Juan Carlos Yugar-Toledo

Characteristics of resistant hypertension: ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness

Resistant hypertension (RHTN) includes patients whose blood pressure (BP) is controlled with the use of four or more antihypertensive medications, and is referred to as ‘controlled resistant hypertension’ (CRH). While specifically comparing patients with CRH and uncontrolled resistant hypertension (UCRH), we hoped to identify distinguishing characteristics that would provide insight into factors contributing to resistance to antihypertensive therapies. RHTN patients were identified as controlled (CRH, n=43) or uncontrolled (UCRH, n=47). No statistical differences were observed between the CRH and UCRH subgroups with respect to age and gender. The body mass index, aldosterone–renin ratio and pulse wave velocity (PWV) were significantly higher in UCRH patients. Although both subgroups showed increased cardiac mass, left ventricular mass index was significantly higher in UCRH compared with CRH patients. Multivariate linear regression analysis indicated that PWV was significantly dependent on age in both UCRH and CRH patients; however, the influence of ageing was more pronounced in the former subgroup. Older age, greater vascular stiffness, higher aldosterone levels and greater left ventricular hypertrophy were significantly associated with lack of BP control in patients with RHTN. These findings suggest important possibilities in terms of preventing and better treating RHTN.

Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy.

Objectives Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. Methods We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T−786C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. Results No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the ‘C Glu b’ haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the ‘C Asp b’ haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). Conclusions Whereas our findings suggest a protective effect for the ‘C Glu b’ haplotype against hypertension and that the ‘C Asp b’ haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to antihypertensive therapy.

Vascular stiffness and endothelial dysfunction: Correlations at different levels of blood pressure

Abstract Resistant hypertensive (RHTN) patients have endothelial dysfunction and aldosterone excess, which contribute to the development of resistance to antihypertensive treatment and cardiovascular complications. Biophysical forces within the arterial wall provide functional regulation of arterial stiffness. Carotid–femoral pulse wave velocity (PWV) and flow-mediated brachial artery dilation (FMD) can be used to evaluate vascular stiffness and endothelial function. Although both techniques have been used in several studies in hypertensive patients, it is unknown whether endothelial dysfunction is also associated with vascular stiffness in RHTN patients. Methods. One hundred and ninety-three consecutive subjects were divided in three groups: 44 RHTN, 35 well-controlled hypertensive patients (HTN) and 25 normal healthy volunteers (NT). FMD was measured by high-resolution ultrasound and PWV was calculated from measurements of the pulse transit time and the distance traveled by the pulse between carotid and femoral arteries. Results. No significant differences were observed in respect to body mass index, age or other biochemical variables among the three groups. FMD (NO-dependent) values were statistically different when comparing RHTN and well controlled HTN patients (respectively, 8.3 ± 4.7% and 10.1 ± 5.9%) and 12.3 ± 6.3% in normal subjects (p < 0.05). One-way analysis of variance (ANOVA) showed a significant difference in BP-adjusted PWV between RHTN and HTN (13.9 ± 1.0 and 11.5 ± 1.1 m/s, respectively; p < 0.05). FMD (NO-dependent) and PWV-adjusted values were strongly correlated in well-controlled HTN and NT subjects (r = − 0.74 and − 0.83, respectively). Although statistically significant, this correlation was lower in RHTN patients (r = − 0.43). Conclusion. We found a close relationship among high BP levels, endothelial dysfunction and vascular rigidity in hypertensive patients, demonstrated by a significantly higher increase in carotid–femoral PWV and a decrease in brachial artery FMD in RHTN when compared with well-controlled hypertensive patients. Although this study was not designed to test the prognostic, the vascular damage differences observed between patients with controlled vs uncontrolled hypertension suggest that the latter group may have a worse cardiovascular prognosis, requiring prospective assessment tests.

Hypertensive crisis: clinical–epidemiological profile

Hypertensive crisis (HC) stands out as one type of acute elevation in blood pressure (BP) and can manifest as hypertensive emergency (HE—with target-organ damage (TOD)) or hypertensive urgency (HU—without TOD), usually accompanied by levels of diastolic BP ⩾120 mm Hg. The aim of this study was to characterize the clinical–epidemiological profile of HC over the course of 1 year in a university reference hospital and perform a review of the literature. The study was a cross-sectional study, conducted over a period of 1 year (2006) in 362 patients who presented for treatment at the emergency hospital with HC, as described above. Among all patients examined, 231 individuals met the criteria for HE and 131 met the criteria for HU. Patients with HE were older (P<0.001) and more sedentary (P=0.026) than those with HU. Furthermore, fewer HE patients than HU patients had previously undergone antihypertensive treatment (P=0.006). The groups did not differ regarding BP levels, gender, smoking or body mass index. Dyspnea (41.1%), thoracic pain (37.2%) and neurological deficit (27.2%) were common signs/symptoms in those with HE. Meanwhile, in the group with HU, we most frequently found headache (42.0%), thoracic pain (41.2%) and dyspnea (34.3%). Among the forms of HE, we most frequently observed acute lung edema (30.7%), myocardial infarction/unstable angina (25.1%), and ischemic (22.9%) and hemorrhagic (14.8%) stroke. HC is a clinical entity associated with high morbidity in the emergency room. Individuals with HE are older and sedentary and have lower rates of antihypertensive treatment. Adequate control of BP should be pursued as a way to avoid this severe complication of hypertension.

Intensive Monitoring of Adherence to Treatment Helps to Identify “True” Resistant Hypertension

Intensive monitoring of adherence in patients with uncontrolled hypertension was evaluated over a 6‐month period. After that period, only patients well characterized as having resistant hypertension were followed for 12 months. The goal of this study was to evaluate whether adherence to a drug regimen helps to identify patients with resistant hypertension. Forty‐four hypertensive patients resistant to a 3‐drug regimen (average blood pressure [BP] mm Hg, mean ± standard deviation) were studied prospectively. Each patient was followed for a 12‐month period. Adherence to treatment was evaluated through self‐report, applying Morisky’s questionnaire and the pill count method. Ambulatory BP monitoring and office BP measures were performed. By pill count, 63.6% of the patients were adherent to treatment at the start of the survey and 94% at the end, although 59% of the patients still did not reach normal BP levels. We found that non‐adherence was not associated with resistance to antihypertensive treatment. Therefore, after investigation, we concluded that patients who presented with uncontrolled arterial BP may be truly resistant hypertensive to treatment.

Ascorbic acid improves impaired venous and arterial endothelium-dependent dilation in smokers

AbstractAim:To compare the acute effects of ascorbic acid on vasodilation of veins and arteries in vivo.Methods:Twenty-six healthy non-smokers and 23 healthy moderate smokers were recruited in this study. The dorsal hand vein compliance technique and flow-mediated dilation were used. Dose-response curves to bradykinin and sodium nitroprusside were constructed to test the endothelium-dependent and -independent relaxation before and after acute infusion of ascorbic acid.Results:Smokers had an impaired venodilation with bradykinin compared with non-smokers (68.3%±13.2% vs 93.7%±20.1%, respectively; P<0.05). Ascorbic acid administration in the dorsal hand vein significantly increased the venodilation with bradykinin in smokers (68.3%± 13.2% vs 89.5%±6.3% before and after infusion, respectively; P<0.05) but not in non-smokers (93.7%±20.1% vs 86.4%±12.4% before and after infusion, respectively). Similarly, the arterial response in smokers had an impaired endothelium-dependent dilation compared with that in non-smokers (8.8%±2.7% vs 15.2%±2.3%, respectively; P<0.05) and ascorbic acid restored this response in smokers (8.8%±2.7% vs 18.7%±6.5% before and after infusion, respectively; P<0.05), but no difference was seen in non-smokers (15.2%±2.3% vs 14.0%±4.4% before and after infusion, respectively). The endothelium-independent dilation did not differ in both the groups studied. No important hemodynamic change was detected using the Portapress device.Conclusion:Smokers had impaired endothelium-dependent vasodilation responsiveness in both arterial and venous systems. Ascorbic acid restores this responsiveness in smokers.

Non-dipping pattern relates to endothelial dysfunction in patients with uncontrolled resistant hypertension

Resistant hypertension (RHTN) includes both patients whose blood pressure (BP) is uncontrolled on three or more medications (uncontrolled RHTN (UCRH)) and patients whose BP is controlled with use of four or more drugs (controlled RHTN (CRH)). It is unknown whether endothelial function and nocturnal drop demonstrate a similar pattern in patients with CRH and UCRH. We examined circadian BP patterns and vascular function in these patients. In all, 40 CRH and 26 UCRH patients, and 25 normotensives underwent biochemical testing, ambulatory BP monitoring, determination of brachial artery responses to endothelial-dependent (flow-mediated; dilation (FMD)) and independent (nitroglycerin mediated) stimuli. The nighttime drop in systolic BP (SBP) and diastolic BP (DBP) was less pronounced in UCRH than in CRH (SBP, 1.9±1.6 versus 4.9±1.7%; DBP, 7.5±1.8 versus 10.9±1.8%, UCRH and CRH, respectively; P<0.05). FMD was greater in control group compared with RHTN patients. Patients with UCRH had significantly impaired FMD compared with CRH (5.9±2.3% versus 7.1±5.1%; P<0.0001). Therefore, UCRH patients have less nocturnal dipping and a more impaired endothelial response compared with CRH patients. These findings suggest that important differences among patients with RHTN may allow identify subgroups with increased cardiovascular risk.

Aldosterone excess or escape: Treating resistant hypertension.

Aldosterone excess or “escape” can occur after treatment with medications that block the renin‐angiotensin‐aldosterone system or in undiagnosed primary aldosteronism. Spironolactone is thought to be an important addition to resistant hypertension (RH) treatment. In this study, resistant (RH) and controlled (CH) hypertensives and normotensive patients were submitted to echocardiography, flow‐mediated vasodilation, carotid intima‐media wall thickness studies, renin plasma activity, and aldosterone plasma levels and plasma and urinary sodium and potassium concentrations at baseline (pre‐spironolactone phase). Subsequently, for only RH and CH groups, 25 mg/d spironolactone was added to preexisting treatments over 6 months. Afterwards, these parameters were reassessed (post‐spironolactone phase). The RH and CH groups achieved reductions in blood pressure (P<.001), decreases in left ventricular hypertrophy (P<.001), improved diastolic function (Kappa index RH: 0.219 and Kappa index CH: 0.392) and increases in aldosterone concentrations (P<.05). The RH group attained improved endothelium‐dependent (P<.001) and independent (P=.007) function. Optimized RH treatment with spironolactone reduces blood pressure and improves endothelial and diastolic function and left ventricular hypertrophy despite the presence of aldosterone excess or escape.

Venous or arterial endothelium evaluation for early cardiovascular dysfunction in hypertensive patients

Veins and arteries have active endothelium, producing vasoactive substances like nitric oxide. The aim of this study was to evaluate whether hypertensive patients exhibit venous endothelial dysfunction and to determine the relationship between endothelial‐dependent and endothelial‐independent vasodilation responses in venous and arterial systems. Sixteen unmedicated patients with stage I and II hypertension and without other risk factors and 15 matched normotensive volunteers had venous and arterial endothelial function evaluated with the dorsal hand vein technique and brachial artery ultrasonography. Hypertensive patients had a marked reduction of maximum dilation to acetylcholine (54.9%±21.6%) compared with normotensive controls (85.2%±27.0%). The flow‐mediated dilation responses were reduced in hypertensive patients compared with controls (6.6%±3.3%vs 12.4%±2.6%, respectively). The responses to nitric oxide were similar in both groups, and the responses with the dorsal hand vein technique and flow‐mediated dilation agreed in both groups. Hypertensive patients had an attenuated endothelial dependent response, indicating that endothelial dysfunction is also present in the venous system.

Gene variation in resistant hypertension: multilocus analysis of the angiotensin 1-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase genes.

Resistant hypertension, a complex multifactorial hypertensive disease, is triggered by genetic and environmental factors and involves multiple physiological pathways. Single genetic variants may not reveal significant associations with resistant hypertension because their effects may be dependent on gene-gene or gene-environment interactions. We examined the interaction of angiotensin I-converting enzyme (ACE), angiotensinogen (AGT), and endothelial nitric oxide synthase (NOS3) polymorphisms with environmental factors (gender, age, body mass index, glycemia, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, and urinary sodium excretion) in 70 resistant, 80 well-controlled hypertensive patients, and 70 normotensive controls. All subjects were genotyped for ACE insertion/deletion (rs1799752); AGT M235T (rs699), and NOS3 Glu298Asp (rs 1799983). Multifactorial associations were tested using two statistical methods: the traditional parametric method (adjusted logistic regression analysis) and gene-gene and gene-environment interactions evaluated by multifactor dimensionality reduction analyses. While adjusted logistic regression found no significant association between the studied polymorphisms and controlled or resistant hypertension, the multifactor dimensionality reduction analyses showed that carriers of the AGT 235T allele were at increased risk for resistant hypertension, especially if they were older than 50 years. The AGT 235T allele constituted an independent risk factor for resistant hypertension.