Integrated microscopy techniques for comprehensive pathology evaluation of an implantable left atrial pressure sensor.

The safety and efficacy of an implantable left atrial pressure (LAP) monitoring system is being evaluated in a clinical trial setting. Because the number of available specimens from the clinical trial for histopathology analysis is limited, it is beneficial to maximize the usage of each available specimen by relying on integrated microscopy techniques. The aim of this study is to demonstrate how a comprehensive pathology analysis of a single specimen may be reliably achieved using integrated microscopy techniques. Integrated microscopy techniques consisting of high-resolution gross digital photography followed by micro-computed tomography (micro-CT) scanning, low-vacuum scanning electron microscopy (LVSEM), and microground histology with special stains were applied to the same specimen. Integrated microscopy techniques were applied to eight human specimens. Micro-CT evaluation was beneficial for pinpointing the location and position of the device within the tissue, and for identifying any areas of interest or structural flaws that required additional examination. Usage of LVSEM was reliable in analyzing surface topography and cell type without destroying the integrity of the specimen. Following LVSEM, the specimen remained suitable for embedding in plastic and sectioning for light microscopy, using the positional data gathered from the micro-CT to intersect areas of interest in the slide. Finally, hematoxylin and eosin (H&E) and methylene blue staining was deployed on the slides with high-resolution results. The integration of multiple techniques on a single specimen maximized the usage of the limited number of available specimens from the clinical trial setting. Additionally, this integrated microscopic evaluation approach was found to have the added benefit of providing greater assurance of the derived conclusions because it was possible to cross-validate the results from multiple tests on the same specimen.

The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure.

OBJECTIVES: We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure. BACKGROUND: The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented. METHODS: Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks. RESULTS: There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated. CONCLUSIONS: The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.

Atrial natriuretic peptide in humans. Production and clearance by various tissues.

Although it is assumed that the human heart secretes atrial peptides, direct proof is not available. We therefore measured immunoreactive atrial natriuretic peptide levels in coronary sinus blood and simultaneously in femoral arterial and venous blood from patients before and during stepwise incremental atrial pacing of up to 200 beats per minute. Since the fate of circulating atrial peptides is unknown, we also measured immunoreactive atrial natriuretic peptide concentrations in arterial and venous blood across the liver, kidney, lower limb, and lung in patients undergoing cardiological investigation. Peptide levels in coronary sinus blood were higher than in samples from the femoral artery or vein. As the heart rate was accelerated by atrial pacing, peptide concentrations increased in coronary sinus blood and to a lesser extent in peripheral samples. Whereas the levels in venous blood draining the liver, kidney, and lower limb were approximately 50% of those in arterial blood, concentrations were similar in samples drawn simultaneously from the pulmonary artery and the aorta. These results show that the human heart produces immunoreactive atrial natriuretic peptide and that secretion increases with atrial tachycardia. The liver, kidney, and lower limb remove the peptide from arterial blood, but there is little change in its concentration during circulation of blood through the lungs.

Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of posture on clearance of atrial natriuretic peptide from plasma.

The effect of posture on plasma atrial natriuretic peptide (ANP) levels during a constant iv infusion of the 28-amino acid polypeptide was investigated in 8 normal men. alpha-Human ANP was infused at a constant rate of 0.5 micrograms/min (162 pmol/min) while the men were supine, then erect, and finally when supine again. Plasma ANP levels rose from 10.9 +/- 1.6 (+/- SEM) to 33.3 +/- 2.4 pmol/L after 60 min of constant infusion with the men in the supine position. On standing, plasma ANP increased further to 40.6 +/- 3.4 pmol/L, then fell to 32.2 +/- 2.7 pmol/L with resumption of supine posture. The calculated MCR of ANP fell from a mean of 7.7 to 5.7 L/min on standing, but rose again to 7.6 L/min upon lying down. We conclude that body posture has a significant effect on the rate of clearance of ANP from plasma.

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic nervous system during converting enzyme inhibition.

Angiotensin II can stimulate the sympathetic system and inhibit vagal (parasympathetic) outflow under experimental circumstances in animals. Blockade of angiotensin II formation by angiotensin-converting enzyme (ACE) inhibitors might therefore be expected to result in a reduction of sympathetic activity and enhanced parasympathetic activity. Whether this is so in normotensive or hypertensive humans and in human cardiac failure is unclear, since available techniques for recording activity of the sympathetic and parasympathetic systems are imperfect. Nevertheless, most evidence that comes from measurements of venous norepinephrine suggests that the ACE inhibitors have little or no effect on sympathetic activity in normotension and hypertension, although the activated sympathetic system in severe cardiac failure is probably suppressed. It appears that the ACE inhibitors have a parasympathomimetic action that may contribute to the hemodynamic effects of these drugs. Additional information using direct recordings of sympathetic traffic or measurements of norepinephrine "spillover" is needed to clarify the effects of ACE inhibitors on the sympathetic system.

Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II.

AIM: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension. METHODS: Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies. RESULTS: Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-four-hour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic GMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides. CONCLUSIONS: Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems.

Brain natriuretic peptide: natriuretic and endocrine effects in essential hypertension.

OBJECTIVE: Documentation of the renal, hormonal and haemodynamic effects and plasma clearance of human brain natriuretic peptide (BNP) given (in a dose inducing increases in plasma BNP concentrations to pathophysiological levels) to patients with essential hypertension. DESIGN: Six male patients with untreated, uncomplicated, mild-to-moderate essential hypertension underwent placebo-controlled single-blind studies in balanced random order. Human BNP (2 pmol/kg per min) and vehicle were given as constant intravenous infusions in a volume of 15 ml/h for 2 h. Continuous recording of intra-arterial blood pressure and heart rate, together with serial blood samples (for hormone assays) and 30-min urine collections, were obtained throughout the studies from 90 min before commencement of infusions to 90 min after completion of infusions. RESULTS: Achieved intra-infusion plasma BNP immunoreactivity (20-30 pmol/l) was similar to levels previously observed in heart failure. Plasma cyclic GMP was increased. Sodium excretion rose to 2.5-fold placebo values. Plasma aldosterone fell to 50% of placebo values. Blood pressure and heart rate were unchanged. The metabolic clearance rate (5.0 +/- 0.4 l/min) and plasma half-life (19.5 min) indicated that BNP has a large volume of distribution (141 +/- 16 litre). CONCLUSIONS: In essential hypertension pathophysiological plasma concentrations of human BNP have significant acute effects promoting natriuresis and suppressing plasma aldosterone. These effects are similar to those of ANP, but the plasma half-life and volume of distribution of BNP are considerably greater than those of atrial natriuretic peptide. These two hormones may play separate complementary roles in fluid volume and blood pressure homeostasis.

Therapeutic controversies with use of beta-adrenoceptor blockade in heart failure.

In response to early reports indicating a beneficial adrenoceptor effect of beta blockade, 2 small trials were conducted to investigate the hemodynamic effects of acute and chronic beta-adrenoceptor blockade in patients with congestive cardiomyopathy. Acute beta-blocker therapy with intravenous acebutolol, 25 mg, resulted in a significant decline in cardiac performance, whereas chronic therapy with acebutolol, 200 mg twice daily, resulted in no beneficial effects on exercise tolerance, as reported by the original Swedish investigators. Further, beta-adrenoceptor blockade has been associated with a number of clinical problems: beta blockers tend to interfere with the compensatory mechanisms that support circulation during early or mild heart failure and therefore have little value as routine therapy at that stage of the disorder. Although excessive beta-adrenoceptor blockade may worsen ventricular function by decreasing myocardial contractility, beta blockers appear to have a useful role in patients with moderate heart failure accompanied by tachycardia. Carefully titrated doses of beta blockers in conjunction with afterload-reducing agents may also provide a benefit in patients with rapid heart rates and grossly elevated levels of circulating catecholamines.

Cardiac involvement in systemic lupus erythematosus detected by echocardiography.

Cardiac involvement in patients with systemic lupus erythematosus (SLE) was assessed by full echocardiography and continuous wave Doppler in 50 consecutive patients and 50 age- and sex-matched control subjects in a prospective, blinded study. The left ventricular ejection fraction was decreased in patients compared to control subjects (61 +/- 9 vs 68 +/- 7%, p less than 0.001), whereas interventricular septum (12 +/- 3 vs 9 +/- 1 mm, p less than 0.001), and posterior wall dimension (9 +/- 2 vs 8 +/- 1 mm, p less than 0.001), left ventricular mass (186 +/- 54 vs 130 +/- 32 g, p less than 0.001) and mitral valve Doppler A:E ratio (0.8 +/- 0.2 vs 0.7 +/- 0.1, p less than 0.01) were increased. Pericardial effusion was detected in 27 patients and 5 control subjects, and valvular regurgitation was more frequent in the patients (aortic 2 vs 0; mitral 23 vs 5, p less than 0.001; tricuspid 34 vs 22, p less than 0.01 and pulmonary 28 vs 17, p less than 0.05). Mitral or aortic regurgitation was more common in patients with active SLE (60 vs 40%, difference not significant) but was not related to the duration of SLE (r = 0.02), duration of prednisone therapy (r = -0.13) or current dosage of prednisone (r = 0.01). This study demonstrates that pericardial effusion, valvular regurgitation and myocardial abnormalities are frequently present in patients with SLE.

Acute hemodynamic, hormonal and electrolyte effects of ramipril in severe congestive heart failure.

The response to ramipril, 10 and 20 mg on consecutive days, in 9 patients with severe (New York Heart Association functional class III or IV) chronic congestive heart failure was measured. Hemodynamic cannulae were placed more than 2 days before ramipril administration to ensure a stable baseline. Dietary sodium (40 mmol daily) and potassium (80 mmol daily) were constant before and during the study, and maintenance doses of digoxin and furosemide (80 to 1,000 mg daily) were continued unchanged. Ramipril induced pronounced, sustained decreases in angiotensin converting enzyme activity, angiotensin II and aldosterone levels, and a reciprocal increase in plasma renin activity. Plasma catecholamines, antidiuretic hormone and cortisol levels were not altered. Urinary sodium and potassium excretion diminished, plasma sodium decreased and plasma potassium increased. Plasma urea and creatinine levels increased. Ramipril treatment resulted in a decrease in systemic arterial pressure that was sustained for 24 hours, a decrease in heart rate and an increase in cardiac index, but little change in pulmonary artery pressure or right atrial pressure. Three patients were drowsy after ramipril administration, and 1 patient had a marked, temporary reduction in urine output. It was concluded that ramipril is a potent, long-acting angiotensin converting-enzyme inhibitor that is likely to be beneficial in patients with severe cardiac failure.

Flecainide acetate for conversion of acute supraventricular tachycardia to sinus rhythm.

The efficacy of intravenous flecainide acetate (maximum 2 mg/kg or 150 mg given at a rate of 15 mg/min) was assessed in patients with acute supraventricular tachycardia (SVT) (within 24 hours). Fifty patients were studied, 46 with spontaneous SVT and 4 with induced SVT at electrophysiologic assessment. Conversion to sinus rhythm was achieved within 45 minutes in 76%: in 25 patients with atrial fibrillation (76% conversion), 15 with atrioventricular (AV) nodal or AV reentrant tachycardia (100% conversion) and 10 with atrial flutter or atrial reentrant tachycardia (40% conversion). Adverse effects were noted in 21 patients (42%): paresthesia in 9, drowsiness in 8, nausea in 2, accelerated ventricular rate in 5, ventricular tachycardia in 1, sinus bradycardia in 1 and hypotension in 5. Adverse effects were associated with larger dosage and atrial flutter or atrial reentrant tachycardia. Thus, flecainide acetate is effective in converting to sinus rhythm acute atrial fibrillation and AV nodal and AV reentrant tachycardias, but not atrial flutter or atrial reentrant tachycardia.

Hemodynamic effects of nitroprusside on valvular aortic stenosis.

The effects of acute reduction of left ventricular (LV) loading in valvular aortic stenosis (AS) were examined. Thirty-five consecutive patients with AS (peak-to-peak aortic valve gradient 66 +/- 26 mm Hg, aortic valve area 0.65 +/- 0.22 cm2) were given intravenous sodium nitroprusside (1 to 3 micrograms/kg/min) to reduce systolic aortic pressures by greater than 10 mm Hg (mean aortic pressure 99 +/- 15 to 80 +/- 15 mm Hg; p less than 0.001). Overall, nitroprusside infusion resulted in little change in cardiac index (2.72 +/- 0.61 to 2.67 +/- 0.58 liters/min/m2; p = not significant). Individual patients had a range of responses. Fourteen patients (group 1) had an increase in cardiac index (2.42 +/- 0.59 to 2.74 +/- 0.67 liters/min/m2; p less than 0.001), whereas 21 (group 2) had a decrease or no change (2.93 +/- 0.56 to 2.61 +/- 0.52 liters/min/m2; p less than 0.001). Comparison of these subgroups showed that a cardiac index increase with nitroprusside was significantly predicted by a higher LV end-diastolic pressure (26 +/- 12 vs 15 +/- 6 mm Hg), lower LV ejection fraction (44 +/- 18 vs 62 +/- 12%). smaller aortic valve area (0.52 +/- 0.12 vs 0.74 +/- 0.22 cm2) and lower cardiac index (2.42 +/- 0.59 vs 2.93 +/- 0.56 liters/min/m2) (all values groups 1 and 2, respectively). It is concluded that there is a disparate response to acute vasodilatation in AS. Potentially beneficial effects are seen in a subgroup of patients, especially those with increased filling pressures and impaired LV function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of omapatrilat on systemic arterial function in patients with chronic heart failure.

The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction < or = 40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 +/- 4.5 vs 2.8 +/- 5.0 mm Hg, p < 0.05) and mean arterial (13.9 +/- 3.0 vs 0.3 +/- 3.3 mm Hg, p < 0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was improved with a dose-related decrease in augmentation index (-13.8 +/- 1.7% vs +6.1 +/- 2.1%, p < 0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the high-dose groups compared with the control group (+266 +/- 43% vs - 14 +/- 92%, p < 0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 +/- 11 vs -2 +/- 7 pmol/L, p < 0.01) in high-dose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure.

Antianginal, hemodynamic and coronary vascular effects of captopril in stable angina pectoris.

A pilot study was performed to assess the short-term effects of intravenous captopril on anginal threshold and systemic and coronary hemodynamics in patients with stable angina pectoris. Twelve patients with documented coronary artery disease, stable angina pectoris and normal left ventricular function were studied by an incremental atrial pacing stress test before and after intravenous captopril (n = 8) or placebo (n = 4). There were no significant differences in the extent of coronary disease or left ventricular function between the 2 groups and resting plasma-renin levels were normal. Captopril increased the time to angina (14 +/- 4 to 9 +/- 5 minutes, p less than 0.05), increased heart rate at development of angina (126 +/- 7 to 142 +/- 7 beats/min, p less than 0.05) and tended to increase coronary blood flow (229 +/- 154 to 296 +/- 259 ml/min, p = 0.11) and decrease coronary vascular resistance (53 +/- 10 to 47 +/- 3 dynes s cm-5/1,000, p = 0.11) at peak stress without alteration in systemic hemodynamics. No significant changes were seen after placebo administration. Therefore, intravenous captopril appears to cause a short-term increase of coronary vascular reserve, and anginal threshold in patients with chronic stable angina. This effect appears to be independent of inhibition of the systemic renin-angiotensin system or systemic hemodynamic changes.

Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the "PRACTICAL" study).

Left ventricular (LV) function and survival can be improved with captopril when initiated later than 24 hours after acute myocardial infarction. Animal studies suggest additional benefits may be obtained with earlier initiation of angiotensin-converting enzyme (ACE) inhibitors. The effects on LV function of captopril and enalapril initiated within 24 hours of myocardial infarction were studied. Two hundred twenty-five patients with acute myocardial infarction were enrolled within 24 hours of the onset of chest pain. They were randomized to receive either captopril 25 mg three times daily, enalapril 5 mg three times daily, or placebo. LV ejection fraction (EF) and volumes were measured by radionuclide ventriculography at baseline during treatment and at 3 months after a 3-day withdrawal from therapy. The ACE inhibitor group had a significant increase in EF (45 +/- 1 to 47 +/- 1%; p = 0.005) and significantly attenuated LV dilatation compared with results in the placebo group (175 +/- 6 to 189 +/- 7 ml in the placebo group vs 168 +/- 4 to 172 +/- 4 ml in the ACE inhibitor group; p = 0.051 for LV end-diastolic volume; and 99 +/- 6 to 108 +/- 7 ml in the placebo group vs 94 +/- 3 to 94 +/- 4 ml; p = 0.026 for LV end-systolic volume). The beneficial effects of ACE inhibitor therapy on LV function were observed irrespective of the degree of initial LV dysfunction and were comparable in both the captopril and enalapril groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohormonal response to head-up tilt and its role in vasovagal syncope.

In a controlled study, 26 patients with a history of recurrent syncope were found to have increased arginine vasopressin, corticotrophin, and atrial natriuretic factor levels after 5 minutes of 60 degrees head-up tilt, long before they became hypotensive. The exaggerated neurohormonal response in these patients may indicate a greater sensitivity to central hypovolemia which may predispose to vasovagal syncope, mediated by the vasodilatory effects of atrial natriuretic factor or the sensitization of mechanoreceptors by arginine vasopressin.

Autonomic control of asystolic vasovagal syncope.

A 30 year old woman with a lifelong history of severe, recurrent, vasovagal syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up tilt. During early tilt, sympathetic activity, heart rate, left ventricular contractility, and cardiac output increased. Mean blood pressure was initially maintained. Presyncope was associated with maximal contractility and bradycardia despite sustained sympathetic activity. Subsequently, asystole occurred associated with complete withdrawal of muscle nerve sympathetic activity. In asystolic vasovagal reactions, presyncope may be triggered by increased left ventricular contractility and is associated with increased levels of parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation may be caused by sudden and complete withdrawal of the increased sympathetic activity.

Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group.

OBJECTIVE: To determine the relations of plasma levels of brain natriuretic peptide (BNP), atrial natriuretic factor (ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate (cGMP; the cardiac peptide second messenger), and plasma catecholamines to left ventricular function and to prognosis in patients admitted with acute myocardial infarction. DESIGN: Plasma hormones and ventricular function (radionuclide ventriculography) were measured 1-4 days after myocardial infarction in 220 patients admitted to a single coronary care unit. Radionuclide scanning was repeated 3-5 months after infarction. Clinical events were recorded over a mean period of 14 months. RESULTS: Both early and late left ventricular ejection fraction (LVEF) were most closely related to plasma BNP (r = -0.60, n = 220, p < 0.001; and r = -0.53, n = 192, p < 0.001, respectively), followed by ANF, N-ANF, cGMP, and the plasma catecholamines. Early plasma BNP concentrations less than twofold the upper limit of normal (20 pmol/l) had 100% negative predictive value for LVEF < 40% at 3-5 months after infarction. In multivariate analysis incorporating all the neurohormonal factors, only BNP remained independently predictive of LVEF < 40% (p < 0.005). Survival analysis by median levels of candidate predictors identified BNP as the most powerful discriminator for death (p < 0.0001). No early deaths (within 4 months) occurred in patients with plasma BNP concentrations below the group median (27 pmol/l), and over follow up only three of 26 deaths occurred in this subgroup. Of all episodes of left ventricular failure, 85% occurred in patients with plasma BNP above the median (p < 0.001). In multivariate analyses, BNP alone gave additional predictive information beyond sex, age, clinical history, LVEF, and plasma noradrenaline for both subsequent onset of LVF and death. CONCLUSIONS: Plasma BNP measured within 1-4 days of acute myocardial infarction is a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and superior to ANF, N-ANF, cGMP, and plasma catecholamines.