Therapeutic Advances in Cardiovascular Disease recent issues

Changes seen in the aging kidney and the effect of blocking the renin--angiotensin system

Tue, 06 Oct 2009 09:21:11 PDT

Background: The objective was to evaluate structural changes of glomeruli during aging and the role of chronic renin—angiotensin system inhibition (RASi) on these changes; starting RASi on Wistar rats at two different moments: the first group after weaning and the second at the midpoint of their lifespan (12 months).

Methods: Thirty rats were divided, after weaning, into three groups of 10: group 1: control (C); group 2 : 30 mg/kg/day losartan (L); group 3 : 10 mg/kg/day enalapril (E). At 18 months, rats were placed in metabolic cages to evaluate proteinuria, then killed. Another group of 24 rats, 12 months old, were divided into three groups of eight: group 1: C; group 2: L; group 3: E. At 18 months the same procedure described above was carried out. Finally, a third group of 20 rats was studied as healthy controls and killed: 10 rats at 7 months and ten at 12 months of age. Tissue samples were collected after sacrifice. To evaluate glomerular fibrotic changes, both focal and periglomerular sclerosis, and mesangial matrix expansion, a scoring scale was established. We also evaluated anti--SM-actin and anti-collagen-III immunolabeling. Glomerular area was measured using an image analyzer.

Results: Proteinuria and serum creatinine increased with age but were reduced in treated animals. Main glomerular changes present in 18-month-old rats were reduced by half in treated animals. Glomerular area showed significant increase with normal aging and all treatment strategies protected against it.

Conclusion: RAS plays a central role in natural process of renal aging, probably by producing effects influencing the biology of aging, the effects of which can be attenuated by RASi.

Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure

Jablonski, K. L., Gates, P. E., Pierce, G. L., Seals, D. R. — Tue, 06 Oct 2009 09:21:11 PDT

Background: Age and increasing systolic blood pressure (BP) are associated with vascular endothelial dysfunction, but the factors involved are incompletely understood. We tested the hypothesis that vascular endothelial function is related to dietary sodium intake among middle-aged and older adults (MA and O) with elevated systolic BP.

Methods: Data were analyzed on 25 otherwise healthy adults aged 48—73 years with high normal systolic BP or stage I systolic hypertension (130—159 mmHg). Self-reported sodium intake was <100 mmol/d in 12 (7 M) subjects (low sodium, 73±6 mmol/d) and between 100 and 200 mmol/d in 13 (9 M) subjects (normal sodium, 144±6 mmol/d).

Results: Groups did not differ in other dietary factors, age, body weight and composition, BP, metabolic risk factors, physical activity and maximal aerobic capacity. Plasma concentrations of norepinephrine, endothelin-1, oxidized low-density lipoproteins (LDL), antioxidant status and inflammatory markers did not differ between groups. Brachial artery flow-mediated dilation (FMD) was 42% (mm ) to 52% (% ) higher in the low versus normal sodium group (p < 0.05). In all subjects, brachial artery FMD was inversely related to dietary sodium intake (FMD mm r =—0.40, p < 0.05; %r =—0.53, p < 0.01). Brachial artery FMD was not related to any other variable. In contrast, endothelium-independent dilation did not differ between groups (p ≥ 0.24) and was not related to sodium intake in the overall group (p ≥ 0.29).

Conclusions: Low sodium intake is associated with enhanced brachial artery FMD in MA and O with elevated systolic BP. These results suggest that dietary sodium restriction may be an effective intervention for improving vascular endothelial function in this high-risk group.

Aggressive statin therapy in multicenter and effectiveness for the reduction of intra-myocardial damage caused by non-ST elevation acute coronary syndrome: AMERICA study

Tue, 06 Oct 2009 09:21:11 PDT

Background: While preprocedural statin treatment for acute coronary syndrome (ACS) is widely regarded as beneficial, there has been no prospective randomized multicenter trial of patients with non-ST elevation ACS in the Japanese population to examine the efficacy of preprocedural aggressive statin use. The aim of this study was to confirm this effect by prospective randomized multicenter design.

Methods: Fifty patients who presented with non-ST elevation ACS were enrolled, and randomly assigned to aggressive statin administration before percutaneous coronary intervention (PCI). Troponin-T (TnT), creatine phosphokinase (CK), CK-myocardial band (CK-MB), high-sense C-reactive protein (hs-CRP), and brain natriuretic peptide (BNP) were measured at baseline and/ or after procedure.

Results: Three days after PCI, the statin group had significantly less CK elevation compared with the nonstatin group (84±17 IU/l versus 180±68 IU/l, respectively, p = 0.02). CK-MB elevation also tended to be lower in the statin group than in the nonstatin group (3.2±1.9 versus. 7.0±3.0, respectively, p = 0.07), as was BNP level (3.2±1.9 versus 7.0±3.0 pg/ml, respectively, p = 0.07). The change of serum LDL cholesterol was significantly correlated with CK (p = 0.01) and TnT (p = 0.02) at 1 day after PCI.

Conclusions: Aggressive statin usage before PCI to Japanese patients with non-ST elevation ACS appears to reduce myocardial damage after procedure. The degree of serum lipid level reduction may reflect the vulnerability of atheromatous plaques that could cause cardiac damage after PCI.

Some mechanical aspects of arterial aging: physiological overview based on pulse wave analysis

Hashimoto, J., Ito, S. — Tue, 06 Oct 2009 09:21:11 PDT

Aging has a striking impact on the arterial structure and function. The principal structural change with age is medial degeneration that leads to a progressive stiffening of the large elastic arteries. Large artery stiffening increases aortic systolic and pulse pressures through an increase in the forward incident wave and an early return of the backward reflected wave. Peripheral muscular arteries/arterioles are only minimally affected in structure by aging itself, but impaired vasomotor function can alter their impedance properties and thereby increase reflection magnitude. An augmented aortic pressure due to enhanced wave reflection increases wasted left ventricular effort and causes cardiac hypertrophy. Increased pulsatile pressure and flow stresses extend to the vulnerable microcirculation of vasodilated organs such as the brain and kidneys, and can predispose to cerebral lacunar infarction and albuminuria. Although most currently available vasodilators appear to have little direct effect on degenerated elastic arteries, they can act instead on less-degenerated muscular arteries to markedly reduce peripheral wave reflection magnitude and central aortic pressure, and thus contribute to the regression of left ventricular hypertrophy. Further studies are necessary to examine whether the effect of vasodilator therapy on reducing wave reflection contributes similarly to the prevention of microvascular damage in the brain and kidneys.

Blocking aldosterone in heart failure

Shafiq, M. M., Miller, A. B. — Tue, 06 Oct 2009 09:21:11 PDT

Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone’s actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.

Treating type 2 diabetes: incretin mimetics and enhancers

Nori Janosz, K. E., Zalesin, K. C., Miller, W. M., McCullough, P. A. — Tue, 06 Oct 2009 09:21:11 PDT

As a consequence of excess abdominal adiposity and genetic predisposition, type 2 diabetes is a progressive disease, often diagnosed after metabolic dysfunction has taken hold of multiple organ systems. Insulin deficiency, insulin resistance and impaired glucose homeostasis resulting from beta-cell dysfunction characterize the disease. Current treatment goals are often unmet due to insufficient treatment modalities. Even when combined, these treatment modalities are frequently limited by safety, tolerability, weight gain, edema and gastrointestinal intolerance. Recently, new therapeutic classes have become available for treatment. This review will examine the new therapeutic classes of incretin mimetics and enhancers in the treatment of type 2 diabetes.

Therapeutic efficacy of renin--angiotensin blockade in patients receiving dialysis

Suzuki, H. — Tue, 06 Oct 2009 09:21:11 PDT

Observational data in dialysis patients has indicated an increased cardiovascular mortality. One pathophysiological cause of this cardiovascular mortality in these patients is volume overload. In addition, an inappropriately activated renin—angiotensin system (RAS) has been proposed as another possible mechanism for the increased cardiovascular mortality. With these possible causes in mind, blockade of the RAS with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) have both emerged as means of preventing cardiovascular events in this population. This review focuses on clinical evidence of the beneficial effects of ACE inhibitors and ARBs in dialysis patients with regard to the improvement of cardiovascular events as well as blood pressure control and maintenance of dialysis therapy.

Dual ACE-inhibition and AT1 receptor antagonism improves ventricular lusitropy without affecting cardiac fibrosis in the congenic mRen2.Lewis rat

Jessup, J. A., Westwood, B. M., Chappell, M. C., Groban, L. — Tue, 28 Jul 2009 07:52:46 PDT

Background: Hypertension and left ventricular (LV) hypertrophy often precede diastolic dysfunction and are risk factors for diastolic heart failure. Although pharmacologic inhibition of the renin-angiotensin system (RAS) improves diastolic function and functional capacity in hypertensive patients with LV hypertrophy, the effects of combination therapy with an angiotensin converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) are unclear.

Method: We assessed the effects of the combined 10-week administration of lisinopril (10 mg/kg/ day, p.o.) and losartan (10 mg/kg/day, p.o.) (LIS/LOS) on diastolic function and LV structure in seven young (5 weeks), prehypertensive congenic mRen2.Lewis male rat, a model of tissue renin overexpression and angiotensin II (Ang II)-dependent hypertension compared to vehicle (VEH) treated (n = 7), age-matched rats.

Results: Systolic blood pressures were 64% lower with the combination therapy (p < 0.001), but there were no differences in heart rate or systolic function between groups. RAS inhibition increased myocardial relaxation, defined by tissue Doppler mitral annular descent (e') by 2.2 fold (p < 0.001). The preserved lusitropy in the LIS/LOS-treated rats was accompanied by a reduction in phospholamban-to-SERCA2 ratio (p < 0.001). Despite lower relative wall thicknesses (VEH: 1.56±0.17 versus LIS/LOS: 0.78±0.05) and filling pressures, defined by the transmitral Doppler-to-mitral annular descent ratio (E/e', VEH: 28.7±1.9 versus LIS/LOS: 17.96±1.5), no differences in cardiac collagen were observed.

Conclusion: We conclude that the lusitropic benefit of early dual RAS blockade may be due to improved vascular hemodynamics and/or cardiac calcium handling rather than effects on extracellular matrix reduction.

High blood pressure in Latin America: a call to action

Rubinstein, A., Alcocer, L., Chagas, A. — Tue, 28 Jul 2009 07:52:46 PDT

High blood pressure (BP) is an enormous global problem, and is especially challenging for low- and middle-income countries such as those of Latin America. Although developed countries have benefited from significant reductions in cardiovascular and cerebrovascular disease in recent decades, comparable reductions have not been achieved in Latin America. In fact, the prevalence of high BP is increasing in many Latin American countries, and the situation will worsen without definitive efforts to correct it. The growing preponderance of hypertension and chronic diseases, coupled with expected increases in population growth, present a mounting threat to Latin American economies. This report provides a comprehensive overview of the burden of high BP throughout Latin America, and presents recommendations for change. The dismal observations warrant a call to action for improved control of high BP and other cardiovascular risk factors across Latin America. Achieving these ambitious goals will require collaborative efforts by many groups, including policymakers, international organizations, healthcare providers, schools and society as a whole.

Smoking cessation pharmacotherapy

Frishman, W. H. — Tue, 28 Jul 2009 07:52:46 PDT

Cigarette smoking remains an important risk factor for premature cardiovascular disease and its many complications. There are clear benefits from treating tobacco dependence on the rate of clinical outcomes. In addition to behavioral therapies, various pharmacologic strategies have been developed to help achieve this goal. First-line therapies include nicotine replacement, bupropion and varenicline, a partial nicotine antagonist. Second-line treatments include clonidine and nortriptyline. Additional treatment strategies with less proven efficacy include monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, opioid receptor antagonists, bromocriptine, anti-anxiety drugs, nicotinic receptor antagonists (e.g. mecamylamine) and glucose tablets. Various approaches under investigation include inhibitors of the hepatic P450 enzyme (e.g. methoxsalen), cannabinoid-1 receptor antagonists (e.g. rimonabant), and nicotine vaccines.

The Jupiter study, CRP screening, and aggressive statin therapy-implications for the primary prevention of cardiovascular disease

Kones, R. — Tue, 28 Jul 2009 07:52:47 PDT

CRP levels are strong, independent predictors of cardiovascular risk and can enhance risk stratification. Jupiter enrolled 17 802 apparently healthy middle-aged men and women with CRP levels over 2.0 mg/l, and LDL less than 130 mg/dl. They were randomized to receive rosuvastatin 20 mg daily or placebo, and followed for a primary endpoint of nonfatal myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death for 1.9 years. Rosuvastatin lowered CRP (37%), LDL (50%), nonfatal myocardial infarction (55%), nonfatal stroke (48%), hospitalization and revascularization (47%), all-cause mortality (20%), and benefited women and minority subgroups. Rosuvastatin was tolerated relatively well, with a small rise in physician-reported diabetes. Jupiter data suggest that patients with high levels of CRP should receive statins. Approximately 4.3% of the population satisfies Jupiter inclusion criteria. A review of the assessment of cardiovascular risk is under way at the National Institutes of Health to guide practitioners.

Nitric oxide mechanisms of nebivolol

Maffei, A., Lembo, G. — Tue, 28 Jul 2009 07:52:47 PDT

β-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral resistance. Third-generation β-blockers avoid this adverse effect by inducing vasodilation through different mechanisms. In particular, nebivolol, a highly selective blocker of β₁-adrenergic receptors, is the only β-blocker known to induce vascular production of nitric oxide, the main endothelial vasodilator. The specific mechanism of nebivolol is particularly relevant in hypertension, where nitric oxide dysfunction occurs. Indeed, nebivolol is able to reverse endothelial dysfunction. Nebivolol induces nitric oxide production via activation of β₃-adrenergic receptors, which can explain the good metabolic profile observed after treatment with this drug. Moreover, nebivolol can also stimulate the β₃-adrenergic receptor-mediated production of nitric oxide in the heart, and this stimulation can result in a greater protection against heart failure. In conclusion, nebivolol has a unique profile among antihypertensive drugs, adding to a very high selectivity against β₁ adrenergic receptors, and an agonist action on β₃ receptors and nitric oxide (NO), which has led to clinically significant improvements in hypertensive patients.

Pulmonary effects of nebivolol

Dal Negro, R. — Tue, 28 Jul 2009 07:52:47 PDT

The pharmacological control of arterial hypertension is a very frequent issue in clinical practice and some critical aspects can arise in particular circumstances and with particular molecules. In the case of hypertensive subjects with respiratory comorbidities, when first introduced, these β-adrenergic receptor antagonists were described as affecting airway patency as a result of their antagonism against β₂-adrenergic receptors within airway muscles. New molecules with a better respiratory tolerability were subsequently designed in order to overcome the narrow therapeutic window of first-generation β-adrenergic receptor antagonists. Nebivolol is a third-generation β-adrenergic receptor antagonist with high β₁-selective adrenergic receptor antagonism and vasodilating properties that induces a substantial decrease of arterial pressure in hypertensive subjects while preserving their left ventricular function. Respiratory effects of nebivolol have been investigated in animal models, in healthy volunteers and in clinical trials carried out on patients suffering from bronchial asthma and chronic obstructive pulmonary disease (COPD). In contrast to older compounds, nebivolol, which modulates the endogenous production of nitric oxide and affects oxidative cascade, proved clinically well tolerated in terms of respiratory outcomes in this type of subject. Moreover, due to the substantial dissociation between its cardiac and pulmonary activity, nebivolol confirmed a very good safety profile when regularly administered to hypertensive subjects with obstructive respiratory comorbidities.

The comparison of early and late outcome of direct and conventional stenting of patients with st elevation myocardial infarction

Tacoy, G., Yazici, G. E., Erden, M., Timurkaynak, T. — Fri, 12 Jun 2009 04:01:58 PDT

Background: The aim of this study was to compare direct and conventional stenting procedure in the subacute stable phase on short- and long-term results in patients with ST elevation myocardial infarction.

Methods: Eighty-eight clinically stable ST-segment elevation myocardial infarction (STEMI) patients were enrolled into the study. The patients were classified as group I (direct stenting) and group II (conventional stenting — stenting after balloon dilatation). Baseline characteristics of patients were scanned from hospital records. Coronary angiograms before and after the revascularization procedure were evaluated with the quantitative coronary angiogram technique. Patients were followed for 5 years for clinical outcomes. The study population consisted of 58 patients (65%) in group I and 30 patients (35%) in group II. Mean ages were 55.8 ± 10.8 and 57.3 ± 9.8, respectively.

Results: There were no significant differences between the two groups regarding clinical characteristics (hypertension, diabetes mellitus, family history of cardiovascular disease, smoking and dyslipidemia). The thrombus score was similar in both groups. Diameter stenosis was lower in group I (54.8 ± 12.7 versus 61.4 ± 12.6; p = 0.023) and TFC (Thrombolysis in Myocardial Infarction frame count) was higher in group II (30.7 ± 14.5 versus 40.8 ± 26.7; p = 0.02) before the percutaneous coronary intervention (PCI). Other quantitative angiographic parameters were not different. For all angiographic criteria, the difference between pre- and post-PCI parameters was significantly different in both groups. However, the change in TFC was higher within the group II compared to pre-PCI TFC rates. This difference was statistically significant (p = 0.002). Procedural success was statistically different between groups (69% in group I, 43% in group II; p50.01). Immediate clinical and angiographic results were similar. At 5-year follow-up the incidence of major adverse cardiac events including death, angina pectoris and myocardial infarction were similar for direct stenting versus conventional angioplasty.

Conclusions: Direct stenting is safe and feasible for the treatment in patients with STEMI at the subacute phase. Immediate clinic, angiographic and late clinical results are similar for direct stenting and conventional stenting following balloon angioplasty. Although conventional stenting improved TFC better than direct stenting, this did not translate to better clinical outcomes.

Atrial fibrillation: cure or treat?

Forleo, G. B., Tondo, C. — Fri, 12 Jun 2009 04:01:58 PDT

Controversies exist with regard to the optimal management of atrial fibrillation (AF). Restoration and maintenance of sinus rhythm is a desirable goal in AF patients because the prevention of recurrences may improve cardiac function, relieve symptoms and should reduce the likelihood of adverse events. Pharmacological therapy for AF has been disappointing with unacceptable rates of AF recurrence and other proarrhythmic sequelae. Recent studies suggested that potential benefit of sinus-rhythm maintenance with respect to mortality may have been neutralized by harmful effects of currently available antiarrhythmic therapies. Because of the inefficacy and dangers with nonablative therapies currently available for maintaining sinus rhythm, alternative treatments are certainly desirable. Curative treatment of atrial fibrillation with catheter ablation is now a legitimate option for a large number of patients. In several studies AF ablation has consistently been demonstrated to be superior to antiarrhythmic medications for the maintenance of sinus rhythm. Nevertheless, many aspects of the therapy are still controversial and large-scale prospective studies are needed to confirm the efficacy and safety of this approach.

Antihypertensive treatment and stroke prevention: are angiotensin receptor blockers superior to other antihypertensive agents?

Armario, P., de la Sierra, A. — Fri, 12 Jun 2009 04:01:58 PDT

Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect.

Retinal changes and cardiac remodelling in systemic hypertension

Cuspidi, C., Negri, F., Giudici, V., Sala, C. — Fri, 12 Jun 2009 04:01:58 PDT

The clinical value of left ventricular hypertrophy (LVH), a cardinal manifestation of hypertensive organ damage, in predicting cardiovascular (CV) events, independently of blood pressure (BP) and other accompanying risk factors, has been widely documented and its role in CV stratification indisputability recognized. Although the examination of the fundus oculi provides a unique opportunity to evaluate retinal microvascular abnormalities, which may mirror systemic arteriolar damage due to high BP, no consistent evidence exists, on the prognostic value of mild degrees of retinopathy, encompassing the vast majority of uncomplicated hypertensive subjects. Personal and literature data indicate that: (1) there is a tight association between advanced retinopathy and LVH suggesting the existence of a parallel involvement of retinal tree and cardiac damage in severe untreated or poorly controlled hypertension; (2) in contrast, a firm conclusion about the relationship between early or nonspecific retinal changes (narrowing or arteriovenous crossing) and cardiac damage is not allowed by the majority of the studies; (3) future investigations, based on computer-assisted methods, are further required to document the relation between initial retinal changes with organ damage and more importantly to test their predictive value for clinical outcomes.

A heart full of stem cells: the spectrum of myocardial progenitor cells in the postnatal heart

Stamm, C., Choi, Y.-H., Nasseri, B., Hetzer, R. — Fri, 12 Jun 2009 04:01:58 PDT

Influencing cellular regeneration processes in the heart has been a long-standing goal in cardiovascular medicine. To some extent, this has been successful in terms of vascular regeneration as well as intercellular connective tissue remodeling processes. Several components of today's routine heart failure medication influence endothelial progenitor cell behavior and support collateral vessel growth in the heart, or have been shown to prevent or reverse fibrosis processes. Cardiomyocyte regeneration, however, has so far escaped therapeutic manipulation strategies. Delivery of exogenous cells of bone marrow origin to the human myocardium may improve heart function, but is not associated with relevant neomyogenesis. However, accumulating evidence indicates that the myocardium contains resident cardiac progenitor cells (CPC) that may be therapeutically useful. This notion indeed represents a paradigm shift but is still controversial. The purpose of this review is to summarize the rapidly expanding current knowledge on CPC, and to assess whether it may be translated into solid therapeutic concepts.

A role for single-pill triple therapy in hypertension

Elijovich, F., Laffer, C. — Fri, 12 Jun 2009 04:01:58 PDT

Hypertension remains the most prevalent chronic disease in the world, and its adequate treatment results in predictable reductions in cardiovascular morbidity and mortality. However, most hypertensive subjects do not achieve goal blood pressure despite availability of multiple antihypertensive agents with various pharmacological mechanisms of action and relatively few side effects. We review the reasons for low hypertension control rates, including factors that affect patients' adherence to therapy, number of agents required to achieve goal blood pressure, pathophysiology-based selection of therapy and diagnosis of resistant hypertension. Within this framework, we discuss the possible impact of a single-pill, triple-therapy combination with an antagonist of the renin—angiotensin system, a calcium-channel blocker and a diuretic. We focus on possible differential diagnostic implications in terms of refractoriness to treatment, and therapeutic implications in terms of successful blood pressure control. We conclude that a single-pill, triple-therapy combination may improve control of hypertension by enhancing compliance, by achieving blood pressure goal rapidly and by reducing physician inertia in prescribing adequate antihypertensive therapy. We also suggest that such a combination may lead to improved accuracy in diagnosing resistant hypertension in general practice, avoiding unnecessary further workup and referrals to hypertension specialists.

Memorial

Ferrario, C. M. — Thu, 19 Mar 2009 04:40:29 PDT

Olmesartan improves left ventricular function in pressure-overload hypertrophied rat heart by blocking angiotensin II receptor with synergic effects of upregulation of angiotensin converting enzyme 2

Kaiqiang Ji, , Minakawa, M., Fukui, K., Suzuki, Y., Fukuda, I. — Thu, 19 Mar 2009 04:40:29 PDT

It is not clear how the blocking effect of angiotensin II receptors by olmesartan affects the functional recovery of pressure-overload hypertrophied heart. Hypertrophied heart was created by abdominal aortic banding above the celiac artery in Wistar rats at the age of eight weeks. Hypertrophied heart was excised and studied at 10 and 16 weeks after the operation (HT groups). For the last four weeks before the experiment, olmesartan (0.2 mg/kg per day) was administered subcutaneously by osmotic minipumps (Olm groups). Left ventricular function was measured by Langendorff perfusion. The levels of mRNA for angiotensin-converting enzyme (ACE), ACE2 and extracellular signal-regulated kinases (ERKs) in myocardium were analyzed by RT-PCR. Left ventricular systolic (+dP/dt_max, left ventricular systolic pressure) and diastolic functions (-dP/dt_max, tau) were impaired in HT groups, while in Olm groups they were significantly improved. The left ventricle to body weight (LV/BW) ratio increased significantly in HT groups, but in Olm groups the LV/BW ratio decreased significantly in comparison with HT groups. The ACE2 mRNA level was significantly higher in Olm groups as compared with HT groups. Plasma angiotensin II and the ERK mRNA level in HT groups increased significantly, but decreased in Olm groups in comparison with HT groups significantly. Olmesartan improved left ventricular function and hypertrophy through the increase of the ACE2 mRNA and decrease of both angiotensin II and ERK mRNA in pressure-overload rat heart.

Effects of enalapril, candesartan or both on neurohumoral activation and LV volumes and function in patients with heart failure not treated with a beta-blocker

White, M., Rouleau, J.-L., Afzal, R., Floras, J., Yusuf, S., McKelvie, R. S. — Thu, 19 Mar 2009 04:40:29 PDT

Background: The long-term effects of the angiotensin-receptor blocker candesartan, the angiotensin-converting enzyme inhibitor enalapril or their combination have been incompletely studied in a large cohort of patients with heart failure not treated with beta-blockers. The objective of this study was to investigate the changes in neurohormones and LV volumes and ejection fraction in patients treated with enalapril, candesartan, or enalapril plus candesartan without concomitant beta-blocker therapy.

Methods: Three hundred and ninety-two patients from the RESOLVD pilot study not treated with a beta-blocker at baseline or at any time during the trial were analyzed. Norepinephrine, endothelin-1, big endothelin-1, angiotensin-II, aldosterone, N-terminal proANP, BNP, and radionuclide angiography were measured before and after 43 weeks of treatment with candesartan alone (n = 162), or enalapril alone (n = 45), or candesartan plus enalapril (n = 185). Endpoints were assessed at baseline and after 43 weeks of therapy.

Results: LV end-diastolic and end-systolic volumes increased significantly at 43 weeks in all groups except for patients treated with enalapril plus candesartan. BNP decreased at 43 weeks only in patients receiving dual angiotensin-II suppression (-6.1 ± 37.8 pmol/l). Angiotensin-II levels were significantly increased in patients treated with candesartan (+23.6 ± 47.1 pg/ml; p<0.05).

Conclusion: We conclude that angiotensin-II modulation, with enalapril and candesartan, without concomitant utilization of beta-blocker lead to a decrease in BNP and an attenuation of the increase in LV end-diastolic and end-systolic volumes without a reversal of this process in the long term.

Hyperaldosteronism in pregnancy

Escher, G. — Thu, 19 Mar 2009 04:40:29 PDT

Aldosterone is a key regulator of electrolyte and water homeostasis and plays a central role in blood pressure regulation. Hormonal changes during pregnancy, among them increased progesterone and aldosterone production, lead to the required plasma volume expansion of the maternal body as an accommodation mechanism for fetus growth. This review discusses the regulation of aldosterone production by aldosterone synthase (CYP11B2); the impact on aldosterone secretion due to the presence of a chimeric gene originating from a crossover between CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism (GRA) — the inherited form of hypertension; enhanced aldosterone production in aldosterone-producing adenoma (APA); and idiopathic hyperaldosteronism (IHA). Features of hyperaldosteronism are also found in patients with apparent mineralocorticoid excess (AME), in which glucocorticoids exacerbate activation of the mineralocorticoid receptor (MR) because of a defect in the 11β-hydroxysteroid dehydrogenase type 2 enzyme. Regulation of aldosterone production and tissue-specific activation of the mineralocorticoid receptor are prerequisites for optimal control of body fluids and blood pressure during pregnancy and contribute largely to the wellbeing of the mother-to-be.

Aldosterone and progression of kidney disease

Cortinovis, M., Perico, N., Cattaneo, D., Remuzzi, G. — Thu, 19 Mar 2009 04:40:29 PDT

Experimental evidence indicates that aldosterone, besides its mineralcorticoid properties, directly contributes to accelerate renal damage through promotion of cell growth, fibrosis and inflammation. As a consequence, attenuation of growth-promoting and fibroproliferative effects of aldosterone might contribute to slow progression of chronic renal injury. Preliminary clinical observations have documented that aldosterone blockers added to angiotensin-converting enzyme inhibitor- and/or angiotensin receptor blocker-based regimens exerted significant antiproteinuric effects in patients with diabetic and nondiabetic nephropathies. Further studies in larger cohorts are now required to definitively address the safety and efficacy of aldosterone antagonism in patients with chronic kidney diseases.

Advances in the prevention of sudden cardiac death in the young

Shephard, R., Semsarian, C. — Thu, 19 Mar 2009 04:40:29 PDT

Sudden cardiac death (SCD) is a tragic and devastating complication of a number of cardiovascular diseases. Although coronary artery disease accounts for a majority of these deaths across all ages, many other aetiologies contribute to this problem when it occurs in the young (age ≤ 35 years), where coronary artery disease is far less common. Specifically, genetic heart disorders are an important cause of SCD in the young. While pharmacological therapies have made some impact on prevention of SCD, the introduction of implantable cardioverter-defibrillator (ICD) therapy has been the single major advance in the prevention of SCD in the young. In addition, the awareness that most causes of SCD in the young are inherited, means family screening of relatives of young SCD victims allows identification of previously unrecognised at-risk individuals thereby enabling prevention of SCD in relatives. The role of genetic testing, both in living affected individuals and in the setting of a `molecular autopsy', is emerging as a key factor in early diagnosis of an underlying cardiovascular genetic disorder. Understanding the genetic basis of SCD, investigating the molecular mechanisms that lead from the gene defect to the clinical phenotype, and elucidating the specific environmental triggers for SCD, will most likely lead to further key improvements in the prevention of SCD in the young.

Blood pressure responder rates versus goal rates: which metric matters?

Basile, J. — Thu, 19 Mar 2009 04:40:29 PDT

Reducing blood pressure (BP) to guideline-recommended goals associated with reductions in cardiovascular risk is central to effective hypertension management. In addition to measuring BP reduction, clinical trials of antihypertensive agents should assess the percentage of patients responding to treatment. The Food and Drug Administration's defined rate of response required for drug approval is a reduction in diastolic BP (DBP) to <90 mmHg and/or a DBP reduction of ≥10 mmHg. Consequently, some patients may be counted as responders even if they have not reached DBP <90 mmHg. An antihypertensive agent's effectiveness may be better assessed by the proportion of patients who achieve recommended BP goals. This article analyzes the frequency of response rates versus goal rates as endpoints in randomized trials since January 2001. Data showed that goal rates, especially combined systolic BP (SBP)/DBP goal rates, are consistently lower than response rates in studies evaluating both endpoints. Goal rates incorporating both SBP and DBP, or having a focus on SBP for individuals >50 years of age, provide the most clinically relevant information and are a more clinically relevant metric of an agent's ability to reduce BP than DBP alone.