antitumor therapy, and 2) ranolazine was active and safe in relieving echocardiographic and/or biohumoral indices of diastolic dysfunction, measured at 5 weeks or 6 months of ranolazine administration. These facts illustrate the translational value of pharmacology, which goes from identifying therapeutic opportunities to validating hypotheses in clinical settings. Pharmacology is a key to the success of cardio-oncology.

Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties.

Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring the co-factor tetrahydrobiopterin (BH(4)). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH(4) depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH(4) ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into two groups that received control diet and two groups that received BH(4) supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH(4) treatment. Diastolic sarcomere length (DOCA-salt 1.70±0.01 vs. DOCA-salt+BH(4) 1.77±0.01µm, P<0.001) and relengthening (relaxation constant, τ, DOCA-salt 0.28±0.02 vs. DOCA-salt+BH(4) 0.08±0.01, P<0.001) were also restored to control by BH(4) treatment. pCa(50) for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH(4) treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt compared to sham, but increased after BH(4) treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH(4) treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH(4) ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.

Rosuvastatin slows the development of diastolic dysfunction in calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aims were to test the effect of rosuvastatin on the progression of left ventricular (LV) diastolic function in patients with aortic stenosis (AS), and to evaluate the use of beta-natriuretic-peptide (BNP) as a marker of diastolic dysfunction in this condition. METHODS: Sixty-one hypercholesterolemic, consecutive new referrals with moderate AS were administered rosuvastatin (Crestor) 20 mg/day for 18 months, while a further 60 subjects with normal cholesterol levels remained untreated. The LV diastolic function was determined using conventional Doppler echocardiography, tissue Doppler imaging (TDI); BNP plasma levels were monitored when subjects entered the study and then assessed prospectively at six-month intervals until the study end. RESULTS: After an 18-month (mean 73 +/- 24 weeks) period of treatment with rosuvastatin (Tx group), patients showed a significantly better diastolic function than untreated subjects (uTx group), as indicated by an isovolumic relaxation time (IVRT) (Tx 102.0 +/- 42.8 versus 97.2 +/- 19.1; p < 0.001; uTx 99.7 +/- 21.7 versus 95.2 +/- 21.8 ms; p = 0.032), E/A ratio (Tx 1.0 +/- 0.6 versus 0.9 +/- 0.3, p = 0.52; uTx 1.2 +/- 0.40 versus 0.9 +/- 0.30 versus, p = 0.006), and E/E' ratio (Tx 11.4 +/- 1.5 versus 11.4 +/- 1.8, p = 0.19; uTx 15.4 +/- 1.2 versus 12.3 +/- 1.5, p < 0.001). Similarly, at study end, plasma levels of BNP were significantly lower in the Tx group than in the uTx group [median (1st-3rd quartiles): 37.0 pg/ml (20.1-65.2 pg/ml) versus 57.1 pg/ml (46.9-98.2 pg/ml); p = 0.017]. CONCLUSION: The results of this prospective follow up study of asymptomatic patients showed that rosuvastatin treatment delays the progression of diastolic dysfunction in moderate AS when assessed using hemodynamic echocardiographic parameters or by the release of plasma physiological markers. Hence, the benefits of statin treatment in AS, which are known to affect the valve endothelium, also extend to changes affecting myocardial function itself.

Systemic lupus erythematosus and systemic autoimmune connective tissue disorders behind recurrent diastolic heart failure.

Diastolic heart failure (DHF) remains unexplained in some patients with recurrent admissions after full investigation. A study was directed for screening SLE and systemic autoimmune connective tissue disorders in recurrent unexplained DHF patients admitted at a short-stay and intermediate care unit. It was found that systemic autoimmune conditions explained 11% from all of cases. Therapy also prevented new readmissions. Autoimmunity should be investigated in DHF.

Caveat anicula! Beware of quiet little old ladies: demographic features, pharmacotherapy, readmissions and survival in a 10-year cohort of patients with heart failure and preserved systolic function.

OBJECTIVE: To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD). DESIGN AND SETTING: A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital. MAIN OUTCOME MEASURES: Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival. RESULTS: Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912). CONCLUSIONS: Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

[Drug therapy of diastolic cardiac insufficiency in patients with type 2 diabetes and concomitant essential arterial hypertension].

Therapeutic efficiency of spirapryl and its combination with carvedilol in the treatment of diastolic cardiac insufficiency in patients with type 2 diabetes and essential arterial hypertension (AH). Criteria for inclusion in the study of 86 patients (20 men and 66 women) were diastolic cardiac insufficiency diagnosed as recommended by the Working Group of European Society of Cardiologists (2002). The patients were divided into 2 groups receiving either spirapryl (n = 42) or spirapryl with carvedilol (alpha, beta-adenoblocker). The patients were examined before and 24 weeks after therapy for the evaluation of their clinical condition, tolerance of physical activity, transmitral and transcuspidal diastolic flows (ECG and Doppler-ECG). All therapeutic modalities significantly improved the patients" conditions, diastolic function, and ECG/ECG characteristics, but the best results were obtained with combined therapy that had beneficial effect on transmitral and transcuspidal diastolic flows (P < 0.01) and tolerance of physical exercises (P < 0.05). It is concluded that combined treatment with spirapryl and its combination with carvedilol is more efficient for the management of diastolic cardiac insufficiency than carvedilol monotherapy.

Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

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.