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Recommendations for practice and mechanistic investigations

Zanchetti, Alberto

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doi: 10.1097/HJH.0000000000000248
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A large number of the articles published in this issue of the journal have practical implications or provide recommendations for management of hypertension, but, as usual, there are also articles exploring mechanisms of hypertension and of hypertension consequences.

As previously done with the European Society of Hypertension-European Society of Cardiology guidelines for the management of hypertension, first published in an extensive version [1] and subsequently in a short ‘practice’ version [2], also the European Society of Hypertension guidelines for ambulatory blood pressure, published in a full 36-page version in 2013 [3], now appears in an agile form of 14 pages only (pp. 1359–1366) so that practitioners who do not have time or interest in receiving the detailed information backing the experts’ recommendations can learn anyway when ambulatory blood pressure monitoring is a resource for diagnosis and treatment of hypertension.

Another important document appearing in this issue of the journal is a consensus document of the European Society of Hypertension Working Group on Hypertension and the Kidney devoted to diagnosis and management of fibromuscular dysplasia (pp. 1367–1378). This is a welcomed document, as fibromuscular dysplasia has recently been, as it were, the Cinderella of renovascular hypertension, most of recent trials and recommendations having focused on atherosclerotic renal artery disease. The lamentable absence of randomized clinical trials makes the opinions of the European experts who have prepared the consensus particularly valuable.

Sodium restriction is one of the most widely recommended procedures for the prevention and management of hypertension. Ruzicka et al. (pp. 1388–1394) provide a systematic review of randomized trials of effective sodium intake reduction and report that, although these trials were able to show a significant and sometimes marked blood pressure reduction, none of the methods used in these trials to effectively reduce sodium intake were suitable for incorporation into existing primary care settings in most countries.

Arterial hypertension being a public health concern, extending knowledge on geographical differences in its prevalence, awareness, treatment and control is of continuing interest. Detailed information about different regions of Germany is now provided by the German Health Interview and Examination Survey (pp. 1405–1414).

The surge of interest for hypertension genomics and the results of a number of genome-wide association studies have prompted the question as to whether a genetic risk score based on the single nucleotide polymorphisms so far identified affects the risk of cardiovascular disease at a population level. Fava et al. (pp. 1424–1428) publish the results of their evaluation of the impact of this ‘genetic’ risk on cardiovascular disease morbidity and mortality in the large prospective Swedish Malmö Diet and Cancer Study: their results are rather elusive, the polygenetic component of blood pressure influencing cardiovascular morbidity and mortality to a small extent only, and being unlikely to be useful – in the authors’ opinion – for prediction at the population level. In an accompanying editorial comment, Pavel Hamet (pp. 1395–1396) expresses a somewhat more optimistic view underlining that ‘the strength of genetic markers is in their presence from birth, allowing developing preventive and therapeutic measures at prime time’.

The predictive value of genetic markers in hypertension has been the object of two other studies published in this issue: Rossi et al. (pp. 1514–1522) report that among patients with an aldosterone-producing adenoma, those carrying somatic mutations in the KCNJ5 K+ channel have more prominent cardiovascular damage; nonetheless, their chances of being cured by adrenalectomy are not compromised. In another article, Ward et al. (pp. 1495–1502) find that maintenance of lower blood pressure after weight loss may partly depend on genetic factors, being more difficult for carriers of the CYP4F2 G1347A polymorphism possibly related to increased renal 20-METE synthesis. Overweight-related hypertension has also been reported to be predicted by leptin levels in a general population of Danish adults (Seven et al., pp. 1488–1494). However, the authors remark that, as BMI remained a strong independent predictor of hypertension, other factors than leptin must be involved in the pathogenesis of overweight-related hypertension. Data presented in another article published in this issue (Hvidt et al., pp. 1400–1401) call attention to the fact that, at least in children, office blood pressure may be a misleading index to study the effects of loss of body weight: in their experience with children, a structured tailored lifestyle intervention on caloric intake combined with physical exercise induced a significant reduction in BMI and in ambulatory, but not office, blood pressure. In an accompanying editorial, Genovesi et al. (pp. 1397–1399) underline that prospective blood pressure studies in children are few, and further rigorous studies, such as that by Hvidt et al., are warranted to clarify the matter.

Treatment of hypertension in obesity is a continuing challenge. Following a review on the use of the phentermine and topiramate combination published in the June issue [4], the journal now publishes an interesting analysis of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which over 33 000 patients randomized to first-step treatment with chlorthalidone or amlodipine or lisinopril were stratified by baseline BMI. BMI status was found not to modify the effects of antihypertensive medications on blood pressure control or cardiovascular disease outcomes (Reisin et al., pp. 1503–1513). In an accompanying editorial, Jordan and Engeli (pp. 1402–1404) remark that in ALLHAT obese patients required more antihypertensive medications, and in one-third of the patients blood pressure remained elevated despite treatment escalation; they conclude that, given the sheer number of obese hypertensive patients, their excess cardiovascular and metabolic risk, and the difficulties in controlling blood pressure in these patients, further studies would be desirable.

Further data from another important antihypertensive treatment trial are reported in this issue of the journal. The authors of the Hypertension in the Very Elderly Trial (HYVET) publish the results of analyses by prespecified subgroups (age, sex, history of cardiovascular disease and initial SBP): in all groups point estimates for all types of outcomes were in favor of benefit, although the small size of the sample rarely allowed attaining the level of statistical significance (Beckett et al., pp. 1478–1487). In his editorial commentary, Bo Carlberg (pp. 1400–1401) calls attention to the fact that approximately two-thirds of HYVET patients were already on antihypertensive treatment when randomized into the trial. Limiting the analysis to this subgroup, that is comparing patients who continued treatment with those who stopped it being randomized to placebo, shows significant reductions in major outcomes in patients continuing treatment, whereas analysis of the subgroup of previously untreated patients does only show a significant reduction of all cardiovascular events but not of mortality. Therefore, the evidence drawn from HYVET appears to favor continuation of antihypertensive therapy in very elderly patients more than initiation of new treatment.

Other useful practical information is provided by two articles focused on blood pressure in pregnancy. Bisson et al. (pp. 1450–1457) have observed that physical activity performed in early pregnancy slightly modulates resting blood pressure in early and late pregnancy, and Salazar-Vega et al. (pp. 1458–1463) call attention to the possibility that hypertension paroxysms during any gestational phase provide a high index of suspicion for the presence of pheochromocytoma.

A group of articles offers useful information on detection of vascular alterations. Keehn et al. (pp. 1464–1469) compare the use of different techniques for the measurement of pulse wave velocity in children. Bossuyt et al. (pp. 1429–1434) report that atherosclerotic lesions are more prevalent at the right than at the left femoral artery, underscoring the importance of the choice of body side when assessing vascular health. Ishida et al. (pp. 1435–1443) show that in young individuals a high normal ankle-brachial index may be a result of arterial stiffness and is associated with proteinuria.

Articles investigating the mechanisms of hypertension and hypertension-related damage include a review by Chan et al. (pp. 1379–1387) on our current understanding of the interactions between heme oxygenase and NADPH oxidase, and the possibility that modulation of NADPH oxidase activity by heme oxygenases is the main mechanism of the beneficial effect of the latter in hypertension. In experiments on systemic heterozygous ATP2B1 null mice, Fujiwara et al. (pp. 1415–1423) suggest that decreased ATP2B1 expression plays a crucial role in the regulation of blood pressure. Kork et al. (pp. 1444–1449) suggest that oxidized low-density lipoprotein may be a biomarker of incipient atherosclerosis in postmenopausal women. Papageorgiou et al. (pp. 1523–1533) show that Factor XII-Kininogen-mediated vasoconstriction contributes significantly to chronic kidney disease in Brown Norway rats, and suggest this novel mechanism may be active in humans with chronic kidney disease. Akahori et al. (pp. 1534–1541) report that administration of atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats, and suggest the atorvastatin effect may be mediated via inhibition of the Rho-Rho kinase pathway.


Conflicts of interest

There are no conflicts of interest.


1. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arerial hypertension. J Hypertens 2013; 31:1281–1357.
2. ESH/ESC Task Force for the Management of Arterial Hypertension2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). J Hypertens 2013; 31:1925–1938.
3. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. on behalf of the European Society of Hypertension Working Group on Blood Pressure MonitoringEuropean Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013; 31:1731–1767.
4. Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of phentermine and topiramate – a new drug combination for the treatment of obesity. J Hypertens 2014; 32:1178–1188.
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