Medical Therapies for Heart Failure With Preserved Ejection Fraction.

Current cardiovascular pharmacotherapy targets maladaptive overactivation of the renin-angiotensin-aldosterone system (RAAS), which occurs throughout the continuum of cardiovascular disease spanning from hypertension to heart failure with reduced ejection fraction. Over the past 16 years, 4 prospective, randomized, placebo-controlled clinical trials using candesartan, perindopril, irbesartan, and spironolactone in patients with heart failure with preserved ejection fraction (HFpEF) failed to demonstrate increased efficacy of RAAS blockade added to guideline-directed medical therapy. We reappraise these trials and their weaknesses, which precluded statistically significant findings. Recently, dual-acting RAAS blockade with sacubitril-valsartan relative to stand-alone valsartan failed to improve outcome in the PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared with Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The majority of patients with HFpEF experience hypertension, frequently with subclinical left ventricular dysfunction, contributed to by comorbidities such as coronary disease, diabetes mellitus, overweight, and atrial fibrillation. Contrasting the findings in HFpEF, trials evaluating RAAS blockade on either side of HFpEF on the cardiovascular continuum in patients with high-risk hypertension and heart failure with reduced ejection fraction, respectively, showed positive outcomes. We do not have a biologically plausible explanation for such divergent efficacy of RAAS blockade. Based on considerations of well-established clinical efficacy in hypertension and heart failure with reduced ejection fraction and the shortcomings of aforementioned clinical trials in HFpEF, we argue that RAAS blockers including MRAs (mineralocorticoid receptor antagonists; aldosterone antagonists) should be used in the treatment of patients with HFpEF.

Heart failure with preserved ejection fraction. / Hjertesvikt med normal ejeksjonsfraksjon.

BACKGROUND: Approximately one half of all patients with heart failure have normal ejection fraction in the left ventricle, and heart failure is attributed to stiffness of the cardiac muscle. The most common cause is hypertension with ventricular hypertrophy. MATERIAL AND METHOD: Literature searches were conducted in PubMed. After we made our selection, a total of 15 articles on heart failure with normal ejection fraction were included. In addition, we included nine articles from our own literature archive. RESULTS: The diagnosis of heart failure with normal ejection fraction presupposes clinical findings consistent with heart failure and objective signs of diastolic dysfunction. The main objective sign is increased left ventricular filling pressure estimated by echocardiography. Ventricular hypertrophy and increased natriuretic peptides support the diagnosis. INTERPRETATION: Underlying conditions and symptoms are treated, and in general the same drugs are used as for heart failure with reduced ejection fraction.

Gender differences in association between uric acid and all-cause mortality in patients with chronic heart failure.

BACKGROUND: Elevated serum uric acid (SUA) is associated with poor prognosis in patients with cardiovascular disease, yet it is still not decided whether the role of SUA is causal or only reflects an underlying disease. The purpose of the study was to investigate if SUA was an independent predictor of 5-year all-cause mortality in a propensity score matched cohort of chronic heart failure (HF) outpatients. Furthermore, to assess whether gender or renal function modified the effect of SUA. METHODS: Patients (n = 4684) from the Norwegian Heart Failure Registry with baseline SUA were included in the study. Individuals in the highest gender-specific SUA quartile were propensity score matched 1:1 with patients in the lowest three SUA quartiles. The propensity score matching procedure created 928 pairs of patients (73.4% males, mean age 71.4 ± 11.5 years) with comparable baseline characteristics. Kaplan Meier and Cox regression analyses were used to investigate the independent effect of SUA on all-cause mortality. RESULTS: SUA in the highest quartile was an independent predictor of all-cause mortality in HF outpatients (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.03-1.37, p-value 0.021). Gender was found to interact the relationship between SUA and all-cause mortality (p-value for interaction 0.007). High SUA was an independent predictor of all-cause mortality in women (HR 1.65, 95% CI 1.24-2.20, p-value 0.001), but not in men (HR 1.06, 95% CI 0.89-1.25, p-value 0.527). Renal function did not influence the relationship between SUA and all-cause mortality (p-value for interaction 0.539). CONCLUSIONS: High SUA was independently associated with inferior 5-year survival in Norwegian HF outpatients. The finding was modified by gender and high SUA was only an independent predictor of 5-year all-cause mortality in women, not in men.

High cardiovascular risk profile in patients with sleep apnea.

OBJECTIVES/HYPOTHESIS: Sleep apnea is associated with hypertension and diabetes, putting these patients at high risk for developing cardiovascular disease. The goal of this study was to identify the individual cardiovascular risk profile and to detect premature and undiagnosed disease in patients with various degrees of sleep apnea. STUDY DESIGN: Cross-sectional. METHODS: Over a 6-month period, we consecutively characterized all patients referred to our sleep laboratory for an initial evaluation of sleep apnea. Clinical history; blood tests with oral glucose tolerance test, when appropriate; test for microalbuminuria; and an electrocardiogram (ECG) were performed. The Framingham general cardiovascular risk score was assessed in each patient. RESULTS: A total of 255 patients were evaluated. Of those, 190 (75%) were diagnosed with sleep apnea. Patients with sleep apnea had a significantly higher Framingham risk score than patients without sleep apnea. Adjusted for age and gender, severe sleep apnea was associated with a 60% increased cardiovascular risk compared with not having sleep apnea. In sleep apnea patients without previously diagnosed hypertension, an additional 45% had significant elevated blood pressure. Among sleep apnea patients without known diabetes, we tested 48% with a pathological glucose disposal. Twenty percent of sleep apnea patients without known heart disease had significant ECG changes. CONCLUSIONS: High Framingham score, undiagnosed hypertension, and pathological glucose disposal were highly prevalent in patients with sleep apnea. Appropriate screening routines are important to detect cardiovascular risk factors in patients with sleep apnea.

Outcome of mitral valve plasty or replacement: atrial fibrillation an effect modifier.

BACKGROUND: Advances in the understanding of mitral valve pathology have laid to mitral valve plasty (MPL) as the procedure of choice of all the mitral intervention as compared to mitral valve replacement (MVR). MATERIAL AND METHODS: A cohort of 355 patients with mitral valve disease operated between January 1993 to January 2007 with closing date first of mars 2011. There were 214 MPL and 141 MVR at the Hospital discharge. This retrospective cohort had the design of exposed (MPL) versus non-exposed (MVR) with outcome total mortality and reoperation during follow up. Also echocardiography follow-up was undertaken to estimate the true long-term failure rate of repair. RESULTS: The mean follow up was 5.3 years SE (3.82) maximum follow up was 14.1 years. Considering the patient time model the association between repair/replacement and total mortality RR = 0.43 95% (0.28-074) p = 0.002 controlling for the confounding effect of 3-vessels disease. Those results were confirmed by propensity score analysis. CONCLUSION: In a cohort of patient with mitral valve disease undergoing MPL/MVR was examined. MPL was associated with better survival, and lower reoperation rate for patients without AF but same rate for patients with AF. We advocate more attention in controlling risk factors of AF in the clinical management of mitral disease. Long-term failure rate of MPL was low during follow up time. A replication of our results by a randomized clinical trial is mandatory.

Prognostic utility of B-type natriuretic peptides in patients with heart failure and renal dysfunction.

BACKGROUND: Renal dysfunction is considered a confounding variable in the interpretation of B-type natriuretic peptides (BNPs) and their amino-terminal fragments (NT-ProBNP) in patients with heart failure (HF). Our aim was to investigate the prognostic utility of BNPs and NT-proBNP in HF outpatients with renal dysfunction, and compare the prognostic significance of the corresponding BNP/NT-ProBNP levels in patients with and without renal dysfunction. METHODS: A total of 2076 patients from 13 HF clinics in the Norwegian Heart Failure Registry were investigated. The BNP/NT-ProBNP levels were categorized centre-wise into four groups using the quartile limits found in patients with preserved renal function. Patients with renal dysfunction, i.e. glomerular filtration rate (GFR) ≤60 mL/min/1.73 m2, were then assigned to BNP groups 1-4 centre-wise according to their level of natriuretic peptides. RESULTS: Renal dysfunction was present in 37.5% of the patients, of whom the majority (59.1%) had levels of natriuretic peptide in the highest BNP group. Patients with renal dysfunction and BNP levels in the lower three BNP groups had similar 2-year survival as patients without renal dysfunction and comparable BNP levels [crude hazard ratio (HR) 1.25, 95% CI 0.82-1.89, P = 0.302, multiple adjusted HR 0.85, 95% CI 0.54-1.33, P = 0.457]. Beyond 2 years of follow-up, renal dysfunction predicted all-cause mortality irrespective of the level of natriuretic peptides at the start of follow-up. CONCLUSION: In HF outpatients, the BNP/NT-ProBNP level predicted 2-year mortality irrespective of renal function and provided important prognostic information on patients with renal dysfunction.

Baseline anemia is not a predictor of all-cause mortality in outpatients with advanced heart failure or severe renal dysfunction. Results from the Norwegian Heart Failure Registry.

OBJECTIVES: The aim of this study was to evaluate the prognostic impact of anemia in outpatients with chronic heart failure attending specialized heart failure clinics and specifically to investigate its prognostic utility in patients with severe renal dysfunction or advanced heart failure. BACKGROUND: Anemia is an independent prognostic marker in patients with heart failure. The effect of anemia on mortality decreases with increasing creatinine levels. METHODS: Multivariate Cox regression analyses were used to investigate the prognostic effect of anemia in 4,144 patients with heart failure from 21 outpatient heart failure clinics in Norway. Severe renal failure was defined as estimated glomerular filtration rate ≤45 ml/min/1.73 m(2) and advanced heart failure as New York Heart Association functional classes IIIb and IV. RESULTS: Baseline anemia was present in 24% and was a strong predictor of all-cause mortality (adjusted hazard ratio [HR]: 1.30, 95% CI: 1.09 to 1.56, p = 0.004). Baseline anemia did not predict mortality in the 752 patients with severe renal dysfunction (adjusted HR: 1.08, 95 % CI: 0.77 to 1.51, p = 0.662) and the 528 patients with advanced heart failure (adjusted HR: 0.87, 95% CI: 0.56 to 1.34, p = 0.542). In the 1,743 patients who attended subsequent visits, sustained anemia independently predicted worse prognosis (adjusted HR: 1.47, 95% CI: 1.10 to 1.94, p = 0.008), whereas transient and new-onset anemia did not. CONCLUSIONS: According to our study, baseline anemia was not an independent predictor of all-cause mortality in outpatients with heart failure and accompanied severe renal dysfunction or advanced heart disease. Sustained anemia after optimizing heart failure treatment might imply worse prognosis independently of renal function and New York Heart Association functional class.

Inflammatory markers as related to disease severity in patients with chronic heart failure: limited effects of exercise training.

BACKGROUND: Chronic heart failure (CHF) is associated with increased inflammation, and exercise training has in some studies been shown to have anti-inflammatory effect, although controversies exist. We investigated the effects of exercise training in CHF patients on markers of inflammation, and further explored any association between inflammation and the severity and etiology of the disease. METHODS: Eighty patients in stable CHF were randomized to 4 months of group-based high intensity exercise training or to a control group. Physical capacity was measured by 6-minute walk test and cycle ergometer test. Blood samples were drawn at baseline, after 4 months and after 12 months follow-up for analyses of a range of biomarkers. RESULTS: Physical capacity was significantly inversely related to CRP, IL-6, VCAM-1 and TGF-ß, and NT pro-BNP levels were significantly correlated to CRP, TNF-α, IL-6, VCAM-1, ICAM-1 and TGF-ß (p < 0.05 for all). Patients with hypertension as etiology of CHF showed higher levels of CRP (p < 0.01), IL-6 (p = 0.05) and TNF-α (p = 0.02) as compared to other etiologies. No significant differences in changes between the exercise group and the control group were obtained in any of the measured variables, except in patients with idiopathic dilated cardiomyopathy (IDCM), where significant reductions in CRP, ICAM-1, TGF-ß and TNF-α levels were observed (p < 0.05 for all). CONCLUSIONS: Measures of CHF severity were significantly correlated with several markers of inflammation. We could not demonstrate over-all anti-inflammatory effect of exercise in this population of CHF patients. However, the etiology of CHF affected the inflammatory profile and the effect of exercise training.

High prevalence of sleep apnea in heart failure outpatients: even in patients with preserved systolic function.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with reduced ejection fraction (EF). However, little is known about the prevalence of SDB in a general heart failure population including patients with preserved EF (HFPEF). METHODS: We prospectively enrolled stable heart failure outpatients from our heart failure clinic to assess the prevalence of SDB independent of systolic left ventricular function. RESULTS: Among 115 patients (62% with reduced EF, 38% with preserved EF, New York Heart Association Class II-IV) SDB was present in 81% (27% central sleep apnea, 54% obstructive sleep apnea [OSA]). HFPEF patients had SDB in 80% of the cases, 62% had OSA. This group had significantly more hypertension. CONCLUSIONS: This study shows a high prevalence of SDB in a general heart failure population, also in patients with HFPEF. These patients have predominantly OSA. Especially in patients with HFPEF SDB should be kept in mind and referral to a sleep specialist should be considered.

The role of beta-blockers in the treatment of chronic heart failure.

The introduction of beta-blockers in the treatment of cardiovascular diseases was a milestone and one of the most important contributions to clinical medicine in the 20th century. For many years, beta-blockers were considered contraindicated in patients with chronic heart failure owing to the negative inotropic action of these substances. With increasing evidence of neurohormonal activation in heart failure patients, there was a focus on the potential role of beta-blockers in the treatment of chronic heart failure. Several large randomized placebo- controlled clinical trials have shown favorable effects of beta-blockers on mortality and morbidity in heart failure patients with impaired systolic function. Beneficial effects in patients with preserved left ventricular systolic function are less clear. A reduction in heart rate is one of several mechanisms by which beta-blockers exert beneficial effects in chronic heart failure. In this article we present results from major clinical trials examining beta-blocker treatment in chronic heart failure patients and discuss heart rate as a therapeutic target in these patients.

The L-arginine-asymmetric dimethylarginine ratio is strongly related to the severity of chronic heart failure. No effects of exercise training.

BACKGROUND: The aim of this study was to relate levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, L-arginine, the substrate for NO generation, and radical oxygen species (ROS) formation to severity of chronic heart failure. The effect of 4 months' group-based exercise training was further investigated. METHOD AND RESULTS: Eighty patients, aged 45-85 years with New York Heart Association (NYHA) functional class II-IIIb, all on optimal medical treatment, were included. A 6-minute walking test and a bicycle exercise test were performed, and fasting blood samples were collected for determination of N-terminal pro-brain natriuretic peptide (NT-proBNP), L-arginine, ADMA, and ROS generation in circulating leukocytes. ADMA levels were significantly higher in patients in NYHA functional class III versus II (P = .024), and the L-arginine-ADMA ratio was significantly lower (P = .005). After adjustment for covariates, L-arginine-ADMA ratio was associated with 6-minute walking distance (P = .004), exercise capacity (P = .026), and inversely with NT-proBNP (P = .015). Stimulated levels of peroxynitrite on monocytes were inversely related to left ventricular ejection fraction (P = .005). No effect of 4 weeks' exercise training on the measured variables was obtained. CONCLUSIONS: The strong relationship seen between L-arginine-ADMA ratio, ROS formation in leukocytes, and severity of chronic heart failure contributes to increased knowledge of endothelial dysfunction related to the NO pathway in such patients.

Renal function in outpatients with chronic heart failure.

BACKGROUND: Impaired renal function confers an adverse prognosis in patients with heart failure (HF). The aims of the present study were to identify factors associated with and predictive of impaired renal function and to assess the relationship between estimated glomerular filtration rate (eGFR) and all-cause mortality in outpatients with HF. METHODS AND RESULTS: Baseline data on 3605 patients (median age 73 years, 70.1% men) from 24 outpatient HF clinics in Norway were analyzed. Median follow-up time was 9 months. Renal dysfunction (eGFR < 60 mL/min) was present in 44.9%. The population was randomized into equal-sized model-building and validation samples to enhance model stability. eGFR was an independent predictor of all-cause mortality (HR 0.94 per 5 mL/min increase, P = .001). Use of spironolactone (P = .002), higher blood pressure (P < .001), and lower hemoglobin levels (P = .002) were predictors of impaired renal function. Increasing doses of loop diuretics were strongly associated with eGFR at baseline (P < .001), but only tended to predict worsening renal function during follow-up (P = .08). CONCLUSIONS: Clinically significant reduction in renal function was prevalent in outpatients with HF, and was a strong predictor of all-cause mortality. Use of loop diuretics and spironolactone should be carefully evaluated as these agents may adversely affect renal function.

Do screening blood pressure and plasma catecholamines predict development of hypertension? Twenty-year follow-up of middle-aged men.

OBJECTIVES: The sympathetic nervous system is implicated in the development and maintenance of hypertension. However, the predictive impact of arterial plasma catecholamines has never been reported. We investigated arterial catecholamines and blood pressures (BPs) prospectively over 20 years in a group of well-characterized middle-aged men. METHODS: Fifty-six of original 79 men were available for the follow-up. Multiple regression analysis was done with mean BP at follow-up as a dependent variable, and arterial plasma catecholamines and BP at baseline as independent variables. RESULTS: Half of the originally normotensive men developed hypertension during follow-up. There were significant differences in the screening BP values measured at baseline between the new hypertensives and the sustained normotensives. Multiple regression analysis revealed arterial adrenaline at baseline as an independent predictor of mean BP at follow-up in the new hypertensives (beta = 0.646, R2 = 0.42, p = 0.007). Furthermore, arterial noradrenaline at baseline was a negative independent predictor of mean BP at follow-up in the sustained normotensives (beta = -0.578, R2 = 0.334, p = 0.020). Noradrenaline increased with age in the group as a whole (1318+/-373 vs 1534+/-505 pmol/l, p = 0.010) while adrenaline did not change. CONCLUSION: Our data suggest that arterial adrenaline is involved in the development of hypertension over 20 years in middle-aged men. Men with sustained normotension may have an inherent protection against sympathetic overactivity. Furthermore, screening BP at baseline in normotensive men differentiated between those who developed hypertension and those who remained normotensive at follow-up.

The antioxidative effects of long-term treatment are more pronounced for carvedilol than for atenolol in post-myocardial infarction patients.

Oxidative stress might exert deleterious cardiovascular effects. The aim of the present study was to compare the antioxidative effects of carvedilol and atenolol. Levels of oxidized low-density lipoprotein cholesterol (ox-LDL), vitamin E, and thiobarbituric acid reactive substances (TBARS) were measured. In a prospective, open, and end-point-blinded study, 232 patients with an acute myocardial infarction (AMI) were randomized to receive either carvedilol or atenolol at equipotent doses, and the previously mentioned 3 parameters were measured at baseline and after 12 months of active treatment, with changes during the study period being compared both within and between the groups. Ox-LDL decreased in both treatment modalities, from 40.5 +/- 15.6 to 35.0 +/- 13.8 U/L, P = 0.0001, in the carvedilol group and from 40.3 +/- 16.5 to 37.4 +/- 13.1 U/L, P = 0.044, in the atenolol group, with a significant between-group difference in the changes (P = 0.036). The levels of vitamin E did not change during carvedilol treatment (31.0 +/- 10.2 vs 31.7 +/- 11.1 micromol/L), but it decreased marginally in the atenolol group (30.8 +/- 12.1 vs 27.2 +/- 9.1 micromol/L, P = 0.056), with a significant between-group difference (P = 0.008). No significant change in TBARS was observed between the carvedilol and atenolol groups (P = 0.454). These results indicate that carvedilol has a more pronounced antioxidative effect than atenolol in post-AMI patients, which might be of clinical importance.

Treatment of hypertension in patients with congestive cardiac failure.

Hypertension is a major risk factor for the development of cardiac failure. Patients with severe heart failure and left ventricular ejection fraction <40% are excluded from the majority of hypertension trials. The European Guidelines recommend treatment of hypertension in patients with heart failure and the introduction of blood pressure-lowering drugs that deal with the underlying disease. Several of the drugs may be needed in combination to achieve target blood pressure.

Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years.

BACKGROUND: Increased sympathetic activity may be an underlying mechanism in cardiovascular disease. It has been hypothesized that the degree of left ventricular (LV) hypertrophy is partly related to the blood pressure level, and partly to neurohormonal factors. The aim of this study was to investigate predictors of LV mass, including arterial plasma noradrenaline as an index of sympathetic activity, with particular emphasis on subjects who developed hypertension over a period of 20 years. METHODS: In a 20-year prospective study of middle-aged men, sustained hypertensives (n = 22), new hypertensives (crossovers) (n = 17) and sustained normotensives (controls) (n = 17) were examined both at baseline and after 20 years of follow-up (at ages 42.1 +/- 0.5 and 62.3 +/- 0.6 years, respectively). Relationships between arterial plasma catecholamines, blood pressure and body mass index at baseline to left ventricular parameters by echocardiography at follow-up were investigated. RESULTS: Groups were homogeneous regarding age, gender, race and body build. The group of sustained hypertensives had significantly more LV hypertrophy (P = 0.025) and diastolic dysfunction (P = 0.010). Among the crossovers, LV mass index was positively correlated to arterial plasma noradrenaline (r = 0.50, P = 0.043) and body mass index (BMI) (r = 0.51, P = 0.039) and showed a positive trend with systolic blood pressure (SBP) at baseline. Arterial plasma noradrenaline (beta = 0.47) was found to predict LV mass index after 20 years independently of BMI (beta = 0.45) and SBP (beta = 0.22) at baseline (R adjusted = 0.345, P = 0.037). Such a relationship was not found in the controls or in the sustained hypertensives, of which 16 were treated with antihypertensive drugs. CONCLUSIONS: Arterial plasma noradrenaline at baseline, as an index of sympathetic activity, predicts LV mass at follow-up independently of systolic blood pressure and body build in middle-aged men who developed hypertension over a period of 20 years.

The angiotensin receptor antagonist valsartan: a review of the literature with a focus on clinical trials.

Valsartan is an angiotensin receptor antagonist that specifically blocks the angiotensin II type 1 receptors. It is an effective and well-tolerated once-daily antihypertensive agent, with a tolerability profile similar to placebo. A recent series of large-scale clinical trials have shown the benefits of valsartan in disease states beyond hypertension. Based on the results of the Val-HeFT (Valsartan in Heart Failure Trial) and VALIANT (Valsartan in Acute Myocardial Infarction Trial) studies, valsartan is indicated for use in patients with heart failure and in patients post-myocardial infarction. Recently, in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial, valsartan was no more cardioprotective than calcium channel blockers, but was shown to reduce the risk of developing new-onset diabetes in hypertensive patients at high risk of cardiac events compared with calcium antagonist treatment. In diabetic patients with microalbuminuria, valsartan has been shown to have benefits beyond those attributable to blood pressure lowering alone.