Francesca Palano

Antihypertensive Treatment and Development of Heart Failure in Hypertension: A Bayesian Network Meta-analysis of Studies in Patients With Hypertension and High Cardiovascular Risk

BACKGROUND It is still debated whether there are differences among the various antihypertensive strategies in heart failure prevention. We performed a network meta-analysis of recent trials in hypertension aimed at investigating this issue. METHODS Randomized, controlled trials published from 1997 through 2009 in peer-reviewed journals indexed in the PubMed and EMBASE databases were selected. Selected trials included patients with hypertension or a high-risk population with a predominance of patients with hypertension. RESULTS A total of 223,313 patients were enrolled in the selected studies. Network meta-analysis showed that diuretics (odds ratio [OR], 0.59; 95% credibility interval [CrI], 0.47-0.73), angiotensin-converting enzyme (ACE) inhibitors (OR, 0.71; 95% CrI, 0.59-0.85) and angiotensin II receptor blockers (ARBs) (OR, 0.76; 95% CrI, 0.62-0.90) represented the most efficient classes of drugs to reduce the heart failure onset compared with placebo. On the one hand, a diuretic-based therapy represented the best treatment because it was significantly more efficient than that based on ACE inhibitors (OR, 0.83; 95% CrI, 0.69-0.99) and ARBs (OR, 0.78; 95% CrI, 0.63-0.97). On the other hand, diuretics (OR, 0.71; 95% CrI, 0.60-0.86), ARBs (OR, 0.91; 95% CrI, 0.78-1.07), and ACE inhibitors (OR, 0.86; 95% CrI, 0.75-1.00) were superior to calcium channel blockers, which were among the least effective first-line agents in heart failure prevention, together with β-blockers and α-blockers. CONCLUSIONS Diuretics represented the most effective class of drugs in preventing heart failure, followed by renin-angiotensin system inhibitors. Thus, our findings support the use of these agents as first-line antihypertensive strategy to prevent heart failure in patients with hypertension at risk to develop heart failure. Calcium channel blockers and β-blockers were found to be less effective in heart failure prevention.

Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction

Left ventricular diastolic dysfunction represents a frequent clinical condition and is associated with increased cardiovascular morbidity and mortality. Diastolic dysfunction is the most common cause of HF-PSF (heart failure with preserved ejection fraction). Therefore it becomes important to understand the pathophysiological mechanisms underlying diastolic dysfunction, as well as the effective therapeutic strategies able to antagonize its development and progression. Among the complex pathophysiological factors that may contribute to the development of diastolic dysfunction, the RAAS (renin-angiotensin-aldosterone system) has been shown to play a significant role. Paracrine and autocrine signals of the RAAS promote structural and functional changes in the heart largely linked to increased myocardial fibrosis. Enhanced and dysregulated activity of the RAAS also contributes to the development of volume overload and vasoconstriction with subsequent increases in left ventricular diastolic filling pressures and a higher susceptibility of developing CHF (congestive heart failure). More recently, it has also been suggested that the RAAS may play a role in triggering myocardial and vascular inflammation through the activation of different cell types and the secretion of cytokines and chemokines. RAAS-induced myocardial inflammation leads to perivascular myocardial fibrosis and to the development or progression of diastolic dysfunction. For these reasons pharmacological blockade of the RAAS has been proposed as a rational approach for the treatment of diastolic dysfunction. In fact, ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor blockers) and AAs (aldosterone antagonists) have been demonstrated to delay the development and progression from pre-clinical diastolic dysfunction towards CHF, as well as to reduce the morbidity and mortality associated with this condition.

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers and Diabetes: A Meta-Analysis of Placebo-Controlled Clinical Trials

BACKGROUND To determine whether the administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) on top of standard cardiovascular (CV) therapies may reduce the incidence of new onset diabetes (NOD) in placebo-controlled clinical trials. The effects of these drugs on CV and non-CV mortality were also tested. METHODS We performed a meta-analysis of all randomized clinical trials (11 trials, n = 84,363 patients, aged 64.2 ± 5.86 years), published until 14 March 2010, in which ACE inhibitors or ARBs were compared with placebo and NOD incidence, CV, and non-CV mortality were reported. RESULTS Over an average follow-up of 4.0 ± 1.0 years, there were 1,284/15,142 (8.5%) cases of NOD in active-treated and 1,411/15,130 (9.3%) cases in placebo-treated patients in the ACE inhibitor trials, and 2,330/18,756 (12.4%) cases in active-treated and 2,669/18,800 (14.2%) cases in placebo-treated patients in the ARB trials. Overall, active therapy reduced NOD compared to placebo (odds ratio (OR) 95%, confidence interval (CI): 0.8 (0.8-0.9); P < 0.01). Both ACE inhibitors (OR 95%, CI: 0.8 (0.7-1.0); P = 0.07) and ARBs (OR 95%, CI: 0.8 (0.8-0.9); P < 0.01) reduced NOD as compared to placebo. Active treatment reduced CV mortality (OR 95%, CI: 0.9 (0.8-1.0); P < 0.01) and had a favorable impact on non-CV mortality (OR 95%, CI: 0.7 (0.9-1.0); P = 0.2) as compared to placebo. CONCLUSIONS Our findings demonstrated that ACE inhibitors or ARBs should be preferred in patients with clinical conditions that may increase risk of NOD, since these drugs reduced NOD incidence. In addition, these drugs have favorable effects on CV and non-CV mortality in high CV risk patients.

Do diabetes, metabolic syndrome or their association equally affect biventricular function? A tissue Doppler study

Metabolic syndrome (MetS) and type 2 diabetes (T2DM) have been associated with an impairment of left (LV) and right ventricular (RV) function as well as an increased risk of heart failure (HF). However, it remains unclear whether these clinical entities or their associations promote a similar derangement of biventricular function. Overall, 345 patients without overt cardiovascular disease consecutively underwent routine blood chemistry including high-sensitivity C reactive protein (hs-CRP) and echocardiographical examination with conventional and tissue Doppler imaging (TDI) of both ventricles. According to the ATP III criteria and fasting glucose levels, the study population was stratified into four groups: (1) healthy controls (n=120); (2) MetS without T2DM (n=84); (3) T2DM without MetS (n=49); and (4) MetS+T2DM (n=92). The Myocardial performance index (MPI) of the RV and LV was obtained with a multi-segmental approach using TDI. Patients with MetS and T2DM exhibited a similar impairment of biventricular function compared with healthy controls, whereas a further decline was observed in patients having both MetS and T2DM. In addition to MetS markers, hs-CRP exhibited the strongest association with the MPI of both ventricles. Regression analyses indicated that individual MetS markers were inferior to MetS in identifying subtle cardiac dysfunction. Independent associations of MetS and T2DM with biventricular dysfunction were comparable, and the coexistence of MetS and T2DM exhibited the highest risk for biventricular dysfunction. Our findings emphasize the importance of MetS as an equivalent of T2DM and support a synergic effect of these clinical conditions on cardiac organ damage requiring more aggressive therapeutic strategies to prevent HF.

Antihypertensive therapy in diabetes: the legacy effect and RAAS blockade.

Two recently published post-monitoring follow-up studies of the United Kingdom Prospective Diabetes Study (UKPDS) have shown that although early and intensive treatment of hyperglycemia provides benefits for cardiovascular mortality that extend over time, the effects of a tight antihypertensive strategy in patients with diabetes did not seem to last during the following years. The authors concluded that blood pressure control is of crucial importance in patients with diabetes but is not protective against cardiovascular events when it is not sustained. Several lines of evidence suggest, however, that early and intensive antihypertensive treatment with some classes of drugs exerts benefits that may persist during the following years. Particularly, blockade of the renin-angiotensin-aldosterone system (RAAS) may interrupt the molecular and cellular mechanisms underlying cardiac and vascular remodeling and the maintenance of high blood pressure values. This review article critically discusses current evidence and explores the rationale for a legacy effect of RAAS blockade in hypertensive patients with diabetes.

Relation between right and left ventricular function in patients undergoing chronic dialysis

Aims Occurrence of heart failure during dialysis treatment is associated with high mortality. However, mechanisms underlying left ventricular dysfunction (LVD) in these patients are still elusive. In patients undergoing haemodialysis, arteriovenous fistula (AVF) is associated with right ventricular dysfunction (RVD) and a further impairment is observed when AVF is brachial rather than radial. However, it is not known whether AVF-induced RVD is associated with an impaired left ventricular function. We studied the relation between right and left ventricular function in 120 patients undergoing either haemodialysis or peritoneal dialysis and 100 healthy age-matched controls. Methods Echocardiography including tissue Doppler imaging (TDI) was performed for both ventricles. Average myocardial performance index (MPI) of the right ventricle (RV MPI) was obtained with a multisegmental approach by using TDI. Results RVD was higher in haemodialysis than peritoneal dialysis patients and a further increase was observed in haemodialysis patients with brachial access. Interestingly, RV MPI inversely correlated with indices of both left ventricular contraction and relaxation and the association was even stronger in haemodialysis patients, particularly in those with brachial AVF. Of note, dialysis patients in the upper tertile of RV MPI showed the larger impairment of left ventricular function. Regression analyses showed that RV MPI was independently associated with reduced left ventricular function. By contrast, LVD did not significantly affect right ventricular performance in this setting. Conclusion AVF-induced RVD may contribute to LVD in dialysis patients. AVF plays a pivotal role in triggering LVD via right-to-left ventricular interdependence.

Fixed-combination therapies in hypertension management: Focus on enalapril/lercanidipine

Recent hypertension guidelines have highlighted the need to achieve blood pressure control in order to effectively reduce cardiovascular and renal morbidity and mortality. However, blood pressure control remains poorly achieved in the general population, particularly in high- or very-high-risk hypertensive patients. In view of the growing need to achieve better blood pressure control and provide adequate cardiovascular and renal protection in hypertensive patients, the implementation of combination therapies – especially fixed-dose combinations – is currently recommended. A greater use of fixed-combination therapies, based on a single daily administration of two drugs, in fact, may favor better compliance and adherence to prescribed antihypertensive medications. Among the possible fixed-dose combinations, the one based on angiotensin-converting enzyme inhibitors and calcium-channel blockers, may be considered an effective, safe and well-tolerated approach and may provide a beneficial impact on cardiovascular risk. This article reviews the potential role of fixed-combination therapy in the treatment of hypertension with a specific focus on an emerging calcium-channel blocker angiotensin-converting enzyme inhibitor fixed-dose combination based on a new-generation dihiidropiridinic calcium-channel blocker (lercanidipine) and the prototype angiotensin-converting enzyme inhibitor (enalapril).

Impact of dialysis modality on the appropriateness of left ventricular mass in patients with end-stage renal disease

artery disease and heart failure. Circulation 2006;114:1202–13. [17] Pagano D, Lewis ME, Townend JN, Davies P, Camici PG, Bonser RS. Coronary revascularization for postischaemic heart failure: how myocardial viability affects survival. Heart 1999;82:684–8. [18] Canty Jr JM, Suzuki G, BanasMD, Verheyen F, BorgersM, Fallavollita JA. Hibernating myocardium. Chronically adapted to ischemia but vulnerable to sudden death. Circ Res 2004;94:1142–9. [19] Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151–8. [20] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.

A Novel Electrocardiographic T-Wave Measurement (Tp-Te Interval) as a Predictor of Heart Abnormalities in Hypertension: A New Opportunity for First-Line Electrocardiographic Evaluation.

The aim of the study was to evaluate the role of conventional and new markers of early cardiac organ damage (OD) on 12‐lead electrocardiography (ECG) in 25 outpatients with newly diagnosed untreated essential hypertension compared with 15 normotensive, otherwise healthy individuals. Each participant underwent ECG, echocardiographic, and blood pressure (BP) measurements. Conventional and new ECG indexes for cardiac OD (Tp‐Te interval, ventricular activation time, and P‐wave analysis) were also measured. Clinic and 24‐hour ambulatory BP levels as well as left ventricular mass indexes were significantly higher in hypertensive than in normotensive patients. No significant differences were found between the two groups for ECG and echocardiographic markers of OD. Only Tp‐Te interval was higher in hypertensive than in normotensive individuals (3.06 mm vs 2.24 mm; P<.0001), even after adjustment for anthropometric and clinical parameters. Preliminary results of this study demonstrated prolonged Tp‐Te interval in newly diagnosed, untreated hypertensive outpatients compared with normotensive individuals.

The clinical relevance of dysfunctional HDL in patients with coronary artery disease: A 3-year follow-up study

The well known atheroprotective effects of high density lipoprotein cholesterol (HDL) are based on reverse cholesterol transport as well as anti-inflammatory properties [1,2]. Primary prevention studies have confirmed that HDL levels are strongly associated with reduced cardiovascular events [3]. However, recent evidence supports the notion that HDL functionality may be impaired under certain conditions [4,5]. Ansell and colleagues reported that HDL isolated from subjects with coronary artery disease (CAD) had less antiinflammatory activity than HDL derived from healthy controls, thus providing the first evidence that HDL may be dysfunctional in this setting [6]. Interestingly, in CAD patients HDL has shown to be even proinflammatory, thus increasing monocyte chemiotaxis, reactive oxygen species production, endothelial dysfunction and cellular apoptosis [6,7]. Hence, HDL may not be protective in secondary prevention of coronary artery disease. This issue needs to be rapidly clarified since therapies that raise HDL levels are being investigated for the treatment of CAD patients [8,9]. In the present study we sought to determine whether higher HDL levels maintain their protective effects also in patients with CAD. From March 2006 to April 2009 we consecutively enrolled 184 patients with a first manifestation of CAD (mean age 62±10 years, male/female ratio 3:1). All patients taking lipid-lowering agents or other cardiovascular medications at admission were excluded from the study. Moreover, patients with relevant comorbidities (renal failure, COPD, infective or inflammatory diseases, autoimmune disorders, cancer) were also not considered. All subjects underwent coronary angiography and routine blood chemistry including high sensitivity C-reactive protein (hs-CRP) and lipid profile comprehensive of ApoB-100 and ApoA1 determination. The study was approved by our Institute Committee and all patients signed an informed consent. The study population was divided into groups with higher (N50 for women, N40 formen) and lower HDL levels (≤50 for women, ≤40 for men, Table 1), according to ATPIII criteria [10]. Groups did not significantly differ for demographic and antropometric characteristics as well as for the prevalence of cardiovascular risk factors and left ventricular ejection fraction (EF). Serum creatinine, fasting plasma glucose, uric acid and Pro-BNP were similar in the two groups. HDL and ApoA1 were significantly different but the groups did not differ with regard to LDL and ApoB-100 levels (Table 1). Patients with high HDL had significantly lower triglycerides and hs-CRP values (Table 1). Notably, statin treatment and dose were similar between the two groups (Table 2). Cardiovascular end-points were assessed by clinic visits and programmed phone contacts up to 3 years after the first admission. Determinations of lipid fractions were performed both at baseline and follow-up. No significant changes in HDL levels were observed during follow-up either in patients with high or low HDL (Fig. 1A,B). Major adverse cardiovascular events (MACE) consisted of: (1) mortality for all causes; (2) myocardial infarction (MI); (3) revascularization by percutaneous coronary intervention or by-pass surgery; (4) cerebrovascular events including transient ischemic attack and stroke. Data analysis was performed with SPSS 13.0 software package (SPSS Inc., Chicago). Numerical data are reported as