Mikolaj Winnicki

Elevated C-Reactive Protein in Patients With Obstructive Sleep Apnea

Background—Obstructive sleep apnea (OSA) has been increasingly linked to cardiovascular and cerebrovascular disease. Inflammatory processes associated with OSA may contribute to cardiovascular morbidity in these patients. We tested the hypothesis that OSA patients have increased plasma C-reactive protein (CRP). Methods and Results—We studied 22 patients (18 males and 4 females) with newly diagnosed OSA, who were free of other diseases, had never been treated for OSA, and were taking no medications. We compared CRP measurements in these patients to measurements obtained in 20 control subjects (15 males and 5 females) who were matched for age and body mass index, and in whom occult OSA was excluded. Plasma CRP levels were significantly higher in patients with OSA than in controls (median [range] 0.33 [0.09 to 2.73] versus 0.09 [0.02 to 0.9] mg/dL, P <0.0003). In multivariate analysis, CRP levels were independently associated with OSA severity (F=6.8, P =0.032). Conclusions—OSA is associated with elevated levels of CRP, a marker of inflammation and of cardiovascular risk. The severity of OSA is proportional to the CRP level.

Impairment of Endothelium-Dependent Vasodilation of Resistance Vessels in Patients With Obstructive Sleep Apnea

Background—Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease. Methods and Results—We studied 8 patients with OSA (age 44±4 years) and 9 obese control subjects (age 48±3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine (P <0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects. Conclusions—Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.

Sympathetic Activation by Sildenafil

Background—Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses. Methods and Results—We studied 14 normal volunteers (age 32±7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141±26%, mean±SEM) compared with placebo (3±8%) (P =0.006); plasma norepinephrine levels also increased by 31±5% after sildenafil administration (P =0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo (P <0.05). Conclusions—Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.

Prevalence and Clinical Significance of Isolated Ambulatory Hypertension in Young Subjects Screened for Stage 1 Hypertension

Little is known about the clinical significance of isolated ambulatory hypertension, a condition characterized by low office but elevated ambulatory blood pressure. This study aimed to investigate the prevalence and the predictive value of isolated ambulatory hypertension diagnosed after 3 months of observation for the development of sustained hypertension within a cohort of 871 never-treated stage-1 hypertensive subjects. The study end point was progression to more severe hypertension and need of antihypertensive medication. In 244 subjects (28%), clinic blood pressure declined to <140/90 mm Hg after 3 months. Of these, 124 (14.2% of total) had low clinic and ambulatory blood pressures after 3 months (nonhypertensive subjects), whereas 120 subjects (13.8% of total) showed low clinic but elevated ambulatory blood pressure (isolated ambulatory hypertension). During the 6 years of observation, the number of end points based on multiple clinic blood pressure readings progressively increased from the nonhypertensive subjects (19%) to the subjects with isolated ambulatory hypertension (35%) and to the subjects with high clinic and high ambulatory blood pressures (65%, P <0.0001). In an adjusted proportional hazard model, isolated ambulatory hypertension status was associated with a 2.2 (P <0.02) increase in the risk of reaching the end point in comparison with the nonhypertensive subjects. Final ambulatory systolic blood pressure was also higher in the former than the latter (P =0.03). Our results indicate that among subjects screened for stage 1 hypertension, individuals with isolated ambulatory hypertension after 3 months of observation have increased risk of developing sustained hypertension in later life compared with subjects in whom both clinic and ambulatory blood pressures are normal.

Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects

Objective Administration of leptin to animals increases sympathetic nerve activity and heart rate. We therefore tested the hypothesis that plasma leptin is linked independently to muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. Methods We measured plasma leptin, plasma insulin, body mass index (BMI), percent body fat, waist : hip ratio, MSNA, heart rate and blood pressure in 88 healthy individuals (50 men and 38 women). Results In men, plasma leptin concentration correlated significantly with BMI (r = 0.75, P < 0.001), percent body fat (r = 0.70, P < 0.001), waist : hip ratio (r = 0.69, P < 0.001), insulin (r = 0.37, P = 0.009), and age (r = 0.38, P = 0.006). Only BMI and waist : hip ratio were linked independently to plasma leptin concentration (r = 0.78, P < 0.001). Plasma leptin concentrations also correlated with heart rate (r = 0.39, P = 0.006) and mean arterial pressure (MAP;r = 0.38, P = 0.007), but not with MSNA (r = 0.17, P = 0.24). After adjustment for BMI and waist : hip ratio, plasma leptin concentration correlated significantly only with heart rate (r = 0.29, P = 0.04), and not with MAP (r = 0.21, P = 0.14). Individuals were divided into high-leptin and low-leptin subgroups on the basis of plasma leptin concentrations adjusted for BMI and waist : hip ratio. Those with high leptin concentrations had significantly faster heart rates than those with low leptin. MAP and MSNA were similar in both subgroups. No relationship between leptin and either heart rate or MSNA was evident in women. Conclusions In normal men, heart rate, but not MSNA, is linked to plasma leptin concentration. This sex-specific relationship between heart rate and plasma leptin is independent of plasma insulin, BMI, waist : hip ratio and percentage body fat.

Effects of a traditional lifestyle on the cardiovascular risk profile: the Amondava population of the Brazilian Amazon. Comparison with matched African, Italian and Polish populations.

OBJECTIVE To determine the relationships between lifestyle and cardiovascular risk factors among the Brazilian Amondava, one of the worlds most isolated populations. DESIGN Cross-sectional, population-based study. Four age- and sex-matched samples from Brazil Africa, Italy and Poland, representing different levels of modernization, were compared. Body weight, height, blood pressure, serum cholesterol and glycaemia were measured, and a standard questionnaire administered. Data concerning dietary habits and physical activity were collected. A personal socio-economic score was calculated, on the basis of type of economy, level of formal education, type of occupation, type of habitat, availability of piped water and electricity, main source of income, housing conditions, availability of radio, television or personal computer, knowledge of a second language, and organized health facilities. SETTING Primary epidemiological screening, at an institution. RESULTS Among the Amondava blood pressure was always <140/90 mm Hg, it did not increase with age and was not correlated with any other variable; 46.6% of subjects had systolic blood pressure <100 mm Hg. Blood pressure among the Amondava (109.6+/-11.1/69.5+/-6.4 mm Hg) was on average lower (P<0.0001) than in all other samples. Among the Amondava, the concentration of total cholesterol was always <200 mg/dl, i.e. similar to that of Africans whose diet included large amounts of vegetable foodstuffs; 90% had glycaemia (<80 mg/dl), and their mean value was the lowest (55.1+/-14.9 mg/dl) of all the groups. CONCLUSIONS In addition to a possible genetic predisposition not analysed in this study, a traditional lifestyle (no contact with civilization, diet based on complex carbohydrates and vegetables, high energy expenditure) may protect against the development of hypertension, hypercholesterolaemia, and diabetes.

Fish-Rich Diet, Leptin, and Body Mass

Background—Leptin has been implicated in cardiovascular disease. A diet rich in fish has been associated with decreased cardiac and vascular risk. Methods and Results—We examined the relationship between diet and leptin in 2 related homogeneous African tribal populations of Tanzania. One tribe consumes freshwater fish as their main diet component (n=279), and the other tribe consumes a primarily vegetarian diet (n=329). In multivariate analysis, plasma leptin levels were associated with type of diet (F=14.3, P <0.001), independent of age, body mass index, body fat, alcohol consumption, or insulin. Both male (2.5±2 [fish diet] versus 11.2±2.4 [vegetarian diet] ng/mL, P =0.017) and female (5.0±1.9 [fish diet] versus 11.8±1.4 [vegetarian diet] ng/mL, P =0.007) fish eaters had lower plasma leptin levels than did their vegetable diet counterparts, even though body mass index values were virtually identical. Conclusions—A diet rich in fish is associated with lower plasma leptin, independent of body fat. These findings may have implications for understanding the reduced cardiovascular risk in subjects on a high-fish diet.

G-Protein β3-Subunit Gene 825T Allele and Hypertension: A Longitudinal Study in Young Grade I Hypertensives

Introduction Essential hypertension affects approximately 25% of individuals in Western societies, with an increased prevalence in older subjects. It has long been recognized that a significant part of the susceptibility for hypertension is inherited. However, unlike monogenic disorders, hypertension develops on the genetic background of multiple gene alterations in concert with environmental factors, eg, nutrition and physical activity. The hunt for hypertension susceptibility genes is nourished from different aspects. One goal is easily understood: if a causative mutation or polymorphism is found, there exists, at least theoretically, the possibility to modify the activity of the gene product through existing or novel drugs. Moreover, since hypertension is not a disorder per se but a major risk factor for stroke, left ventricular hypertrophy, myocardial, and renal insufficiency, genetic testing could identify individuals at highest risk in order to provide them with optimized medical care to prevent the aforementioned sequels. Finally, one could envisage a scenario in which certain genotypes may be used to guide antihypertensive therapy in terms of drug class and dosage.Abstract—The 825T allele of the GNB3 gene has been associated with essential hypertension and obesity in cross-sectional studies. We have therefore planned a longitudinal cohort study to assess whether the GNB3 825T allele is predictive of blood pressure increase in young subjects with grade I hypertension. We genotyped at the GNB3 825 locus 461 participants of the Hypertension and Ambulatory Recording Venetia Study (HARVEST) study (age, 18 to 45 years) at low cardiovascular risk, according to 1999 ISH/WHO criteria. The study end point was eligibility for antihypertensive medication, that is, progression to grade II hypertension during the first year of observation or office systolic blood pressure ≥150 mm Hg and/or office diastolic blood pressure ≥95 mm Hg in two later consecutive visits during follow-up. At baseline, there was no statistically significant difference among genotypes with respect to body mass index, blood pressure, and heart rate. During follow-up (mean, 4.7 years), 113 (51.1%) patients with CC genotype and 145 (60.4%) patients with TT/TC genotype reached the end point. According to survival analysis, the patients carrying the 825T allele had an increased risk of reaching the blood pressure end point (CI, 1.108 to 1.843; P =0.006). In young patients with grade I hypertension, the 825T allele is associated with increased risk of progression to more severe hypertension requiring antihypertensive therapy. The GNB3 825T allele may be considered a genetic marker of predisposition for hypertension.

C-344T polymorphism of the aldosterone synthase gene and blood pressure in the elderly: a population-based study.

Objectives Whether the C-344T polymorphism of the aldosterone synthase gene is important for blood pressure control remains controversial. It has been proposed that an association between this polymorphism and blood pressure might be evident in elderly subjects. The aim of the present study was to test this hypothesis in an epidemiological context. Design A cross-sectional epidemiological evaluation of a highly homogeneous unselected general population of elderly Caucasians. Methods Lifestyle, medical history, anthropometrics, skinfold thickness, supine blood pressure, heart rate and biochemical measures were recorded in 437 subjects aged ≥ 65 years living in a secluded valley. All were genotyped for C-344T allele status and underwent measurements of plasma aldosterone and renin. Results The C-344T genotypic frequency did not deviate from Hardy–Weinberg equilibrium. The aldosterone to renin ratio was 19% lower in the CC than in the TT genotype. Systolic blood pressure was significantly lower in subjects with the CC genotype, higher in the TT (+9.6 mmHg versus CC) and intermediate in the CT (+7.9 mmHg versus CC). Adjustment for age, gender, smoking and antihypertensive treatment did not affect this association. Diastolic blood pressure did not differ across genotypes. A significant increase of systolic blood pressure with increasing age and with increasing skinfold thickness was observed in the TT homozygotes but not in the C-carriers. Conclusions These data support the concept that the C-344T polymorphism plays a role in controlling systolic blood pressure and the age-related increase in systolic blood pressure in response to age and to body fat, possibly through differences in modulation of aldosterone synthesis.

Physical Activity and Angiotensin-Converting Enzyme Gene Polymorphism in Mild Hypertensives

It has been suggested that the insertion(I) allele of the I/deletion(D) polymorphism of the angiotensin converting enzyme (ACE) gene is associated with endurance exercise and increased physical conditioning in response to this type of exercise. To investigate the association between the ACE I/D polymorphism and physical activity status in 355 never treated, stage I hypertensives (265 men, 90 women, mean age: 33 ± 9 years), in whom power exercise is contraindicated, participants of the HARVEST study. Physical activity was assessed using a standardized questionnaire. BMI and age did not vary among genotypes. None of active subjects performed power oriented exercises. ACE I/D frequencies (II‐18%, ID‐55%, DD‐27%) were in Hardy–Weinberg equilibrium. Sedentary lifestyle was more common among DD than II hypertensives (76% in DD, and 48% in II, Chi2 = 13.9, P = 0.001). In stepwise MANOVA using age, marital status, profession, sex, and ACE genotype as predictors of physical activity, marital status (F = 24.4, P < 0.0001) and ACE genotype (F = 16.03, P < 0.0001) contributed to more than 50% of the variance in physical activity status of the population. Our results suggest that the ACE I/D polymorphism may be a specific genetic factor associated with physical activity levels in free‐living borderline and mild hypertensive subjects.