Meryem Tuncel

Sympathetic overactivity as a cause of hypertension in chronic renal failure.

Objective To review the current literature on sympathetic mediation of hypertension in chronic renal failure. Background Hypertension is present in the vast majority of patients with chronic renal failure and constitutes a major risk factor for the excessive cardiovascular morbidity and mortality in this patient population. Although, traditionally, this hypertension is thought to be largely volume-dependent, an increasing body of literature suggests that there is an important sympathetic neural component. Microneurographic studies have demonstrated sympathetic overactivity without baroreflex impairment in both hypertensive chronic hemodialysis patients as well as in those with less advanced renal insufficiency. Sympathetic nerve activity was found to be normal in hemodialysis patients with bilateral nephrectomy, leading to the hypothesis that sympathetic overactivity in uremia is caused by a neurogenic signal (carried by renal afferents) arising in the failing kidney. This hypothesis is supported by rat studies showing that renal deafferentation abrogates hypertension in the 5/6 nephrectomy model of chronic renal insufficiency. In addition, in patients with chronic renal insufficiency and renin-dependent hypertension, sympathetic overactivity was normalized by chronic angiotensin converting enzyme inhibition but not by calcium channel blockade, implicating a major central neural action of angiotensin II. Conclusions Sympathetic overactivity in chronic renal failure is caused by neurohormonal mechanisms arising in the failing kidney. Future clinical studies are needed to determine whether normalization of sympathetic activity should constitute an important therapeutic goal in this high-risk patient population.

Transdermal Estrogen Replacement Therapy Decreases Sympathetic Activity in Postmenopausal Women

Background—Menopause heralds a dramatic increase in incident hypertension, suggesting a protective effect of estrogen on blood pressure (BP). In female rats, estrogen has been shown to decrease sympathetic nerve discharge (SND) and BP. SND, however, has not been recorded during estrogen replacement therapy (ERT) in humans. Methods and Results—In 12 normotensive postmenopausal women, we conducted a randomized crossover placebo-controlled study to test whether chronic ERT caused a sustained decrease in SND and BP. Twenty-four-hour ambulatory BP, SND, and arterial baroreflex sensitivity were measured before and after 8 weeks of transdermal estradiol (200 &mgr;g/d), oral conjugated estrogens (0.625 mg/d), or placebo. To test the acute effects of estrogen on SND, additional studies were performed in the same women receiving intravenous conjugated estrogens or sublingual estradiol. After 8 weeks of transdermal ERT, the basal rate of SND decreased by 30% (from 40±4 to 27±4 bursts per minute, P =0.0001) and ambulatory diastolic BP fell by 5±2 mm Hg (P =0.0003). In contrast, SND and BP were unaffected either by 8 weeks of oral ERT or by acute estrogen administration. Neither transdermal nor oral ERT had any effects on baroreflex sensitivity. Conclusions—In normotensive postmenopausal women, chronic transdermal ERT decreases SND without augmenting arterial baroreflexes and causes a small but statistically significant decrease in ambulatory BP. Sympathetic inhibition is evident only with chronic rather than acute estrogen administration, implying a genomic mechanism of action. Because the effects of transdermal ERT are larger than those of oral ERT, the route of administration may be an important consideration in optimizing the beneficial effects of ERT on BP and overall cardiovascular health.

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women

OBJECTIVES We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism. METHODS In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured. RESULTS Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis. CONCLUSIONS In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.

Overweight and Sympathetic Overactivity in Black Americans

A large body of clinical investigation implicates an important role for the sympathetic nervous system in linking obesity with hypertension. However, the experimental support for this hypothesis is derived from strictly white cohorts. The goal of this study was to determine whether being overweight begets sympathetic overactivity in black Americans, the ethnic minority at highest risk for hypertension. We recorded postganglionic sympathetic nerve discharge with microelectrodes in muscle nerve fascicles of the peroneal nerve in 92 normotensive young adult black men and women within a wide range of body mass index. The same experiments were performed in a control group of 45 normotensive white men and women of similar ages and body mass indices. The major new findings are 2-fold. First, in young, normotensive, overtly healthy black women, being overweight begets sympathetic overactivity (r =0.45, P =0.0009), a putative intermediate phenotype for incident hypertension. Second, in black men, sympathetic nerve discharge is dissociated from body mass index (r =0.03, P =NS). This dissociation is explained in part by a 20% to 40% higher rate of sympathetic nerve discharge in lean black men compared with lean white men and lean black and white women (28±3 versus 18±2, 21±2, and 17±2 bursts/min, respectively;P <0.05). Sympathetic nerve discharge in lean black men is comparable to that of overweight black men and women as well as white men and women. These data provide the first microneurographic evidence for tonic central sympathetic overactivity in blacks, both adiposity-related sympathetic overactivity in black women and adiposity-independent sympathetic overactivity in black men.

Hypertensive emergencies. Etiology and management.

Although systemic hypertension is a common clinical disorder, hypertensive emergencies are unusual in clinical practice. Situations that qualify as hypertensive emergencies include accelerated or malignant hypertension, hypertensive encephalopathy, acute left ventricular failure, acute aortic dissection, pheochromocytoma crisis, interaction between tyramine-containing foods or drugs and monoamine oxidase inhibitors, eclampsia, drug-induced hypertension and possibly intracranial hemorrhage. It is important to recognize these conditions since immediate lowering of systemic blood pressure is indicated. The diagnosis of hypertensive emergencies depends on the clinical manifestations rather than on the absolute level of the blood pressure. Depending on the target organ that is affected, the manifestations of hypertensive emergencies can be quite expressive, yet variable. Thus, the physician has to make the clinical diagnosis urgently in order to render appropriate therapy. Several parenteral drugs can quickly and effectively lower the blood pressure in hypertensive emergencies. Intravenous fenoldopam, a selective dopamine (DA1) receptor agonist, offers the advantage of improving renal blood flow and causing natriuresis. Intravenous nicardipine may be beneficial in reserving tissue perfusion in patients with ischemic disorders. Whereas trimethaphan camsilate is the drug of choice for managing acute aortic dissection, hydralazine remains the drug of choice for the treatment of eclampsia. The α-adrenoceptor, phentolamine, is useful in patients with pheochromocytoma crisis. Enalaprilat is the only ACE inhibitor available for parenteral use and may be particularly useful in treating hypertensive emergencies in patients with heart failure. However, ACE inhibitors may cause a precipitous fall in blood pressure in patients who are hypovolemic. Although useful as adjunctive therapy in hypertensive crises, diuretics should be used with caution in these patients because prior volume depletion may be present in some conditions such as malignant hypertension. The treating physician should be familiar with the pharmacological and clinical actions of drugs which are indicated for and useful in the treatment of hypertensive emergencies. Once the patient’s situation has stabilized, the patient may be switched to an oral medication and the physician should discuss long term follow up plans. With appropriate clinical diagnosis, hypertensive emergencies can be successfully treated and the complications can be prevented with timely intervention.

Disorders of Lipid Metabolism and Chronic Kidney Disease in the Elderly

The growing population of elderly with chronic kidney disease (CKD) is at greater risk for cardiovascular disease given an independent risk of CKD, as well as from added dyslipidemia of aging and renal dysfunction. Changes in lipid metabolism with more isodense and high-dense, triglyceride-rich particles, low high-density lipoprotein cholesterol, and increased triglyceride levels occur with CKD and aging, which are noted to have significant atherogenic potential. In addition, lipid abnormalities may lead to the progression of CKD. Cardiovascular mortality in the end-stage renal disease population is more than 10 times higher than the general population. Treatment of dyslipidemia in the general population suggests important benefits both in reducing cardiovascular risk and in the prevention of cardiovascular disease. Secondary analyses of elderly subgroups of various large prospective studies with statins suggest treatment benefit with statin use in the elderly. Similarly limited data from secondary analyses of CKD subgroups of larger prospective trials using statins also suggest a possible benefit in cardiovascular outcomes and the progression of kidney disease. However, randomized trials have yet to confirm similar benefits and targets of treatment for dyslipidemia in the elderly with CKD and end-stage renal disease. Treatment in the elderly with CKD should be individualized and outweigh risks of side effects and drug-drug interactions. There is a need for further specific investigation of dyslipidemia of CKD in the aging population in relation to renal disease progression and cardiovascular outcome.

Adiposity-independent sympathetic activity in black men

Obesity is thought to lead to sympathetic overactivity as a compensatory adjustment to weight gain. However, most of the experimental support for the hypothesis has been derived from white cohorts. Our previous study in blacks indicated that sympathetic nerve activity (SNA) is closely correlated with body mass index only in women, whereas, in black men, SNA is elevated and dissociated from adiposity (Abate et al., Hypertension 38: 379-383, 2001). To further determine whether total and regional adiposity are determinants of SNA in blacks, we performed a prospective weight loss study in 12 normotensive obese black men and 9 obese black women. SNA, body mass index, and abdominal fat mass were measured before and 16 wk after hypocaloric diet. The major new findings are that, in obese black men, the dietary-induced weight loss of 11.3+/-0.8 kg resulted in reduction in plasma leptin, insulin, and visceral abdominal fat but had no effect on SNA (from baseline of 26+/-4 to 28+/-3 bursts/min, P=not significant). In contrast, in black women, weight loss of 8.0+/-0.9 kg caused similar reductions in plasma leptin, insulin, and visceral abdominal fat and led to a reduction in SNA by 40% (from baseline of 22+/-2 to 13+/-3 bursts/min, P<0.05). In conclusion, these new data from this prospective study provide strong support for a major adiposity-independent sympathetic activity in black men and adiposity-related sympathetic activity in black women.

Cardiac Repolarization Abnormalities Among Patients With Various Stages of Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are at increased risk of life‐threatening cardiovascular arrhythmias. Although these arrhythmias are usually secondary to structural heart diseases that are commonly associated with CKD, a significant proportion of cases with sudden cardiac death have no obvious structural heart disease. This study aims to explore the relationship of cardiac repolarization in patients with CKD and worsening kidney function.

OR-45: Is sympathetic nervous system important in mediating blood pressure lowering effect of weight loss ?

Reduction in sympathetic vasoconstrictor drive has been hypothesized to be a major mechanism explaining the blood pressure-lowering effects of dietary weight loss, but the evidence to support this notion is derived from strictly Caucasian cohorts. To determine if weight loss also leads to sympathoinhibition in African Americans (AA), the demographic group in the U.S. with the highest prevalence of hypertension, we measured sympathetic nerve activity (SNA) with microneurography in 11 normotensive (NT) young adult AA men and 6 NT young adult AA women before and after 16 weeks of a hypocaloric diet. In the women, 20 lb weight loss led to greater then 50% reduction in SNA (22 3to 10 1 bursts/min) but 24-hour ambulatory blood pressure (BP) was unchanged (116 2/68 1 to 116 3/70 1 mmHg, p ns). In the men however, 24 lb weight loss had no effect on SNA (26 4 to 27 3) but lowered the 24-hour ambulatory BP by 5/4 mm Hg (from 124 2/74 2 to 119 3/70 2 mmHg, P 0.05). To explore the mechanism of the blood pressure lowering effect of weight loss in these men, we measured 24-hour urinary sodium excretion and found that the 24-hour BP fell only in the men who had reduced their sodium intake along with the hypocaloric diet. In 6 men in whom urinary sodium excretion fell markedly from 165 11 to 45 17 meq/day, 24-hour BP fell by 8/6 mm Hg (from 123 4/74 5 to 115 3/68 3 mmHg) over the 16 week protocol, whereas in the 5 men in whom urinary sodium excretion did not fall, 24-hour BP remained unchanged despite comparable amounts of weight loss in both subgroups. Thus, in women, a substantial reduction in SNA with weight loss was not sufficient to lower BP whereas in men a small but significant reduction in blood pressure was closely linked to reduced dietary sodium intake and dissociated from SNA. These prospective data in normotensive young adult AA men and women call in to question the importance of the sympathetic nervous system in producing the blood pressure lowering effect of dietary weight loss.

Hypertension and Diabetes

As a consequence of increasing obesity seen in all industrially developed societies, the incidence of type 2 diabetes mellitus is rapidly rising, soon to inflict more than 300 million people worldwide and more than 20 million people in the United States. More than half of these diabetics will also be hypertensive, and the coexistence of diabetes and hypertension more than doubles the likelihood of serious cardiovascular events over rates seen with either disease alone.