Therapeutic Advances in Cardiovascular Disease

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.

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.

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.

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.

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.

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.