Current Hypertension Reviews (v.7, #1)

Masked Hypertension and Diabetes by Kazuo Eguchi, Kazuomi Kario (1-4).
In patients with diabetes, control of blood pressure (BP) is as important as glycemic control in preventingcardiovascular disease. In hypertension and diabetes guidelines, the evaluation of BP is limited to clinic BP; out-of-officeBP monitoring is not recommended for diabetic patients. Recently, an accumulation of evidence has shown that out-ofofficeBP monitoring is useful for risk stratification in diabetes. Especially, masked hypertension, defined as normal clinicBP but high BP in the ambulatory condition, is a big clinical problem. Masked hypertension in diabetes is associated withadvanced 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, butCAN in the early stage is difficult to detect. CAN could be a cause of increased fluctuation of BP and abnormal circadianrhythm of BP. For example, masked nocturnal hypertension, defined as normal BP in the daytime but high BP at night, isdifficult to diagnose, and is also associated with advanced target organ damage. In conclusion, masked hypertension existsalso in substantial proportion of diabetic patients and is associated with advanced target organ damage. The cardiovascularprognosis of masked hypertension in diabetes will be clarified in the near future. The primary mechanism underlyingmasked hypertension or masked nocturnal hypertension in diabetes would be the presence of CAN, which is also anindependent predictor for cardiovascular prognosis. Further study is needed to test the cardiovascular prognosis of maskedhypertension in diabetes in order to clarify whether or not out-of-office BP measurement is really necessary in themanagement of BP.

Nocturnal Hypertension and Chronic Kidney Disease by Michio Fukuda, Masashi Mizuno, Genjiro Kimura (5-8).
The importance of the kidneys, as well as the renal function curve, in determining the arterial pressure (BP) hasbeen widely-accepted (long-term BP regulation). Our recent studies have suggested that kidneys may participate in thepathogenesis of a circadian BP rhythm (short-term BP regulation). We have postulated that sodium sensitivity of BP isincreased by both reduced glomerular ultrafiltration coefficient and by enhancement of tubular sodium reabsorption inchronic kidney disease (CKD). Glomerular filtration rate (GFR) is reduced in the former condition and is augmented inthe latter. In patients with high-sodium sensitivity, the nocturnal BP dip is diminished, resulting in non-dipper pattern ofcircadian BP rhythm irrespectively of the mechanisms causing sodium sensitivity. We have found that in patients withmore severe renal dysfunction it took longer “dipping time” for their nocturnal mean arterial pressure to fall below 90% oftheir daytime mean value and showed non-dipper circadian rhythms for BP and natriuresis. These findings encourage usto postulate that reduced renal capacity to excrete sodium into urine causes nocturnal elevation of BP (i.e. non-dipper) inorder to compensate for diminished daytime natriuresis by enhancing night-time pressure-natriuresis. Both high sodiumsensitivityand non-dippers are risks for cardiovascular disease. Investigation on the renal mechanisms of non-dipper andnocturnal 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 beassociated with target organ damage and poor cardiovascular prognosis. Although the etiology of masked hypertensionappears to be complex, several lifestyle-related factors not only play important roles in the pathophysiology of essentialhypertension but are also related to masked hypertension. Masked hypertension can be classified according to the 24-hourblood 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 andmental and physical stress. Nighttime hypertension is seen in various conditions including a high salt intake, renaldysfunction, obesity, sleep apnea, and autonomic failure. Therefore, lifestyle modifications are effective in the treatmentof masked hypertension. Alcohol restriction is expected to lower morning blood pressure, smoking cessation and stressmanagement preferably lower daytime blood pressure, and sodium restriction and weight reduction may be effective tocontrol nighttime blood pressure. It is important to identify the subtype and related factor(s) for each individual withmasked hypertension, and to treat each patient appropriately according to the cause of masked hypertension.

Clinical Significance of the Blood Pressure Changes from Day to Night by Paolo Verdecchia, Fabio Angeli, Giorgio Gentile, Giovanni Mazzotta, Roberto Gattobigio, Gianpaolo Reboldi (13-19).
Blood pressure (BP) decreases by 10% to 20% from day to night. However, in 25% to 35% of hypertensivesubjects there is some reduction in the day-night BP decline. In 3% to 5% of uncomplicated hypertensive subjects there isactually an increase, not a decrease, in BP from day to night. Many studies from independent centers showed that not onlyleft ventricular hypertrophy, but also ventricular arrhythmias, silent cerebrovascular disease, microalbuminuria andprogression of renal damage are more advanced in subjects with blunted or abolished fall in BP from day to night than inthose with normal day-night BP difference. There is also evidence from longitudinal studies that a blunted, abolished oreven 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 prognosticsignificance is no longer reliable. Studies which compared the prognostic value of daytime BP with that of night-time BPinevitably found the superiority of the latter for predicting prognosis. The exciting potential therapeutic implication thatthe control of night-time BP could be more rewarding, in terms of prevention of cardiovascular disease, than that ofdaytime BP has yet to be addressed in appropriately designed intervention trials. Of note, 24-hour ABP monitoring is theonly practical way to assess the day-night rhythm of BP.

Myocardial hypertrophy secondary to hypertension is associated with a parallel addition of sarcomeres thatcharacteristically increases cardiomyocyte cell size and width. From a cellular perspective, concentric hypertrophy differsfrom eccentric hypertrophy in that with eccentric hypertrophy, cardiomyocytes adapt by increasing sarcomeres in seriesthereby inducing an increase in cell length. Recently, specific signaling cascades have been associated with concentric andeccentric hypertrophic phenotypes, i.e. calcineurin and IGF, respectively. Even though compensatory concentrichypertrophy is often regarded as an adaptation to normalize wall stress in hypertension, it is frequently manifest withabnormal cardiac function. While recent reports have questioned the necessity of wall stress normalization, themechanisms associated with the dichotomous adaptive and maladaptive aspects of myocardial hypertrophy are importantto understand. Few data exist with respect to how exercise training superimposed on hypertension impacts LVremodeling. Several recent studies in animals have shown that exercise superimposed on hypertension can inducecardiomyocyte proliferation and reduce apoptosis while potentiating cardiomyocyte hypertrophy. Interestingly, neitherAkt nor calcineurin abundance seems to underlie exercise-induced hypertrophy in hypertension. In fact, calcineurinabundance is blunted in exercise trained hypertensive hearts. In humans, exercise training in hypertensive patients hasbeen shown to either regress or not change the extent of cardiac hypertrophy. Overall there are only a few studiesexamining cardiac morphometry and function in subjects with hypertension. The purpose of this review will be to coverthe major human and animal findings on this topic, address relevant hypertrophic signaling pathways with exercisesuperimposed on hypertesnion, and broaden the discussion of exercise and hypertension towards how exercise impacts thecardiomyocyte cell cycle.

Evidences from epidemiologic studies demonstrate that heart rate is an independent risk factor forcardiovascular disease events within a wide range of subjects. An increase in the resting heart rate predisposes tocardiometabolic 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 indicatingthat heart rate is associated with every process of atherosclerosis. Postprandial dysmetabolism induced by excessive intakeof high-calorie diet generates oxidative stress leading to inflammation, sympathoexitation, and heart rate elevation. Whilethe heart rate accelerates atherosclerosis via sympathetic nervous system, heart rate per se promotes atherosclerosisindependent of sympathoexitation. Elevated heart rate accelerates the frequency of vascular wall stress, and low oroscillatory shear stress found downstream of non-target lesion, resulting in structural changes in the vascular wall andendothelial dysfunction. Evidence of heart rate lowering strategy for patients with coronary artery disease is consideredmainly to be attributed to lowering the frequency of flow oscillation found downstream of non-target lesion. This localeffect of heart rate-lowering strategy is a unique one that no other drugs have. Heart rate provides us a lot of informationabout the patients' cardiovascular risk status. Moreover, heart rate per se could be an independent risk factor and might bean important therapeutic target.

Soluble uric acid (UA) has traditionally been viewed by most scientific authorities as a biologically inertsubstance, possibly having anti-inflammatory properties as an antioxidant. Compelling evidence from a multitude ofexperimental and clinical studies carried out worldwide by different groups during the past two decades indicate that anelevated serum uric acid in humans is associated with hypertension, cardiovascular and kidney disease, diabetes andobesity as well as systemic inflammation, increased CRP and endothelial dysfunction.Hyperuricemia induces hypertension and renal injury via a crystal-independent mechanism, involving renalvasoconstriction 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 suggestthat these pathologic entities may be pathogenetically related and basically linked to environmental and dietary changesthat 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 importanceas major determinants in the occurrence of disease, a reappraisal of an old hypothesis “ fructose induced hyperuricemia isleading to development of cardio-renal disease ” may open the way toward new approaches to prevention andmanagement of hypertension, and of various hypertension-related disease entities.

Use of Diuretics in Women for Management of Hypertension by Eric J. MacLaughlin, Joseph J. Saseen (54-58).
Cardiovascular disease remains the number one killer of women in the United States. Hypertension isconsidered a major cardiovascular risk factor, but remains poorly controlled in women. Thiazide diuretics arerecommended as first line treatment in women with hypertension based on numerous outcomes studies demonstratingdecreased risk of cardiovascular events. However, despite definitive evidence demonstrating clinical benefits and genericavailability, diuretic-based therapy is underutilized. This article will focus on the role of thiazide diuretics forhypertension, discuss the mechanism by which diuretics lower blood pressure, describe outcomes studies that supporttheir use in women, and provide practical considerations for use and monitoring.