Unsupervised clustering to differentiate rheumatoid arthritis patients based on proteomic signatures.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have different presentations and prognoses. Cluster analysis based on proteomic signatures creates independent phenogroups of patients with different pathophysiological backgrounds. We aimed to identify distinct pathophysiological clusters of RA patients based on circulating proteomic biomarkers. METHOD: This was a cohort study including 399 RA patients. Clustering was performed on 94 circulating proteins (92 CVDII Olink®, high-sensitivity troponin T, and C-reactive protein). Unsupervised clustering was performed using a partitioning cluster algorithm. RESULTS: The clustering algorithm identified two distinct clusters: cluster 1 (n = 223) and cluster 2 (n = 176). Compared with cluster 1, cluster 2 included older patients with a higher burden of comorbidities (cardiovascular and RA related), more erosive and longer RA duration, more dyspnoea and fatigue, walking a shorter distance in the Six-Minute Walk Test, with more severe diastolic dysfunction, and a 4.5-fold higher risk of death or hospitalization for cardiovascular reasons. Tumour necrosis factor (TNF) receptor superfamily-related pathways were mainly responsible for the model's discriminative ability. CONCLUSION: Using unsupervised cluster analysis based on proteomic phenotypes, we identified two clusters of RA patients with distinct biomarkers profiles, clinical characteristics, and different outcomes that could reflect different pathophysiological backgrounds. TNF receptor superfamily-related proteins may be used to distinguish subgroups.

Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Ventricular-arterial coupling (VAC) in a population-based cohort of middle-aged individuals: The STANISLAS cohort.

BACKGROUND AND AIMS: Data exploring normal values of different ventricular-arterial coupling (VAC) parameters and their association with anthropometric and cardiovascular (CV) factors are scarce. We aim to report values of two different methods of VAC assessment according to age and sex and explore their association with CV factors within a large population-based cohort of middle-aged individuals. METHODS: For 1333 (mean age 48 ± 14) individuals participating in the 4th visit of the STANISLAS cohort, VAC was assessed by two methods [1]: arterial elastance (Ea)/end-systolic elastance (Ees) and [2] Pulse wave velocity (PWV)/Global longitudinal strain (GLS). RESULTS: The mean values of Ea/Ees and PWV/GLS were 1.06 ± 0.20 and 0.42 ± 0.12, respectively. The two methods of VAC assessment were poorly correlated (Pearson's correlation coefficient r = 0.14 (0.08; 0.19)). Increased PWV/GLS was associated with older age and a higher degree of cardiovascular risk factors (i.e., BMI, blood pressure, LDL, diabetes, hypertension) in the whole population as well as in the parent generation. In contrast, higher Ea/Ees were associated with decreasing age, and lower prevalence of risk factors in the whole cohort but neutrally associated with risk factors in the parent generation. CONCLUSIONS: Higher PWV/GLS is significantly associated with CV factors regardless of age. In contrast, worse Ea/Ees is associated with a better CV risk profile when considering individuals aged 30 to 70 but neutrally associated with CV factors when considering only older patients. These results may suggest that PWV/GLS should preferably be used to explore VAC. In addition, age-individualized threshold of Ea/Ees should be used.

Prognostic model for total mortality in patients with haemodialysis from the Assessments of Survival and Cardiovascular Events (AURORA) study.

OBJECTIVES: Risk factors of mortality in patients with haemodialysis (HD) have been identified in several studies, but few prognostic models have been developed with assessments of calibration and discrimination abilities. We used the database of the Assessment of Survival and Cardiovascular Events study to develop a prognostic model of mortality over 3-4 years. METHODS: Five factors (age, albumin, C-reactive protein, history of cardiovascular disease and diabetes) were selected from experience and forced into the regression equation. In a 67% random try-out sample of patients, no further factors amongst 24 candidates added significance (P < 0.01) to mortality outcome as assessed by Cox regression modelling, and individual probabilities of death were estimated in the try-out and test samples. Calibration was explored by calculating the prognostic index with regression coefficients from the try-out sample to patients in the 33% test sample. Discrimination was assessed by receiver operating characteristic (ROC) areas. RESULTS: The strongest prognostic factor in the try-out sample was age, with small differences between the other four factors. Calibration in the test sample was good when the calculated number of deaths was multiplied by a constant of 1.33. The five-factor model discriminated reasonably well between deceased and surviving patients in both the try-out and test samples with an ROC area of about 0.73. CONCLUSIONS: A model consisting of five factors can be used to estimate and stratify the probability of death for individuals The model is most useful for long-term prognosis in an HD population with survival prospects of more than 1 year.

NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients.

Aims: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

OBJECTIVE: Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. METHODS: In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. RESULTS: When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). CONCLUSIONS: Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. KEY MESSAGES: In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

Neural modulation for hypertension and heart failure.

Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5-7, 2014.

Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats.

BACKGROUND AND PURPOSE: Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its overactivity in obesity is thought to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesized that early MRA treatment may target obesity-related disorders and consequently delay the development of HF. EXPERIMENTAL APPROACH: Twenty spontaneously hypertensive HF dyslipidaemic obese SHHF(cp/cp) rats and 18 non-dyslipidaemic lean SHHF(+/+) controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA treatment [eplerenone (eple), 100 mg∙kg(-1) ∙day(-1) ] from 1.5 to 12.5 months of age. KEY RESULTS: Eleven months of eple treatment in obese rats (SHHF(cp/cp) eple) reduced the obesity-related metabolic disorders observed in untreated SHHF(cp/cp) rats by reducing weight gain, triglycerides and total cholesterol levels and by preserving adiponectinaemia. The MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating the eccentric cardiac hypertrophy observed in untreated SHHF(cp/cp) animals and preserving ejection fraction (70 ± 1 vs. 59 ± 1%). The MRA also improved survival independently of these pressure effects. CONCLUSION AND IMPLICATIONS: Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF(+/+) and SHHF(cp/cp) rats, whereas SHHF(cp/cp) rats further benefited from the MRA treatment through a reduction in their obesity and dyslipidaemia. These findings suggest that preventive MRA therapy may provide greater benefits in obese patients with additional risk factors of developing cardiovascular complications.

Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.

BACKGROUND: In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF. METHODS AND RESULTS: A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 microgram/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively. CONCLUSIONS: In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.

Evidence of functional myocardial ischemia associated with myocardial dysfunction in brain-dead pigs.

BACKGROUND: Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs. METHODS AND RESULTS: Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10+/-3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt(max), rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt(max), RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt(max), RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism. CONCLUSIONS: Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.

Incidence, clinical and etiologic features, and outcomes of advanced chronic heart failure: the EPICAL Study. Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine.

OBJECTIVES: Characterize the incidence, clinical and etiologic features and outcomes of advanced congestive heart failure. BACKGROUND: This condition is frequent, severe and costly, yet no population-based epidemiological data are available that take into account modern advances in diagnosis and therapy. METHODS: The EPICAL (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) study was based on a comprehensive registration of patients with ACHF (defined as hospital admission for presence of NYHA class III or IV symptoms, radiological and/or clinical signs of pulmonary congestion and/or signs of peripheral edema, left ventricular ejection fraction <30% or a cardiothoracic ratio >60%) in patients aged 20-80 years during year 1994, in the community of the Lorraine region in France (n = 1,592,263). Average follow-up for readmission to hospital and mortality was 18 months (12-24 months). RESULTS: From 2,576 registered patients, 499 were enrolled into the study among which, 358 were new presentations. This represents a crude incidence rate of 225 per million. 46.3% had a coronary heart disease. One-year mortality rate was 35.4% and the rate of mortality and/or readmission to hospital was 81%. Patients were admitted to hospital 2.05 times per year (64% of these for worsening heart failure), spending 27.6 days per year in hospital. Twenty received a heart transplant (4%). On discharge, 74.8% were using ACE inhibitors and 49.6% digitalis. CONCLUSIONS: Mortality and hospitalization rate of advanced CHF remain very high despite recent therapeutic progress. Major therapeutic and managed-care research is required.

Effects of medical therapy on outcome assessment using exercise thallium-201 single photon emission computed tomography imaging: evidence of a protective effect of beta-blocking antianginal medications.

OBJECTIVES: The purpose of this study was to determine whether antianginal medications modify the prognostic significance of exercise single photon emission computed tomography (SPECT) ischemia. BACKGROUND: Antianginal medications (especially beta-adrenergic blocking agents) limit exercise SPECT ischemia, but it is not known whether such medications also modify the prognostic effect of exercise SPECT ischemia. METHODS: We included 352 patients with coronary heart disease, who had exercise Tl-201 SPECT and coronary angiography, and who were initially treated medically. Survival Cox models were applied in patients for whom classes of antianginal medications taken at exercise SPECT were the same as those prescribed for follow-up (GI; n = 136), and in patients for whom new classes of antianginal medications, including beta-blockers (GII; n = 79) or not including beta-blockers (GIII; n = 113), were added for follow-up. RESULTS: During a mean 5.3+/-1.6 years of follow-up, 45 patients had cardiac death or myocardial infarction. Variables reflecting necrosis (irreversible defect extent, left ventricular ejection fraction) and those from coronary angiography provided equivalent prognostic information in the three groups. In contrast, the SPECT variable reflecting ischemia (reversible defect extent), which provided comparable prognostic information in GI (p = 0.005) and GIII (p = 0.004), lost its prognostic significance (p = 0.54) in GII, and was associated with a lower relative risk in GII than in GI or GIII (both p < 0.05). CONCLUSIONS: In patients with coronary heart disease, the introduction of antianginal medications, when including beta-blockers, appears to have a favorable effect on the deleterious prognostic effect of exercise ischemia.

Managing hypertension: a question of STRATHE.

Current international guidelines recommend the use of therapeutic strategies with proven efficacy in the management of hypertension to achieve a target blood pressure of < 140/90 mmHg. After lifestyle intervention, they endorse three different management strategies: (i) first-line use of a low-dose combination of two agents from different antihypertensive classes, with the option of doubling the dose of the combination; (ii) use of a sequential monotherapy strategy, initiating with one antihypertensive to be replaced by another one from a different class, if necessary; and (iii) a stepped care strategy, initiating with one antihypertensive, and increasing the dose or adding another agent from a different class, if necessary. The objective of the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study was to compare the efficacy and tolerability of these three treatment strategies in patients with uncomplicated essential hypertension (n = 533). In all, 62% of the patients in the low-dose combination group were normalised (< 140/90 mmHg), compared with 49% of the sequential monotherapy group (P = 0.01) and 47% of the stepped-care group (P = 0.005). The percentage of patients achieving normalisation without experiencing drug-related adverse events was also significantly higher in the low-dose combination group (56%) than in the sequential monotherapy (42%, P = 0.001) and stepped-care groups (42%, P = 0.004), consistent with the observation that the reduced dosage of the antihypertensive agents in such preparations translates into improved acceptability. The results of STRATHE provide further support for an antihypertensive management strategy involving the low-dose combination of perindopril (2 mg) and indapamide (0.625 mg).

Review of heart failure treatment in type 2 diabetes patients: It's at least as effective as in non-diabetic patients!

Our society is currently facing an epidemic of diabetes and heart failure. Historically, certain cardiology treatments, mainly beta-blockers, have been considered 'dangerous' in diabetic patients, but the time has come for personalized medicine to be applied in the field of cardiology, especially in heart failure (HF). To determine whether HF treatment should be individualized according to diabetes status, this review of the available randomized evidence was carried out, with special emphasis on treatment-effect modification in relation to diabetes. Based on a large body of evidence in the literature, our review concludes that HF treatment should be the same for diabetic and non-diabetic patients. In concurrence, international guidelines now strongly advocate the use of HF drugs, including beta-blockers, in diabetic HF patients. The benefit of HF treatment is at least as favourable in such patients as in non-diabetic patients on a relative basis. Given the higher risk of events in diabetics, this could translate to an even greater absolute impact of HF treatment in these patients, which should further encourage caregivers to more aggressively manage HF in diabetic patients. To this end, non-cardiologists, including general practitioners and endocrinologists/diabetologists who treat diabetic HF patients, should be considered part of the HF drug optimalization process, including the referral of patients to specialized centres for possible implantable cardiac defibrillators and/or cardiac resynchronization indication assessment.

Increased visit-to-visit blood pressure variability is associated with worse cardiovascular outcomes in low ejection fraction heart failure patients: Insights from the HEAAL study.

BACKGROUND: Recent data have highlighted shortcomings of the usual blood pressure (BP) hypothesis in several populations, and emphasized the importance of visit-to-visit variability of BP in predicting cardiovascular events. Herein, we aimed at assessing the association between visit-to-visit BP variability and outcomes in chronic heart failure (CHF) patients enrolled in the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL). METHODS AND RESULTS: The HEAAL study randomized 3834 patients with HF and reduced ejection fraction administered 150 mg or 50mg losartan daily in a double blind, randomized, controlled trial. The patients were followed up for up to 6.8 years after randomization, and BP was measured at 3 time points in the first year and at semi-annual visits in the years thereafter. Three measures of visit-to-visit BP variability were computed for each subject: the standard deviation, the coefficient of variation and the average absolute visit-to-visit variation. Cox proportional hazard models were used to investigate the relationship between variations in systolic blood pressure, baseline covariates and the time to death or heart failure hospitalization (i.e. primary outcome). In multivariate analyses stratified on baseline BP, the patients with higher visit-to visit BP variability exhibited poorer outcomes (average absolute difference in SBP in mmHg:hazard ratio: 1.023 [95% CI (1.013, 1.034), P<0.0001]), independent from high dose losartan (still beneficial). CONCLUSIONS: For the first time, visit-to-visit BP variability was found elevated in CHF patients with reduced ejection fraction, and associated with poorer cardiovascular outcomes. Such assessments should be prioritized for testing prevention strategies in CHF. CLINICAL TRIAL REGISTRATION: This study is registered with the ClinicalTrials.gov, number NCT00090259.

Apolipoprotein E4, lipoprotein lipase C447 and angiotensin-I converting enzyme deletion alleles were not associated with increased wall thickness of carotid and femoral arteries in healthy subjects from the Stanislas cohort.

Studies have shown contrasting results concerning the relation between carotid intima-media thickness (IMT) and apolipoprotein E (apo E) and angiotensin-converting enzyme (ACE) polymorphisms. Subjects, 76 men and 74 women, between 33 and 50 years, without any history of cardiovascular disease and without any anti-hypertensive or lipid lowering medication were selected from the Stanislas cohort. The IMT of carotid and femoral arteries were investigated by B-mode ultrasonography. The common apo E, (C/G)447 lipoprotein lipase (LPL) and I/D ACE gene polymorphisms and serum ACE activity were determined. In the overall sample, male sex, age, systolic blood pressure, BMI, serum apo B level and tobacco consumption were positively correlated with carotid and femoral IMT. The common apo E polymorphism, the (C/G)LPL447 polymorphism and ACE activity were not related to carotid and femoral IMT variability in either men or women. Unexpectedly, the I allele of the ACE gene was related to higher femoral IMT than the D allele in non-smokers only. Similar results were observed after adjustment for the main covariates of IMT variability. In conclusion, amongst our young adult sample the candidate risk factors for cardiovascular disease, apo epsilon4, C447-LPL and D-ACE alleles and ACE activity were not associated with increased carotid and femoral IMT.

Ambulatory 24-h blood pressure assessment of the felodipine-metoprolol combination versus amlodipine in mild to moderate hypertension. Lorraine General Physician Investigators Group.

OBJECTIVE: To measure the time effect profiles of a once daily administered combination tablet felodipine-metoprolol 5/50 mg (Logimax, Astra) and amlodipine 5 mg (Norvasc, Pfizer) on blood pressure and heart rate using 24-h ambulatory blood pressure monitoring. DESIGN: Randomized multicentre parallel-group study with a single-blind placebo run-in period of 4 weeks duration and a 6-week double-blind active treatment period. PATIENTS AND METHODS: Out of 245 randomized outpatients (90 men, 155 women) with uncomplicated mild-to-moderate primary hypertension and mean sitting diastolic blood pressure (DBP) 95-115 mmHg inclusive, 212 (102 on felodipine-metoprolol, 110 on amlodipine) were eligible for analysis. 24-h ambulatory blood pressure monitoring was performed at the end of the placebo run-in (baseline) and after 6 weeks active treatment (posttreatment). RESULTS: Both felodipine-metoprolol and amlodipine induced smooth and consistent reduction in DBP and systolic blood pressure throughout the 24-h period, hence not altering the diurnal rhythm. However, felodipine-metoprolol reduced all average blood pressures (24-h, day- and night-time) more than amlodipine (for 24-h average blood pressure 14.4/9.5 mmHg and 8.9/5.5 mmHg, respectively). Medians of individual diastolic trough-to-peak (T/P) ratios were similar for felodipine-metoprolol and amlodipine (54 and 50%, respectively), while for the systolic T/P ratios, the corresponding values were 74 and 35%, repectively; no significant difference between treatments was seen. As distinguished from amlodipine, both heart rate and rate pressure product were markedly decreased on felodipine-metoprolol throughout the 24-h period and even during the early morning hours. In general, both treatments were well tolerated. CONCLUSIONS: Both felodipine-metoprolol and amlodipine achieved optimal control of blood pressure during the inter-dosing interval in line with their pharmokinetic profiles. The vasodilatory adverse events were slightly more reported with felodipine-metoprolol combination, but due to more pronounced lowering of the average blood pressures and the potent additional effect on heart rate and rate pressure product, the efficacy/tolerability balance seems to be equal to or better than that obtained with monotherapy such as amlodipine.

Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators' Group.

OBJECTIVE: To compare the therapeutic coverage and safety of amlodipine and perindopril in patients with mild to moderate hypertension (diastolic blood pressure > or = 90 mmHg and < or = 109 mmHg). DESIGN: A double-blind, randomized, parallel-group, multicentre study. METHODS: Following a 2-week placebo wash-out period, the patients were randomly allocated to treatment with either amlodipine at 5-10 mg once a day or perindopril at 4-8 mg once a day, for 60 days. Trough: peak ratios were calculated by two different methods (global and individualized approaches) from 24 h ambulatory blood pressure recordings made after the placebo period and after the active treatment period. Residual lowering of blood pressure after single-blind, single-dose omission was also investigated with further 24 h ambulatory blood pressure monitoring. Safety assessments were made throughout the study. RESULTS: The placebo-adjusted, global, diastolic blood pressure trough: peak ratio was 0.80 in the amlodipine group (n = 47) and 0.81 in the perindopril group (n = 49) in an intent-to-treat analysis. The corresponding global systolic blood pressure trough: peak ratio was 0.83 for amlodipine and 0.68 for perindopril. Individual trough: peak ratios were non-normally distributed. Mean (+/- SD) individual trough: peak ratios (intent-to-treat analysis) for diatolic blood pressure were 0.50 +/- 0.69 for amlodipine (median 0.42) and 0.15 +/- 3.27 for perindopril (median 0.33). In the per protocol analysis, the corresponding values were 0.50 +/- 0.72 (median 0.34) for amlodipine and 0.01 +/- 3.90 for perindopril (median 0.21). Both treatments produced comparable decreases in clinic systolic and diastolic blood pressure between days 0 and 60. Forty-eight hours after the last dose, both systolic and diastolic blood pressure were lower in amlodipine-treated patients than perindopril-treated patients. Amlodipine and perindopril were generally well tolerated. The most frequently reported adverse event was leg oedema in amlodipine-treated patients (19.1%), and coughing in perindopril-treated patients (14.3%). CONCLUSIONS: These results showed no statistically significant difference in trough: peak ratios between amlodipine and perindopril. However, the ambulatory blood pressure trough: peak ratios showed very large variations. Determination of trough: peak ratios by the conventional approach or by an individual approach can yield disparate values. After omitting one dose, a condition imitating noncompliance, blood pressure was more effectively controlled with amlodipine than with perindopril.