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Problems of antihypertensive management: diabetes mellitus, ethnic differences, organ damage and resistance to treatment

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000001334

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

Correspondence to Professor Alberto Zanchetti, Istituto Auxologico Italiano IRCCS and Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università degli Studi di Milano, Via F. Sforza, 35, 20122 Milano, Italy. Tel: +39 02 50320484; e-mail:;

Several problematic aspects of hypertension management have been investigated in studies published in the current issue of the Journal of Hypertension.

A group of four studies focus on cardiovascular aspects of diabetes and their therapeutic management. In individuals from the Maastricht Study, Veugen et al. (pp. 1052–1060) find that the systolic–diastolic difference in carotid stiffness is increased in type 2 diabetes, probably a result from accelerated arterial wall matrix remodeling, but this increase is not observed in prediabetes. Dasgupta et al. (pp. 1061–1069) have studied carotid–femoral pulse wave velocity, as risk indicator, in a cohort of patients with type 2 diabetes and hypertension and report that physical activity, quantitatively measured by an accelerometer, has an added beneficial value on top of good risk control by cardioprotective medications. Thomopoulos et al. (pp. 922–944) publish the results of a set of comprehensive meta-analyses comparing the effects of blood pressure (BP)-lowering treatment in hypertensive patients with and without diabetes. Contrary to past recommendations, in diabetes there is little or no further benefit in lowering SBP below 130 mmHg, whereas continuing benefit is seen in the absence of diabetes also at SBP below 130 mmHg. Thomopoulos et al. also find that, although all BP-lowering drugs can beneficially be prescribed in hypertensive patients with diabetes, there are some additional cardiovascular and renal benefits by including a renin–angiotensin system blocker in the treatment program. Kumarathurai et al. (pp. 1070–1078) have investigated whether the BP-lowering effect of the GLP-1 receptor agonist liraglutide, as previously shown in clinical trials using office BP measurements, is also supported by ambulatory BP measurements, and report no BP-lowering effect of liraglutide could be demonstrated in a small placebo-controlled trial using 24-h ambulatory BP monitoring. In an editorial, Nilsson (pp. 953–954) comments that the cardiovascular benefits so far demonstrated by liraglutide and other GPL-receptor agonists remain enigmatic, and suggests the effects of these compounds on central hemodynamics and aortic stiffness should be investigated. Randomized controlled trials of BP and lipid lowering are also the objective of a meta-analysis of Hirakawa et al. (pp. 905–913), who have identified 13 BP-lowering and 10 lipid-lowering trials with a prolonged follow-up after the termination of the randomized treatment, thus allowing the evaluation of the long-term effects of these therapeutic approaches: the authors report that the benefits of both types of treatment on all-cause and cardiovascular mortality were persistent, but attenuated after discontinuation of randomized treatment, indicating the importance of continuing therapy.

Three studies are focused on ethnic aspects of hypertension. Mokwatsi et al. (pp. 960–967) find that already at age 6–8 years black boys in South Africa, as compared with white boys from similar schools, have increased arterial stiffness in all sections of the arterial tree, along with higher DBP, carotid intima–media thickness and advanced glycation end products. Chiang et al. (pp. 968–974) have investigated the association of 25-hydroxyvitamin D and BP in young adults with African ancestry in the United States, South Africa, Ghana, Jamaica, and Seychelles, reporting that the association is strongest when the vitamin D levels are lower than 20 ng/ml. Sherwood et al. (pp. 975–981) have tested responsiveness of β-adrenergic and α-adrenergic receptors in the early stages of hypertension, and shown that a blunted β-adrenergic responsiveness and an enhanced α-adrenergic responsiveness are especially evident in African Americans.

Hypertension-associated organ damage is the focus of another group of studies. Van Mil et al. (pp. 1026–1034) have studied carotid artery reactivity to a cold pressor test and reported that lower carotid reactivity is associated with older age and number of cardiovascular risk factors. As carotid reactivity is correlated with coronary artery responses to the cold pressor test, the authors suggest carotid reactivity may represent a valuable technique to assess cardiovascular risk. Agabiti Rosei and Rizzoni (pp. 914–921) review the considerable evidence accumulated in recent years, also through their personal work, that changes in microvascular structure (mostly subcutaneous small resistance arteries) may have a significant prognostic relevance, and remark that new techniques for the evaluation of microvascular morphology in the retina may represent a noninvasive technique allowing a more extensive predictive use of microvascular changes. In an accompanying editorial, Heagerty (pp. 945–946) suggests that also confocal microscopy of the nail fold vasculature may be an alternative noninvasive approach. The cardiovascular predictive role of renal microvascular dysfunction has been investigated by Nemcsik et al. (pp. 1109–1118) in patients with nondialyzed chronic kidney disease. They report that postocclusive reactive hyperemia assessed by laser Doppler flowmetry has a predictive role, but the robustness of traditional risk factors outweighs the predictive role of microvascular biomarkers. In commenting these data, Bruneau (pp. 958–959) remarks that, nonetheless, Nemcsik et al.'s findings offer promise for the potential use of laser Doppler flowmetry as an early assessment tool to detect subclinical microvascular dysfunction in the kidney. Alterations in fibrin clot properties are described in hypertensive patients with, but not without, obstructive sleep apnea by Jóźwik-Plebanek et al. (pp. 1035–1043): the relationship of these clot alterations with sleep apnea are supported by their improvement after 3 months with continuous positive airway pressure treatment. In an accompanying editorial, Doumas et al. (pp. 950–952) comment that it would be really important and clinically meaningful to assess the link of fibrin clot properties with severity of obstructive sleep apnea. Cognitive decline is another of the possible complications of hypertension in the elderly, and Li et al., (pp. 1044–1051) have explored executive and memory abilities in a group of elderly hypertensive patients (and controls) in the context of a functional magnetic resonance study, finding a relationship between worsening of cognitive function and altered patterns of activation of fronto-parietal cortex.

The problem of resistance to treatment is dealt with in three studies in the current issue. Schneider et al. (pp. 1086–1092) have conducted a randomized double-blind trial in 51 patients with treatment-resistant hypertension, comparing a similar BP reduction produced either by adding the mineralocorticoid receptor antagonist eplerenone or other antihypertensive agents. After a 6-month follow-up only patients allocated to eplerenone had a significant reduction of left ventricular mass (precisely measured by magnetic resonance imaging). These interesting data suggest the mineralocorticoid receptor antagonists should be used preferentially to achieve an effective reduction of left ventricular hypertrophy in difficult to treat hypertensive patients. Rosa et al. (pp. 1093–1099) publish the 24-month results of a randomized trial in true resistant hypertension (elevated BP confirmed by ambulatory monitoring, treatment with more than five drugs, adherence to treatment verified at baseline), showing that renal denervation was well tolerated and without any serious adverse effects, but its BP-lowering effect was not superior to that of intensified medical treatment including spironolactone. In an accompanying editorial, Hamdidouche and Boutouyrie (pp. 955–957) discuss whether renal denervation can be considered as an alternative or a complement in the management of resistant hypertension. In another study on renal denervation, Tsioufis et al. (pp. 1100–1108) report that in a group of hypertensive patients with the metabolic syndrome, this procedure does not only reduce elevated muscle sympathetic activity at rest, but also restores its responsiveness to a standard glucose tolerance test, without significantly changing, however, the HOMA-IR response.

There are other interesting studies in the current issue of the Journal, touching other aspects of hypertension research. Scheepers et al. (pp. 982–993) have done cross-sectional analyses in school-age children from the Dutch KOALA Birth Cohort Study, and found that uric acid and the ratios of uric acid/xanthine and xanthine/hypoxanthine were significantly associated with DBP, suggesting that both uric acid concentration and increased xanthine oxidase activity are associated with BP. The current interest in the relationships between uric acid and BP is also witnessed by another study on this topic: Saladini et al. (pp. 994–1001), in a cohort of young to middle-aged study participants prospectively followed up for about 11 years, report that serum uric acid was a predictor of hypertension, and suggest that exercise may counteract the mechanisms involved in the association between hyperuricemia and future hypertension.

Three studies focus on problems of BP measurement. Benmira et al. (pp. 1002–1010), considering that the widely used oscillometric methods only measure mean BP and estimate SBP and DBP using various undisclosed algorithms, present a new technique measuring the time interval from the foot to the apex of the SBP peak of the oscillometric signal, which in their study yielded excellent correlations with SBP values determined by the auscultatory method. Vinyoles et al. (pp. 1011–1018), analyzing data from the large Spanish Ambulatory BP Monitoring Registry, report that a 24-h ambulatory pulse pressure of ≥50 mmHg is the value that best corresponds to an office pulse pressure ≥60 mmHg. Shaw et al. (pp. 1019–1025) have tested the reliability of a sit-to-stand manoeuvre to diagnose orthostatic hypotension in cases where a supine-to-standing manoeuvre cannot be performed, and suggest that a SBP drop at least 15 mmHg or a DBP drop at least 7 mmHg are useful criteria. These results are discussed in an accompanying commentary by Casiglia and Jordan (pp. 947–949), who remark that the lower BP threshold for diagnosis mandates particularly careful BP measurements, and suggest that, whenever possible, the usual supine-to-upright test should be applied.

Finally, Murata et al. (pp. 1079–1085) review a large number of consecutive cases of primary aldosteronism and conclude that cases with plasma aldosterone within the normal range are associated with a lower cardio and cerebrovascular risk than cases with high plasma aldosterone concentrations.

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Conflicts of interest

There are no conflicts of interest.

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