Current Hypertension Reviews - Volume 7, Issue 1, 2011

In patients with diabetes, control of blood pressure (BP) is as important as glycemic control in preventing cardiovascular disease. In hypertension and diabetes guidelines, the evaluation of BP is limited to clinic BP; out-of-office BP monitoring is not recommended for diabetic patients. Recently, an accumulation of evidence has shown that out-ofoffice BP monitoring is useful for risk stratification in diabetes. Especially, masked hypertension, defined as normal clinic BP but high BP in the ambulatory condition, is a big clinical problem. Masked hypertension in diabetes is associated with advanced target organ damage, such as silent brain damage, cardiac hypertrophy, renal damage, and atherosclerosis. Cardiovascular autonomic neuropathy (CAN) has been reported to be associated with cardiovascular complications, but CAN in the early stage is difficult to detect. CAN could be a cause of increased fluctuation of BP and abnormal circadian rhythm of BP. For example, masked nocturnal hypertension, defined as normal BP in the daytime but high BP at night, is difficult to diagnose, and is also associated with advanced target organ damage. In conclusion, masked hypertension exists also in substantial proportion of diabetic patients and is associated with advanced target organ damage. The cardiovascular prognosis of masked hypertension in diabetes will be clarified in the near future. The primary mechanism underlying masked hypertension or masked nocturnal hypertension in diabetes would be the presence of CAN, which is also an independent predictor for cardiovascular prognosis. Further study is needed to test the cardiovascular prognosis of masked hypertension in diabetes in order to clarify whether or not out-of-office BP measurement is really necessary in the management of BP.

The importance of the kidneys, as well as the renal function curve, in determining the arterial pressure (BP) has been widely-accepted (long-term BP regulation). Our recent studies have suggested that kidneys may participate in the pathogenesis of a circadian BP rhythm (short-term BP regulation). We have postulated that sodium sensitivity of BP is increased by both reduced glomerular ultrafiltration coefficient and by enhancement of tubular sodium reabsorption in chronic kidney disease (CKD). Glomerular filtration rate (GFR) is reduced in the former condition and is augmented in the latter. In patients with high-sodium sensitivity, the nocturnal BP dip is diminished, resulting in non-dipper pattern of circadian BP rhythm irrespectively of the mechanisms causing sodium sensitivity. We have found that in patients with more severe renal dysfunction it took longer “dipping time” for their nocturnal mean arterial pressure to fall below 90% of their daytime mean value and showed non-dipper circadian rhythms for BP and natriuresis. These findings encourage us to postulate that reduced renal capacity to excrete sodium into urine causes nocturnal elevation of BP (i.e. non-dipper) in order to compensate for diminished daytime natriuresis by enhancing night-time pressure-natriuresis. Both high sodiumsensitivity and non-dippers are risks for cardiovascular disease. Investigation on the renal mechanisms of non-dipper and nocturnal hypertension may be the shortest way to solve cardio-renal connection.

Masked hypertension is commonly seen in treated and untreated individuals and has been shown to be associated with target organ damage and poor cardiovascular prognosis. Although the etiology of masked hypertension appears to be complex, several lifestyle-related factors not only play important roles in the pathophysiology of essential hypertension but are also related to masked hypertension. Masked hypertension can be classified according to the 24-hour blood pressure profile. Morning hypertension may be caused by evening alcohol consumption, mental and physical stress, and the morning use of short-acting antihypertensive drugs. Daytime hypertension is related to habitual smoking and mental and physical stress. Nighttime hypertension is seen in various conditions including a high salt intake, renal dysfunction, obesity, sleep apnea, and autonomic failure. Therefore, lifestyle modifications are effective in the treatment of masked hypertension. Alcohol restriction is expected to lower morning blood pressure, smoking cessation and stress management preferably lower daytime blood pressure, and sodium restriction and weight reduction may be effective to control nighttime blood pressure. It is important to identify the subtype and related factor(s) for each individual with masked hypertension, and to treat each patient appropriately according to the cause of masked hypertension.

Blood pressure (BP) decreases by 10% to 20% from day to night. However, in 25% to 35% of hypertensive subjects there is some reduction in the day-night BP decline. In 3% to 5% of uncomplicated hypertensive subjects there is actually an increase, not a decrease, in BP from day to night. Many studies from independent centers showed that not only left ventricular hypertrophy, but also ventricular arrhythmias, silent cerebrovascular disease, microalbuminuria and progression of renal damage are more advanced in subjects with blunted or abolished fall in BP from day to night than in those with normal day-night BP difference. There is also evidence from longitudinal studies that a blunted, abolished or even reversed BP drop from day to night is associated with an increase in the risk of serious cardiovascular complications. However, if the quantity or quality of sleep is poor during overnight BP monitoring, night-time BP rises and its prognostic significance is no longer reliable. Studies which compared the prognostic value of daytime BP with that of night-time BP inevitably found the superiority of the latter for predicting prognosis. The exciting potential therapeutic implication that the control of night-time BP could be more rewarding, in terms of prevention of cardiovascular disease, than that of daytime BP has yet to be addressed in appropriately designed intervention trials. Of note, 24-hour ABP monitoring is the only practical way to assess the day-night rhythm of BP.

Myocardial hypertrophy secondary to hypertension is associated with a parallel addition of sarcomeres that characteristically increases cardiomyocyte cell size and width. From a cellular perspective, concentric hypertrophy differs from eccentric hypertrophy in that with eccentric hypertrophy, cardiomyocytes adapt by increasing sarcomeres in series thereby inducing an increase in cell length. Recently, specific signaling cascades have been associated with concentric and eccentric hypertrophic phenotypes, i.e. calcineurin and IGF, respectively. Even though compensatory concentric hypertrophy is often regarded as an adaptation to normalize wall stress in hypertension, it is frequently manifest with abnormal cardiac function. While recent reports have questioned the necessity of wall stress normalization, the mechanisms associated with the dichotomous adaptive and maladaptive aspects of myocardial hypertrophy are important to understand. Few data exist with respect to how exercise training superimposed on hypertension impacts LV remodeling. Several recent studies in animals have shown that exercise superimposed on hypertension can induce cardiomyocyte proliferation and reduce apoptosis while potentiating cardiomyocyte hypertrophy. Interestingly, neither Akt nor calcineurin abundance seems to underlie exercise-induced hypertrophy in hypertension. In fact, calcineurin abundance is blunted in exercise trained hypertensive hearts. In humans, exercise training in hypertensive patients has been shown to either regress or not change the extent of cardiac hypertrophy. Overall there are only a few studies examining cardiac morphometry and function in subjects with hypertension. The purpose of this review will be to cover the major human and animal findings on this topic, address relevant hypertrophic signaling pathways with exercise superimposed on hypertesnion, and broaden the discussion of exercise and hypertension towards how exercise impacts the cardiomyocyte cell cycle.

Evidences from epidemiologic studies demonstrate that heart rate is an independent risk factor for cardiovascular disease events within a wide range of subjects. An increase in the resting heart rate predisposes to cardiometabolic abnormalities and is closely associated with them. Heart rate is also closely associated with inflammation, endothelial function, plaque formation and progression, eventually plaque rupture, and cardiovascular death indicating that heart rate is associated with every process of atherosclerosis. Postprandial dysmetabolism induced by excessive intake of high-calorie diet generates oxidative stress leading to inflammation, sympathoexitation, and heart rate elevation. While the heart rate accelerates atherosclerosis via sympathetic nervous system, heart rate per se promotes atherosclerosis independent of sympathoexitation. Elevated heart rate accelerates the frequency of vascular wall stress, and low or oscillatory shear stress found downstream of non-target lesion, resulting in structural changes in the vascular wall and endothelial dysfunction. Evidence of heart rate lowering strategy for patients with coronary artery disease is considered mainly to be attributed to lowering the frequency of flow oscillation found downstream of non-target lesion. This local effect of heart rate-lowering strategy is a unique one that no other drugs have. Heart rate provides us a lot of information about the patients' cardiovascular risk status. Moreover, heart rate per se could be an independent risk factor and might be an important therapeutic target.

Soluble uric acid (UA) has traditionally been viewed by most scientific authorities as a biologically inert substance, possibly having anti-inflammatory properties as an antioxidant. Compelling evidence from a multitude of experimental and clinical studies carried out worldwide by different groups during the past two decades indicate that an elevated serum uric acid in humans is associated with hypertension, cardiovascular and kidney disease, diabetes and obesity as well as systemic inflammation, increased CRP and endothelial dysfunction. Hyperuricemia induces hypertension and renal injury via a crystal-independent mechanism, involving renal vasoconstriction mediated by endothelial dysfunction and activation of renin-angiotensin system. The epidemic increase in prevalence of hypertension, obesity, metabolic syndrome and diabetes in all societies suggest that these pathologic entities may be pathogenetically related and basically linked to environmental and dietary changes that have occurred and affected the human kind over the past century. Whereas classical risk factors like excessive caloric intake, physical inactivity and smoking will maintain their importance as major determinants in the occurrence of disease, a reappraisal of an old hypothesis - fructose induced hyperuricemia is leading to development of cardio-renal disease - may open the way toward new approaches to prevention and management of hypertension, and of various hypertension-related disease entities.

Cardiovascular disease remains the number one killer of women in the United States. Hypertension is considered a major cardiovascular risk factor, but remains poorly controlled in women. Thiazide diuretics are recommended as first line treatment in women with hypertension based on numerous outcomes studies demonstrating decreased risk of cardiovascular events. However, despite definitive evidence demonstrating clinical benefits and generic availability, diuretic-based therapy is underutilized. This article will focus on the role of thiazide diuretics for hypertension, discuss the mechanism by which diuretics lower blood pressure, describe outcomes studies that support their use in women, and provide practical considerations for use and monitoring.