Sympathetically mediated hypertension in autonomic failure.

BACKGROUND: Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS: In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS: Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.

Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance.

BACKGROUND: The hemodynamic and autonomic abnormalities in idiopathic orthostatic intolerance (IOI) have been studied extensively. However, the mechanisms underlying these abnormalities are not understood. If genetic predisposition were important in the pathogenesis of IOI, monozygotic twins of patients with IOI should have similar hemodynamic and autonomic abnormalities. METHODS: We studied two patients with IOI and their identical twins. Both siblings in the first twin pair had orthostatic symptoms, significant orthostatic tachycardia, increased plasma norepinephrine levels with standing, and a greater than normal decrease in systolic blood pressure with trimethaphan infusion. RESULTS: Both siblings had a normal response of plasma renin activity to upright posture. In the second twin pair, only one sibling had symptoms of orthostatic intolerance, an orthostatic tachycardia, and raised plasma catecholamines with standing. The affected sibling had inappropriately low plasma renin activity with standing and was 8-fold more sensitive to the pressor effect of phenylephrine than the unaffected sibling. CONCLUSIONS: We conclude that in some patients, IOI seems to be strongly influenced by genetic factors. In others, however, IOI may be mainly caused by nongenetic factors. These findings suggest that IOI is heterogenous, and that both genetic and environmental factors contribute individually or collectively to create the IOI phenotype.

Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure.

Supine hypertension, which is very common in patients with autonomic failure, limits the use of pressor agents and induces nighttime natriuresis. In 13 patients with severe orthostatic hypotension due to autonomic failure (7 women, 6 men, 72 +/- 3 yr) and supine hypertension, the effect of 30 mg nifedipine (n = 10) and 0.025 to 0.2 mg/h nitroglycerin patch (n = 11) on supine BP, renal sodium handling, and orthostatic tolerance was determined. Medications were given at 8 p.m.; patients stood up at 8 a.m. Nitroglycerin was removed at 6 a.m. Compared with placebo, nifedipine and nitroglycerin decreased systolic BP during the night by a maximum of 37 +/- 9 and 36 +/- 10 mmHg, respectively (P < 0.01). At 8 a.m., supine systolic BP was 23 +/- 7 mmHg lower with nifedipine than with placebo (P < 0.05), but was similar with nitroglycerin and placebo. Sodium excretion during the night was not reduced with nitroglycerin (0.13 +/- 0.02 mmol/mg creatinine [Cr] versus 0.15 +/- 0.03 mmol/mg Cr with placebo), but it was increased with nifedipine (0.35 +/- 0.06 mmol/mg Cr versus 0.13 +/- 0.02 mmol/mg Cr with placebo, P < 0.05). Nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. It is concluded that nifedipine and transdermal nitroglycerin are effective in controlling supine hypertension in patients with autonomic failure. However, nifedipine has a prolonged depressor effect and worsens orthostatic hypotension in the morning. The decrease in pressure natriuresis that would be expected with the substantial decrease in BP obtained with nitroglycerin and nifedipine may be offset by a direct effect of both drugs on renal sodium handling.

Heart conduction disturbances and cardiovascular collapse after disopyramide and low-dose metoprolol in a patient with hypertrophic obstructive cardiomyopathy.

Disopyramide as an antiarrhythmic can be prescribed to patients with atrial fibrillation and, owing to its negative inotropic effect, to patients with hypertrophic obstructive cardiomyopathy. It is known that in patients with cardiac conduction disturbances and heart failure, disopyramide can adversely affect heart rhythm and conduction and induce cardiovascular collapse. A patient with hypertrophic obstructive cardiomyopathy and paroxysms of atrial fibrillation is described who was treated with disopyramide and also, during the 5 days before admission, with metoprolol. In spite of normal cardiac conduction and function before disopyramide, this treatment was followed by hypotension, bradycardia, and cardiac conduction disturbances. Our case shows the potential for disopyramide, especially when combined with metoprolol, to induce grave adverse effects even in patients with normal cardiac conduction and ventricular function.

Influence of hemodynamic changes on neuroendocrine response in acute heart failure.

We studied 15 patients with acute deterioration of chronic left ventricular heart failure. We compared the influence of reduction of ventricular filling pressures with glyceryl trinitrate versus reduction of ventricular filling pressures with diuretics on plasma concentration of epinephrine, norepinephrine, aldosterone and renin activity. Reduction of ventricular filling pressures with glyceryl trinitrate had no influence on plasma concentrations of epinephrine, norepinephrine, aldosterone and renin activity. After reduction of ventricular filling pressures with diuretics plasma concentrations of epinephrine, norepinephrine and aldosterone decreased, while plasma renin activity did not change. We conclude that there is a difference in the influence of reduction of ventricular filling pressures with glyceryl trinitrate versus reduction of ventricular filling pressures with diuretics, on neuroendocrine response in patients with acute deterioration of left ventricular heart failure. Thus some of the neuroendocrine effects of glyceryl trinitrate are likely to be different from those of diuretics, though that they both produce a reduction in left ventricular filling pressure.

Subacute rupture of the left ventricular free wall after acute myocardial infarction. Three cases of long-term survival without emergency surgical repair.

Rupture of the left ventricular free wall after acute myocardial infarction (AMI) has been regarded as uniformly fatal unless emergency surgical repair is performed. Among 2,862 patients admitted with AMI to our ICU during the last 8 years, 107 patients developed rupture of the left ventricular free wall. Twenty-nine patients had a subacute course and three of them survived for prolonged periods without having to have emergency surgical repair. At the onset of rupture on day 1 through 7 after AMI, the three survivors developed sudden hypotension accompanied by a new pericardial effusion. They were initially managed with hemodynamic support. Two patients had elective open-heart surgery 2 to 3 months after AMI, whereas one patient did nt require surgery. All three survived 1 1/2 to 8 1/2 years after AMI. This report indicates that a small subset of patients with subacute ventricular free wall rupture has a benign course that may allow for prolonged survival without having to have emergency surgical repair.

Paradoxical elevation of pulmonary vascular resistance after nifedipine in primary pulmonary hypertension. A case study.

The case of a 55-year-old woman with primary pulmonary hypertension is described who developed 2 hours after sublingual administration of a 10 mg capsule of nifedipine a severe rise in pulmonary arterial and right atrial pressures accompanied with dyspnoea and cyanosis. The event lasted for two hours and subsided without intervention. With repeated nifedipine intake in the form of orally administered slow-release tablets no complications occurred. The authors ascribe the marked rise in pulmonary vascular resistance to rapid reduction of plasma nifedipine concentration after sublingual administration, due to a faster drug resorption compared to oral intake. The necessity of cautious introduction of vasodilating drugs in pulmonary hypertension and of gradual dosage increase is stressed.

Detection of electrocardiographically imperceptible ventricular pre-excitation by phase imaging.

The sequence of ventricular contraction was studied by radionuclide phase imaging in 25 patients with Wolff-Parkinson-White syndrome. The studies were performed when no signs of precontraction were present in the electrocardiogram; in these cases pre-excitation was either intermittent or suppressable by injection of ajmaline. In 11 of the 16 patients with free wall accessory pathways, precontraction could be detected in spite of electrocardiographically absent pre-excitation. Discrete precontraction was seen also in 2 of the 9 patients with paraseptal accessory pathways. We conclude that antegrade conduction through the accessory pathway does not need to be completely blocked if signs of pre-excitation are absent on the electrocardiogram, and that phase imaging is, at least in some patients (especially those with free wall accessory pathways), a more sensitive technique for detection of pre-excitation (precontraction) than the electrocardiogram.

Multiple accessory pathways: a combined electrophysiological and radionuclide study.

Electrophysiological study in a patient with Wolff-Parkinson-White syndrome revealed multiple accessory pathways: Kent bundle and Mahaim nodoventricular and fasciculoventricular fibers. Radionuclide phase imaging disclosed two distinct ventricular activation sequences during sinus rhythm or slow atrial pacing and during fast atrial pacing. The third activation pattern could be recorded after injection of ajmaline, which abolished signs of preexcitation in the electrocardiogram. Phase image in combination with pacing and pharmacological interventions can, at least in some cases, detect complex preexcitation syndromes noninvasively.