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Predictive, mechanistic, and therapeutic studies on hypertension and cardiovascular morbidity and mortality

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000000268

Istituto Auxologico Italiano, Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università di Milano, Milan, Italy

Correspondence to Alberto Zanchetti, Professor, Centro di Fisiologia Clinica e Ipertensione, Università di Milano, Via F. Sforza, 35, 20122 Milan, Italy. Tel: +39 2 50320484; e-mail:

This month's issue opens with a statement of the Task Force for the management of arterial hypertension that prepared the European Societies of Hypertension and Cardiology (ESH and ESC) guidelines published in our Journal in July 2013 [1] regarding some aspects of the target blood pressure in elderly hypertensive patients and in patients with diabetes (pp. 1551–1552), and clarifying the ESH-ESC recommendations in the context of the several hypertension guidelines recently appeared.

A consistent proportion of studies in the current issue of the Journal of Hypertension is focused on the search for factors predicting the development of hypertension and hypertension-related cardiovascular morbidity and mortality, but a number of studies also approach mechanistic problems and therapeutic solutions.

Studies exploring the genetic aspects obviously belong to those focused on prediction. Mallamaci et al. (pp. 1621–1628) have tested the association between a polymorphism in the GLUT9 gene, a major genetic determinant of plasma uric acid, and blood pressure in a family-based study, and found that the polymorphism is strongly associated with clinic and 24-h ambulatory blood pressure, an association that is compatible with the hypothesis that uric acid is a causal risk factor for hypertension. However, the finding that, after adjustment for other risk factors, the association remains significant only for clinic blood pressure and the so-called white-coat effect (the difference in clinic and daytime ambulatory blood pressure) opens the problem whether uric acid may be more closely related with the white-coat effect and blood pressure variability. In a stimulating study, Petry et al. (pp. 1553–1561) review the experimental and clinical evidence that maternal blood pressure in pregnancy may be affected by the genetic variants arising from the fetal genome. Laganović et al. (pp. 1613–1620) explore the hypothesis that impaired intrauterine growth leads to accelerated telomere attrition, which in turn may result in shorter telomeres in early adulthood as a marker of increased cell senescence and early vascular aging, reporting the apparent paradox that vascular aging is indeed increased, but telomeres are longer than in normal controls. Follow-up of this cohort will provide further insight into the problem. Childhood influences on the adult blood pressure have also been investigated with ambulatory blood pressure monitoring by Gebäck et al. (pp. 1658–1664) in adult women with urinary tract infection in childhood, reporting that women with urinary tract infection associated renal damage are at increased risk of hypertension and should be considered for regular blood pressure screening, preferably with ambulatory blood pressure.

In a very large epidemiological investigation including more than 31 000 participants in the Kailuan study in China, Wang et al. (pp. 1600–1605) found that, independent of other baseline parameters such as blood pressure, blood lipids, and diabetes, an elevated resting heart rate significantly increases the risk of incident hypertension in the following 3.5 years. On the other hand, in individuals participating in the 1946 British Birth Cohort, Tikhonoff et al. (pp. 1590–1599) report that symptoms of anxiety and depression across adulthood result in lower SBP in late middle age, which is not explained by lifestyle factors and antihypertensive treatment. Finally, based on a systematic review and meta-analysis, Angelousi et al. (pp. 1562–1571) report that orthostatic hypotension is associated with a higher risk for cardiovascular events, but available data are insufficient to enable a precise assessment of the association of orthostatic hypotension with strokes and falls.

Studies on the mechanisms of hypertension or hypertension-dependent cardiovascular damage include three studies focusing on the measurement of pulse wave velocity and central blood pressure. Verwoert et al. (pp. 1606–1612) have analyzed data from the population-based Rotterdam study, and found significant associations of both aortic pulse wave velocity and carotid distensibility with isolated systolic hypertension and the combined systolic and diastolic hypertension, with higher values of aortic stiffness occurring in isolated systolic hypertension particularly at older age. The widespread clinical measurement of carotid-femoral pulse wave velocity in the elderly is advocated by Zhang et al. (pp. 1572–1576) on the basis of a review of the current knowledge, and Hashimoto and Ito (pp. 1665–1671), in a study on a cohort of hypertensive patients, suggest that concomitant plasma brain natriuretic peptide elevation and (micro)albuminuria may be explained by a rise in aortic pulse pressure simultaneously causing damage or dysfunction in the heart and kidney, such as in the cardiorenal syndrome of hypertension. In an accompanying comment, Izzard (pp. 1580–1581) raises the possibility that impaired myogenic properties of proximal renal arteries may share the responsibility of the renal injury with the increased aortic pulse.

Mechanisms of hypertension-related renal damage have also been investigated by Wang and Sun and by Buhl et al. Wang and Sun (pp. 1629–1636) have focused on the relationship of the antiaging gene Klotho, known to be predominantly expressed in the kidney, with the endothelin system, also known to be important in the regulation of renal function: in spontaneously hypertensive rats, Klotho gene delivery abolished the upregulation of endothelin-1 levels and the downregulation of endothelinB protein expression in the kidney. In patients with type 2 diabetes mellitus and resistant hypertension, a significant correlation was found between urine plasminogen, blood pressure, and urine albuminuria: when superfused with urine samples with plasmin, single collecting duct cells in vitro displayed significantly increased amiloride-sensitive inward currents, suggesting that inappropriate activation of the epithelial sodium channel may contribute to treatment-resistant hypertension in these patients (Buhl et al., pp. 1672–1677).

Finally, Saeki et al. (pp. 1582–1589) have investigated the mechanism of the increase in blood pressure occurring during winter months, known to be associated with higher cardiovascular mortality, and report that indoor temperature is more strongly associated with ambulatory blood pressure than outdoor temperature, suggesting that improving house thermal environment may help reducing winter excess mortality. In an editorial commentary, Modesti and Parati (pp. 1577–1579) underline that further studies on the effects of environment temperature on blood pressure and cardiovascular disease have to consider the amount of time spent outdoors and indoors, and other factors such as clothes, bed blankets, etc.

Therapeutic aspects of hypertension and hypertension-related damage have been investigated in another group of studies. On the experimental side, Takai et al. (pp. 1637–1649) show that in stroke-prone spontaneous hypertensive rats a chymase inhibitor attenuates the increase in matrix metalloproteinase-9 activity in aortic tissue, improves acetylcholine-induced vascular relaxation, and prolongs the survival. In a study on patients with sleep apnea and resistant hypertension, Lloberes et al. (pp. 1650–1657) report that continuous positive air pressure (cPAP) treatment achieved a significant reduction of plasma aldosterone concentration only in patients with white-coat-resistant hypertension, although the cPAP effect on blood pressure was higher in patients with true resistant hypertension. Cohen-Mazor et al. (pp. 1678–1692) have evaluated a novel bipolar radiofrequency delivery system for renal denervation in a porcine model by histological changes and measuring renal norepinephrine.

Witham et al. (pp. 1693–1699) have investigated therapeutic possibilities for ameliorating orthostatic hypotension in elderly hypertensive patients. As previous data suggest the condition is associated with low 25-hydroxyvitamin D levels, they have done a randomized study of administering oral vitamin D3 or placebo every 3 months for 1 year, but have been unable to significantly improve orthostatic hypotension. Mancia et al. (pp. 1700–1707) report a large international study testing the effects of lercanidipine alone, enalapril alone, and both drugs in combination by using home blood pressure in addition to office measurement, finding that the fixed dose combination of lercanidipine and enalapril ensures control of both office and home blood pressure, with a favorable tolerability profile. Mancia et al. (pp. 1708–1718) also report novel observations regarding the discontinuation of antihypertensive drug therapy as provided by the large database of the Lombardy region in Italy: responsible factors, in addition to the type of antihypertensive agent, include cotreatments, clinical conditions, and even demographic characteristics of the geographical areas where the patients live.

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Conflicts of interest

There are no conflicts of interest.

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1. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2013; 31:1281–1357.
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