Fetnat M. Fouad-Tarazi

Sympathetic overactivity in patients with chronic renal failure

BACKGROUND Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. METHODS We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity. CONCLUSIONS Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.

The Usefulness of Head‐Up Tilt Testing and Hemodynamic Investigations in the Workup of Syncope of Unknown Origin

To enhance the clinical evaluation of patients suffering from recurrent syncope of unknown origin, the integrity of mechanisms controlling blood pressure was examined in 151 patients utilizing a screening tilt test. Ninety‐eight patients had an abnormal blood pressure and/or heart rate response to tilt testing, including provoked syncopal attacks in 63 patients. Whenever indicated, the screening tilt test was followed by blood volume and hemodynamic determinations, as well as autonomic nervous system testing to identify contributing pathophysiological abnormalities (hypovolemia, venous pooling, autonomic dysfunction). Detailed analysis of this battery of tests allowed us to conclude that: (1) The tilt test is commonly a provocative tool in the workup of patients with recurrent syncope due to vasovagal ‐ vasodepressor reactions and other abnormalities of blood pressure regulation; (2) Its usefulness is augmented by associated hemodynamic and blood volume evaluations; (3) The identification of contributory pathophysiological mechanisms of blood pressure control facilitates specific therapeutic interventions.

Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine

PURPOSE To investigate the efficacy and safety of midodrine for treatment of patients with orthostatic hypotension due to autonomic failure. PATIENTS Ninety-seven patients with orthostatic hypotension were randomized in a 4-week, double-blinded, placebo-controlled study with a 1-week placebo run-in period. Patients ranged in age from 22 to 86 years (mean: 61 years). METHODS After a 1-week run-in phase, either placebo or midodrine at a dose of 2.5 mg, 5 mg, or 10 mg was administered three times a day for 4 weeks. Both the placebo group and the 2.5-mg midodrine group received constant doses throughout the double-blind phase. The patients receiving 5 mg or 10 mg of midodrine were given doses that were increased at weekly intervals by 2.5-mg increments until the designated dose was reached. Efficacy evaluations were based on an improvement at 1-hour postdose in standing systolic blood pressure and in symptoms of orthostatic hypotension (syncope, dizziness/lightheadedness, weakness/fatigue, and low energy level). RESULTS Midodrine (10 mg) increased standing systolic blood pressure by 22 mm Hg (28%, p < 0.001 versus placebo). Midodrine improved (p < 0.05) the following symptoms of orthostatic hypotension compared to placebo: dizziness/lightheadedness, weakness/fatigue, syncope, low energy level, impaired ability to stand, and feelings of depression. The overall side effects were mainly mild to moderate. One or more side effects were reported by 22% of the placebo group compared with 27% of the midodrine-treated group. Scalp pruritus/tingling, which was reported by 10 of 74 (13.5%) of the midodrine-treated patients, was most frequent. Other reported side effects included supine hypertension (8%) and feelings of urinary urgency (4%). CONCLUSION We conclude that midodrine is an effective and well-tolerated treatment for moderate-to-severe orthostatic hypotension associated with autonomic failure.

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

Acute hypotension is an important complication of hemodialysis, but the underlying mechanisms remain poorly understood. Because hemorrhage-induced hypovolemia can trigger a sudden decrease in sympathetic activity resulting in bradycardia and vasodilation, we hypothesized that hemodialysis-induced hypovolemia also can trigger the same type of vasodepressor reaction, which would exacerbate the volume-dependent fall in blood pressure. We therefore measured blood pressure, vascular resistance, and sympathetic nerve activity (intraneural microelectrodes) during sessions of maintenance hemodialysis in 7 patients with and 16 patients without a history of hemodialysis-induced hypotension. During hemodialysis, blood pressure at first remained unchanged as calf resistance increased in both hypotension-resistant (from 37 +/- 4 to 49 +/- 5 U, P < 0.05) and hypotension-prone (from 42 +/- 6 to 66 +/- 12 U, P < 0.05) patients; sympathetic activity increased comparably in the subset of patients in whom it could be measured. With continued hemodialysis, calf resistance and sympathetic activity increased further in the hypotension-resistant patients, but in the hypotension-prone patients the precipitous decrease in blood pressure was accompanied by decreases in sympathetic activity, vascular resistance, and heart rate as well as symptoms of vasodepressor syncope. On an interdialysis day, both groups of patients increased vascular resistance normally during unloading of cardiopulmonary baroreceptors with lower body negative pressure and increased heart rate normally during unloading of arterial baroreceptors with infusion of nitroprusside. These findings indicate that in a group of hemodialysis patients without diabetes or other conditions known to impair autonomic reflexes, hemodialysis-induced hypotension is not caused by chronic uremic impairment in arterial or cardiopulmonary baroreflexes but rather by acute, paradoxical withdrawal of sympathetic vasoconstrictor drive producing vasodepressor syncope.

Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope.

Background— Previous studies that assessed the effects of &bgr;-blockers in preventing vasovagal syncope provided mixed results. Our goal was to determine whether treatment with metoprolol reduces the risk of syncope in patients with vasovagal syncope. Methods and Results— The multicenter Prevention of Syncope Trial (POST) was a randomized, placebo-controlled, double-blind, trial designed to assess the effects of metoprolol in vasovagal syncope over a 1-year treatment period. Two prespecified analyses included the relationships of age and initial tilt-test results to any benefit from metoprolol. All patients had >2 syncopal spells and a positive tilt test. Randomization was stratified according to ages <42 and ≥42 years. Patients received either metoprolol or matching placebo at highest-tolerated doses from 25 to 200 mg daily. The main outcome measure was the first recurrence of syncope. A total of 208 patients (mean age 42±18 years) with a median of 9 syncopal spells over a median of 11 years were randomized, 108 to receive metoprolol and 100 to the placebo group. There were 75 patients with ≥1 recurrence of syncope. The likelihood of recurrent syncope was not significantly different between groups. Neither the age of the patient nor the need for isoproterenol to produce a positive tilt test predicted subsequent significant benefit from metoprolol. Conclusions— Metoprolol was not effective in preventing vasovagal syncope in the study population.

Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension

PURPOSE In this double-blind study, the authors compared the safety and efficacy of the investigational oral agent midodrine, a specific alpha 1-sympathomimetic agent, with ephedrine, a nonspecific alpha- and beta-adrenergic receptor agonist. Eight patients (4 men and 4 women) with refractory orthostatic hypotension resulting from autonomic failure were studied. This study was based on the notion that neurogenic orthostatic hypotension results from attenuation of adrenergic nerve traffic and not from alpha-adrenergic receptor dysfunction. Although arteriolar vasoconstrictors seem to be appropriate therapeutic agents, their success has been limited, and the search for an ideal drug is ongoing. METHODS The authors employed a blocked, double-blind, randomized crossover design. The single-blind placebo run-in period was 2 days. The double-blind titration period with either midodrine or ephedrine was 3 to 5 days; the titration end point was to increase standing systolic blood pressure to > or = 80 mm Hg and to maintain a supine pressure below 180/100 mm Hg. The maintenance period was 3 to 5 days. A 4-day placebo washout period was interposed at the crossover point. RESULTS The ability to stand improved in patients treated with midodrine but not with ephedrine. Midodrine significantly increased both systolic (P < 0.001) and diastolic (P < 0.001) standing blood pressure over placebo (P < 0.001) and ephedrine (P < 0.05). In contrast, ephedrine-induced changes in standing pressures did not significantly differ from placebo (P > 0.05). Midodrine treatment improved the frequency of the ability to stand as compared with ephedrine, and was associated with a significantly higher incidence of standing systolic pressures > 80 mm Hg than was placebo (P < 0.001). Both midodrine and ephedrine significantly increased supine systolic and diastolic blood pressures over placebo (P < 0.001, P < 0.01, P < 0.01, P < 0.01, respectively), but were not significantly different from each other. Ephedrine significantly increased (P < 0.05) the pulse rate as compared with placebo and midodrine, whereas midodrine produced a statistically significant (P < 0.05) but clinically minimal decrease in pulse rate compared with placebo. Neither drug affected clinical laboratory variables. CONCLUSIONS Midodrine safely and effectively improved orthostatic hypotension caused by autonomic failure. Our data suggest that the ability to stand is improved better by midodrine than by ephedrine.

Echocardiographic studies of regression of left ventricular hypertrophy in hypertension.

The availability of echocardiography has allowed direct determinations of left ventricular wall thickness and calculation of left ventricular mass. As a result, the past decade has witnessed a remarkable evolution in our understanding of structural changes in the heart. Moreover, cardiac hypertrophy was found to be reversible by some forms of therapy. In general, reduction of left ventricular mass became evident after 8 to 12 weeks of antihypertensive therapy. Sympatholytics (including methyldopa and reserpine), converting enzyme inhibitors (captopril and enalapril), and calcium entry blockers led to significant regression of left ventricular hypertrophy. On the other hand, arteriolar vasodilators (hydralazine, trimazosin, and minoxidil) were not associated with regression of hypertrophy despite adequate blood pressure control. Finally, data regarding diuretics and β-blockers are controversial. These differences in results among various antihypertensive drugs reflect the multiplicity of factors modulating left ventricular hypertrophy.

Plasma Volume and Its Regulatory Factors in Congestive Heart Failure After Implantation of Long-term Left Ventricular Assist Devices

BACKGROUND Congestive heart failure is associated with blood volume expansion caused by stimulation of the renin-aldosterone system and arginine vasopressin. The use of left ventricular assist devices as bridges to heart transplantation has improved the survival of patients during this critical period. In studying heart failure physiology on support devices, we hypothesized that improvement of cardiac function by a left ventricular assist device is associated with normalization of volume load secondary to normalization of its regulatory substances. METHODS AND RESULTS We studied 15 patients (13 men, 2 women: age 51 +/- 8 years) with end-stage heart failure who were cardiac transplant candidates eligible for HeartMate implantation. We measured plasma volume and plasma levels of atrial natriuretic peptide, aldosterone, renin, and arginine vasopressin sequentially before HeartMate implantation (baseline), after HeartMate implantation (weeks 4 and 8), and after transplantation. Baseline plasma volume was 123 +/- 20% of normal; it was 122 +/- 22% at week 4 and decreased to 115 +/- 14% at week 8. Atrial natriuretic peptide was 359 +/- 380 pg/mL at baseline, 245 +/- 175 pg/mL at week 4, and 151 +/- 66 pg/mL at week 8. Plasma aldosterone fell from 68 +/- 59 ng/dL at baseline to 17 +/- 16 ng/dL at week 4 (P < .05 versus baseline) and was 32 +/- 50 ng/dL at week 8. Plasma renin activity decreased from 80 +/- 88 ng/dL at baseline to 11 +/- 12 ng/dL at week 4 and was 16 +/- 38 ng/dL at week 8 (both P < .05 versus baseline). Arginine vasopressin fell from 5.0 +/- 4.8 fmol/mL at baseline to 1.1 +/- 0.7 fmol/mL at week 4 and 1.2+/-0.8 fmol/mL at week 8 (both P < .05 versus baseline). CONCLUSIONS The reduction of plasma renin activity, plasma aldosterone, and arginine vasopressin occurred earlier than the reduction of plasma volume and atrial natriuretic peptide after HeartMate implantation, possibly because of decreased pulmonary congestion and improved renal perfusion. The reduction of atrial natriuretic peptide cannot be responsible for the lack of adequate decrease of plasma volume; its reduction can be taken as a marker of improved cardiac pump function and decreased atrial stretch.

Changes in left ventricular volume during head-up tilt in patients with vasovagal syncope: An echocardiographic study

We tested the hypothesis that patients who have vasovagal syncope during head-up tilt have a greater decrease in their left ventricular volume in response to tilt than do normal subjects. Measurements were done in the supine position and during graded tilt by using two-dimensional echocardiography. We compared seven patients with vasovagal syncope with nine normal volunteers. The rate of reduction of end-diastolic volume index during tilt was faster in the vasovagal group than in normal subjects. A more significant reduction of stroke index and ejection fraction during tilt was found in the vasovagal group than in normal subjects, possibly because of more peripheral translocation of blood volume in the venous system during tilt and an early vagal effect on ventricular contraction.

Head-up tilt and hemodynamic changes during orthostatic hypotension in patients with supine hypertension

OBJECTIVES This study assessed the mechanism(s) of the decrease in upright blood pressure in patients with supine hypertension by using the tilt test and a hemodynamic approach. BACKGROUND Orthostatic hypotension in patients with supine hypertension creates a pathophysiologic and therapeutic dilemma. METHODS We studied 28 consecutive patients with history of orthostatic intolerance amounting to recurrent syncope in 13 of them (15 men, 13 women; mean [SD] age 65 +/- 11 years). They all had supine hypertension (systolic blood pressure > 160 mm Hg) and orthostatic hypotension (found to be a decrease in systolic blood pressure > 30 mm Hg during tilt test). Cardiac output, cardiopulmonary volume and systemic resistance were assessed by radionuclide first-pass technique (technetium-99m red blood cell tagging). Total blood volume was determined by radioiodinated serum albumin, and the ratio of cardiopulmonary to total blood volume was used as an index of venous capacitance. RESULTS Twenty-one patients had accentuated venous pooling defined as a tilt-induced decrease in cardiopulmonary volume/total blood volume ratio > 15% from baseline or a supine ratio < 14% (normal 16% to 18%), or both. Seven of the 28 patients had autonomic insufficiency; 6 of the 7 also had venous pooling; 1 patient had autonomic insufficiency only. Neither clinical history nor changes during tilt differentiated the subgroups. Plasma catecholamine levels increased during head-up tilt in all subgroups, and differences in their increase were not significant between patients with venous pooling and those with autonomic insufficiency. However, radionuclide hemodynamic variables revealed that patients with venous pooling compensated for the decrease in stroke volume by increasing peripheral resistance, whereas patients with autonomic dysfunction did not. CONCLUSIONS Orthostatic hypotension in patients with supine hypertension may have multiple etiologies. Hemodynamic assessment with determination of cardiopulmonary volume and systemic vascular resistance differentiated between venous pooling and autonomic insufficiency in these patients; head-up tilt and plasma catecholamine levels did not. These findings may have important therapeutic implications.