Hypertension and its management: a problem in need of new treatment strategies

Although treatments of hypertension have significantly decreased morbidity and mortality from cerebrovascular disease, the associated reductions in coronary artery disease have been very disappointing. Hypertension is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to the development of heart disease. Angiotensin II receptor blockers (ARBs), such as the highly selective ARB valsartan, provide an alternative treatment strategy to address the multiple issues in coronary artery disease. These agents are well-tolerated and have a once-daily regimen that improves compliance. They bring multiple cardiovascular benefits beyond blood pressure (BP) control, such as renoprotection and cardiovascular growth reduction

Contrasting clinical properties and exercise responses in obese and lean hypertensive patients

AbstractOBJECTIVESWe sought to test whether the differences in activity of the renin-angiotensin and sympathetic nervous systems at rest or during exercise can explain the differing cardiovascular properties and outcomes of lean and obese hypertensive patients.BACKGROUNDAlthough lean hypertensive patients have fewer metabolic abnormalities than obese hypertensive patients, paradoxically they appear to have a poorer cardiovascular prognosis.METHODSTo evaluate the heightened risks in lean hypertensive patients, this study compared metabolic, neuroendocrine and cardiovascular characteristics at rest and during a standardized treadmill protocol in obese (body mass index [BMI] = 32.5 ± 0.3 kg/m2, n = 55) and lean (BMI = 24.3 ± 0.2 kg/m2, n = 66) hypertensive patients. Normotensive obese (n = 21) and lean (n = 55) volunteers served as control subjects.RESULTSCompared with the lean normotensive subjects, the lean and obese hypertensive patients had greater left ventricular mass index (LVMI) values, but on multivariate analysis, LVMI correlated with plasma renin activity (p < 0.001) and plasma norepinephrine (PNE) (p < 0.01) in the lean but not the obese hypertensive patients. Arterial compliance (stroke volume/pulse pressure ratio) was reduced in the lean hypertensive patients, in whom it correlated (p = 0.033) with PNE. The PNE rose less (22%) in the obese than in the lean (55%) hypertensive patients in response to standing (p < 0.05). Likewise, during treadmill exercise, there were lesser increases in renin (65% vs. 145%, p < 0.01) and epinephrine (200% vs. 500%, p < 0.05) in the obese hypertensive patients. These changes were also less in obese patients than in lean control subjects, indicating attenuated neurohormonal responses to stress in obesity.CONCLUSIONSCompared with obese hypertensive patients, cardiovascular properties in lean hypertensive patients are more dependent on catecholamines and the renin system. The different neuroendocrine responses to dynamic stimuli in lean and obese patients also might help to explain the disparity in their cardiovascular outcomes

Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process

Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress