Basic and clinical hypertension research has substantially improved our understanding on the mechanisms mediating arterial hypertension and associated organ damage. Yet, in many hypertensive patients, blood pressure is not sufficiently controlled . In some patients, blood pressure is simply not measured. In others, blood pressure is assessed, but suitable antihypertensive medications are not prescribed. However, even in the setting of clinical trials conducted by hypertension specialists, a relatively large proportion of the patients are treatment-resistant . Treatment-resistant arterial hypertension is commonly defined as blood pressure above the target of 140/90 mmHg or lower in high-risk population on at least three antihypertensive drugs of different classes. All these medications should be given in full doses and one medication should be a diuretic [3,4]. Given the large number of patients characterized by drug-resistant hypertension, the small number of mechanistic, epidemiological, and clinical studies dealing with the issue is surprising. In fact, the exact prevalence of treatment-resistant hypertension and its impact on cardiovascular morbidity and mortality are unknown. One study compared cardiac and extracardiac organ damage between patients with resistant hypertension and well matched patients with satisfactory blood pressure control . Patients with resistant hypertension showed more left ventricular hypertrophy, carotid intima–media thickening and plaques, urinary albumin excretion, and hypertensive retinopathy compared with controlled patients . Whether and to what extent drug-resistant hypertension is characterized by a neurohumoral and sympathetic activation greater in magnitude than that seen in patients not resistant to antihypertensive drugs is only partially defined, however.
Obesity predisposes to treatment-resistant arterial hypertension. Epidemiological studies suggest that 60–70% of hypertension may be directly attributable to excess adiposity, both in women and in men . The age-adjusted relative risk for the development of hypertension was 1.75 in men and 1.46 in women . Regression models corrected for the age-related rise in blood pressure demonstrated an increase in systolic blood pressure of 1 mmHg for a gain of 1.7 kg/m2 and 4.5 cm (men), or 1.3 kg/m2 and 2.5 cm (women) in BMI or waist circumference, respectively . Moreover, in a primary care setting the odds ratio for achieving blood pressure values less than 140/90 mmHg in diagnosed and treated hypertensive patients was 0.8 in overweight patients, 0.6 in grade 1, 0.5 in grade 2, and 0.7 in grade 3 obese patients . Hypertensive participants of the Framingham Heart Study were less likely to be controlled to a blood pressure less than 140/90 mmHg when they were older, had left ventricular hypertrophy, or they were obese . Similarly, obesity was an important predictor for treatment failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study . However, in terms of blood pressure control fat and fat may not be the same.
Visceral adiposity and drug-resistant hypertension
Earlier studies using abdominal computed tomography to quantify subcutaneous and visceral adipose tissue suggested that visceral abdominal fat is an independent predictor for arterial hypertension . In this issue of the Journal, Ishikawa et al.  present data on a study relating visceral adipose tissue to difficult to treat arterial hypertension in men but not in women. The authors determined subcutaneous and visceral abdominal adipose tissue through computed tomography in 572 hypertensive men on stable antihypertensive medications participating in the Japanese Morning Surge – Home Blood Pressure (J-HOP) study. Then, they calculated the ratio between visceral and subcutaneous adipose tissue. The authors defined difficult to treat hypertension as when the patient had an office blood pressure more than 140/90 mmHg on three antihypertensive drugs regardless of diuretic use and resistant hypertension, when one of the drugs was a diuretic. Compared with women, men were almost three times more likely having difficult to treat hypertension and more than twofold more likely to have resistant hypertension. Remarkably, BMI was similar in controlled patients and in patients with difficult to treat arterial hypertension. Yet, the visceral to subcutaneous adipose tissue ratio was significantly increased in difficult to treat men and tended to do so in difficult to treat women. When the analysis was restricted to patients with resistant hypertension the relationship disappeared.
The observation that diuretic use may attenuate the relationship between visceral adiposity and hypertension control is important, both from a scientific and from a clinical point of view. In particular, the study by Ishikawa et al.  further supports the idea that volume expansion is a crucial mechanism in the pathogenesis of difficult to treat or resistant hypertension. An earlier study in 279 consecutive patients with drug-resistant hypertension showed excessive aldosterone and natriuretic peptide levels compared with control individuals . The increase in natriuretic peptides may have been secondary to volume expansion. Obesity-associated arterial hypertension in general involves renin–angiotensin system activation [15,16], volume expansion, and raised cardiac output [17–19] rather than vasoconstriction. Pharmacological studies and direct sympathetic nerve recordings suggest involvement of the sympathetic nervous system [20–22]. Indeed, obese hypertensive patients exhibit an increase in renal and in cardiac sympathetic activity . Baroreflex dysfunction and the sleep apnea syndrome may contribute to sympathetic overactivity in this setting [22,24]. Furthermore, adipose tissue may directly be involved because it expresses all the components of the renin–angiotensin system [16,25] and may produce substances directly stimulating aldosterone release . Excessive aldosterone release is also an important mechanism predisposing to resistant hypertension . In addition to an activation of the sympathetic nervous system and the renin–angiotensin system, structural kidney changes described in animal models of obesity may also promote sodium retention .
Overall, the literature suggests that visceral adiposity makes the control of arterial hypertension more difficult. Moreover, visceral adiposity is one of the leading features of the metabolic syndrome. Given the relatively high-added metabolic and cardiovascular risk, current guidelines suggest that patients fulfilling metabolic syndrome criteria should be treated more aggressively . However, current treatment recommendations and clinical trials give little guidance on how to achieve this goal considering that many patients do not respond to first line antihypertensive therapies. The idea that blood pressure could be cured through weight loss is appealing. Unfortunately, many patients are unable to attain long-term reductions in adiposity through life style interventions. Short-term studies may overestimate the long-term effect of weight loss on blood pressure. Finally, weight-loss studies focusing on blood pressure control are rare. The issue has been recently reviewed in a contribution by the European Society of Hypertension Working Group on Obesity in this Journal .
A recent study examined influences of dietary salt restriction on office and 24-h ambulatory blood pressure in individuals with resistant hypertension . In this study, 12 patients were randomized to low (50 mmol/day) or high-sodium (250 mmol/day) diets for 7 days each in a crossover fashion. The low-sodium diet lowered office blood pressure 23/9 mmHg, which can hardly be achieved with a single antihypertensive drug. In another study, mineralocorticoid receptor inhibition with spironolactone decreased blood pressure in patients with resistant hypertension, especially in those with abdominal obesity and lower arterial stiffness . The authors suggested that spironolactone is a useful fourth or fifth antihypertensive drug. Newer drugs, such as the direct renin inhibitor alsikiren, which has been tested in obese hypertensives , or the endothelin receptor antagonist darusentan, which has been tested in resistant hypertension  could emerge as suitable add-on therapies in patients with treatment-resistant hypertension. Finally, device-based treatments may prove useful in patients not responding to antihypertensive pharmacotherapy. One approach that is currently being tested in clinical trials is electrical carotid baroreceptor stimulation, which lowers blood pressure through sympathetic inhibition [34,35]. Another promising approach for the treatment of resistant hypertension is catheter-based renal denervation, which appears to elicit its depressor response through interruption of efferent sympathetic and afferent renal nerve traffic [36,37].
Visceral adiposity appears to be an important risk factor for difficult to treat or truly resistant arterial hypertension. Volume expansion and neurohumoral mechanisms are involved. Many patients are affected and continue to be exposed to an unacceptable cardiovascular risk. Yet, the issue is not sufficiently recognized and studied by the scientific community. Moreover, drug companies are not inclined to testing drugs in this ‘niche’ indication. The large number of patients in this ‘niche’ deserves better treatments.
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