Effects of omapatrilat on hemodynamics and safety in patients with heart failure.

Omapatrilat, a novel vasopeptidase inhibitor, is a highly potent and selective inhibitor of neutral endopeptidase and angiotensin-converting enzyme; its therapeutic potential is being investigated for treatment of hypertension and heart failure. In the present study, the safety, tolerability, and hemodynamic effects of single oral doses of omapatrilat (1 to 50 mg) are compared with placebo in patients with heart failure. Patients with heart failure (New York Heart Association functional class II to IV) and a resting left ventricular ejection fraction < or = 40% were enrolled in a double-blind, placebo-controlled, sequential-panel study of single doses of omapatrilat of 1, 2.5, 5, 10, 25, or 50 mg, followed by hemodynamic assessment for 24 hours. At 4 to 6 hours after dosing, the 25- and 50-mg doses of omapatrilat, compared with placebo, reduced mean pulmonary capillary wedge pressure by approximately 6 mm Hg from 20 and 23 mm Hg at baseline to 14 and 16 mm Hg. The 50-mg omapatrilat dose maintained this effect compared with placebo with an approximately 2.5-mm Hg reduction in mean pulmonary capillary wedge pressure at 24 hours. Omapatrilat improved additional hemodynamic parameters, including cardiac index, systemic vascular resistance, stroke volume index, and mean arterial pressure. Additionally, by 2 hours after dosing with omapatrilat 25 and 50 mg, a trend in peak increases from baseline in plasma atrial natriuretic peptide (twofold) and cyclic guanosine monophosphate (nearly twofold) was observed. Moreover, omapatrilat was well tolerated. Thus, omapatrilat administered orally to patients with heart failure was safe and well tolerated and resulted in improved hemodynamic performance.

Visual dysfunction between migraine events.

PURPOSE: To evaluate interictal visual dysfunction in persons with migraine in terms of spatiotemporal selectivity and location within the visual pathways. METHODS: The vision of a group of 15 persons who had experienced migraine with aura was compared with that of 15 normal age-matched control subjects. A range of thresholds was measured to evaluate precortical (background modulation, contrast thresholds for static, and moving stimuli), area V1 (orientation discrimination and motion discrimination thresholds), and higher order (global dot motion thresholds) visual processes. Testing was performed centrally and at 10 degrees in the superior visual field. For each of the tests, the spatial and temporal parameters of the stimuli were selected to bias detection toward either parvocellular or magnocellular visual mechanisms. RESULTS: No defects were found for parvocellular processes. Significant (P: < 0.05) losses were apparent with the temporal background modulation method (16 Hz), orientation discrimination (0.5 cyc/deg), and global dot motion tasks. CONCLUSIONS: Both cortical and precortical visual dysfunction were identified in migraine group 7 days after the headache. This loss was selective for targets with temporal modulation of approximately 16 Hz.

Visual field losses in subjects with migraine headaches.

PURPOSE: To characterize the visual fields of subjects with migraine headaches using static and temporal modulation perimetry. METHODS: Sixteen subjects with migraines (15 with aura, 1 without) and 15 nonheadache controls were tested. Perimetry was conducted 7 days after the offset of a headache with both static and temporally modulated targets using the Medmont M-600 automated perimeter (Medmont Pty Ltd., Camberwell, Victoria, Australia). Flicker thresholds were measured using the autoflicker test, which varies flicker rate with eccentricity. A subset of four subjects with migraines (3 with aura, 1 without) had the temporal tuning characteristics of their loss evaluated using fixed temporal frequencies (4, 6, 9, 12, and 16 Hz). RESULTS: Field losses were identified with temporal modulation perimetry in 11 of 16 migraine subjects. The majority of these losses occurred in the presence of normal static thresholds (8/11). The deficits displayed temporal tuning, being greatest for higher temporal frequencies (> or =9 Hz). None of the subjects revealed deficits typical of cortical lesions. The migraine-without-aura subject displayed a selective loss to temporally modulated stimuli, which was consistent with the aura group. This defect altered over time, decreasing for 30 to 40 days but remaining, to a smaller extent, for up to 75 days after the headache event. CONCLUSIONS: Visual dysfunction that is selective for temporally modulated targets occurs in migraine subjects. The migrainous pattern of dysfunction shares some features with that identified in early stages of glaucoma and raises the possibility for a common precortical vascular involvement in these two conditions.

Symptomatic improvement and reduced hospitalization for patients attending a cardiomyopathy clinic.

BACKGROUND: The major costs associated with the management of congestive heart failure (CHF) are inpatient costs. Outcome studies are therefore important to establish whether intensive outpatient care for heart failure can reduce these costs while at the same time improving outcomes in this disabling disorder. HYPOTHESIS: Care delivered in a cardiomyopathy clinic might result in objective improvement in cardiac function and symptoms while reducing hospital admissions and emergency department visits. METHODS: The outcomes of 21 patients treated for 6 months in a cardiomyopathy clinic are evaluated. New patients referred to the clinic with ejection fraction (EF) < 0.45 were enrolled. The Minnesota Living with Heart Failure questionnaire was completed at initial and final visits. All patients underwent baseline and final echocardiogram, radionuclide left ventriculogram, and cardiopulmonary exercise testing. Patients were followed by a nurse practitioner and a cardiologist with maximization of standard treatment. Congestive heart failure-related hospitalizations and clinic and emergency room visits for both 6-month periods before and during the study were determined. RESULTS: There was significant (p < 0.05) improvement in these parameters: Heart failure score increased 23 points; New York Heart Association class decreased from 2.6 to 2.2; EF increased from 0.24 to 0.36; diastolic and systolic left ventricular dimensions decreased from 65 to 59 mm and from 57 to 50 mm, respectively. The number of clinic visits increased 5-fold, whereas there were 86% (14 to 2, p = 0.017) and 100% (8 to 0, p = 0.002) reductions in the number of CHF hospitalizations and emergency visits. There was one death during follow-up. CONCLUSION: Managing patients in a cardiomyopathy clinic may result in a better quality of life, with both symptomatic improvement and decreased hospitalizations.

Influence of exercise induced myocardial ischemia on right ventricular dP/dt: potential implications for rate responsive pacing.

BACKGROUND: Right ventricular (RV) dP/dtmax has been used as a simple parameter for rate responsive pacing to simulate the normal sinus node function. However, the effect of acute myocardial ischemia on RV dP/dtmax has not yet been evaluated. METHODS: RV high fidelity pressure was measured in 21 patients at rest and during supine bicycle exercise. Nine patients (Group 1 = controls) had no or only minimal alterations of the coronary arteries and 12 (Group 2 = CAD) had significant coronary artery disease with exercise induced left ventricular (LV) wall-motion abnormalities (n = 10) and/or angina pectoris (n = 6). RV pressure and its first derivative (RV dP/dt) were determined by an 8 French micromanometer catheter. The time constant of RV pressure decay (Tau) was calculated from the negative reciprocal of RV pressure versus negative dP/dt during isovolumic relaxation. RV volumes and ejection fraction were calculated from RV biplane angiograms (multiple slice method) at rest and during exercise. RESULTS: Heart rate (HR), RV dP/dtmax and dP/dtmin increased significantly during exercise, whereas Tau decreased. There were no significant differences between the two groups, although RV ejection fraction increased from 67% to 72% in the control group but decreased from 63% to 51% in the CAD group (P < 0.05). An exponential relationship was found between HR and dP/dtmax with a correlation coefficient of 0.82 (P < 0.01; SEE = 7% of the mean value). CONCLUSIONS: Acute exercise induced myocardial ischemia does not significantly influence RV dP/dtmax during sinus rhythm. Consequently, this index of RV contractility may be used in patients with coronary artery disease as a simple parameter for rate responsive pacing.

Calcium channel blockers for heart rate control in atrial fibrillation complicated by congestive heart failure.

OBJECTIVES: To review the safety and efficacy of verapamil and diltiazem with respect to ventricular response in atrial fibrillation (AF) in the setting of left ventricular (LV) systolic dysfunction. DATA SOURCES: Pertinent articles were identified through a MEDLINE search of the English language literature from 1984 to 1993, followed by a manual search of the bibliographies of pertinent articles. STUDY SELECTION: Studies selected were case reports, controlled trials, review articles and editorials. DATA EXTRACTION: Effects of verapamil and diltiazem on hemodynamics, ventricular response in AF, clinical parameters and mortality were reviewed. DATA SYNTHESIS: There are limited data about the effects of verapamil and diltiazem on ventricular function in patients with congestive heart failure. In vitro diltiazem has fewer negative inotropic effects than verapamil. Clinically there are some reports of hemodynamic and clinical deterioration in patients with significant LV dysfunction given verapamil although most patients improve with verapamil. There are more data concerning diltiazem in the setting of AF complicated by congestive heart failure. The drug does not appear to exacerbate heart failure, although hypotension can result. In chronic AF complicated by heart failure, there is concern that diltiazem may increase mortality. Options for therapy are digoxin, beta-blockers and atrioventricular node ablation. CONCLUSIONS: Calcium channel blockers may have a role in the acute reduction of ventricular response in patients with AF complicated by congestive heart failure; however, their safety in chronic heart rate control remains to be proven.

Intravenous diltiazem for the treatment of patients with atrial fibrillation or flutter and moderate to severe congestive heart failure.

The objective of this multicenter, randomized, double-blind, placebo-controlled study was to determine the safety and efficacy of intravenous diltiazem in the treatment of 37 patients with rapid (ventricular rate, mean +/- SD 142 +/- 17 beats/min) atrial fibrillation or flutter and moderate to severe congestive heart failure (ejection fraction, mean +/- SD 36 +/- 14%; New York Heart Association class III [23 patients], class IV [14 patients]). During the double-blind portion of the study, patients received either intravenous diltiazem, 0.25 mg/kg over 2 minutes, or placebo followed 15 minutes later by diltiazem or placebo, 0.35 mg/kg over 2 minutes, if the first dose was tolerated but ineffective. Placebo nonresponders were given open-label intravenous diltiazem in a similar fashion as in the double-blind portion of the study. In the double-blind part of the study, 21 (18 with 0.25 mg/kg, 3 with an additional 0.35 mg/kg) of the 22 patients (95%) responded to diltiazem, and 0 of 15 patients (0%) responded to placebo (p < 0.001). All 15 patients (13 with 0.25 mg/kg and 2 with an additional 0.35 mg/kg) who received placebo during the double-blind period had a therapeutic response to diltiazem during open-label therapy. Overall, 36 of 37 patients (97%) had a therapeutic response to intravenous diltiazem. Heart rate response to diltiazem after the 2-minute bolus infusions consisted of a > or = 20% decrease in heart rate from baseline in 36 patients; in addition, 17 patients also had heart rates decreased to < 100 beats/min, whereas no patient had conversion to sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitral A velocity wave transit time to the outflow tract as a measure of left ventricular diastolic stiffness. Hemodynamic correlations in patients with coronary artery disease.

BACKGROUND: Subjects in sinus rhythm have two distinct diastolic flow velocities in the left ventricular (LV) outflow tract directed toward the aortic valve. These follow E and A waves of the transmitral flow and are referred to as Er and Ar waves, respectively. The A wave transit time from the mitral valve to the LV outflow tract is shorter than that of the E wave and is shorter in those with LV hypertrophy and the aged, suggesting its possible dependence on LV late diastolic stiffness. METHODS AND RESULTS. We measured the peak-to-peak and onset-to-onset A wave transit times from the mitral valve to the LV outflow tract (AArp and AAro intervals, respectively) using Doppler echocardiography in 20 patients undergoing left heart catheterization for evaluation of coronary artery disease. These intervals were correlated with indices of LV late diastolic stiffness obtained from high-fidelity LV pressure tracings and angiographic volume assessments. The AArp and AAro intervals correlated significantly with LV Dp/DV (conventionally dP/dV) (r = -.68 and -.83, respectively), volume stiffness, V.Dp/DV (r = -.74 and -.80, respectively) and LV (V/P) (Dp/DV) (r = -.69 and -.74, respectively). The AAro interval correlated better with the square roots of LV Dp/DV and volume stiffness (r = -.86 and -.87, respectively). CONCLUSIONS: We conclude that AArp and AAro intervals are easily obtainable Doppler parameters that reflect LV late diastolic stiffness in patients with coronary artery disease and possibly in other patients groups.

Arteriovenous fistula: a complication of cardiac pacemaker lead placement and its management with percutaneous embolization.

A right internal mammary artery to right brachiocephalic vein fistula was discovered following implantation of a permanent cardiac pacemaker. The fistula was closed via percutaneous embolization.

Texture discrimination in carpal tunnel syndrome.

The ability to discriminate textured surfaces was measured in patients with carpal tunnel syndrome (CTS). Patients were initially diagnosed using clinical and electrophysiological criteria. The textured surfaces were gratings of alternating ridges and grooves. The gratings differed in their spatial period only, with the ratio of the ridge width to the groove width remaining constant (1:5). A two-alternative forced-choice paradigm was employed in which subjects, both patients and age-matched controls, rubbed their index finger (D2) or little finger (D5) back and forth across the surfaces. The grating spatial period at which subjects could discriminate a difference between the standard grating (spatial period = 2000 microns) and the comparison grating (spatial period in the range 2000-2900 microns) with a probability of 0.75 was taken as the measure of discriminative ability. Statistical comparison of the mean 75% values showed that: (i) when patients used D2 their discriminative ability was significantly impaired in comparison with the discriminative ability of controls using either D2 or D5; (ii) there was no significant difference in discriminative ability between patients and controls when patients used D5 to discriminate the textures; (iii) the 75% values for patients using D2 or D5 did not differ significantly. The degree of abnormality of each patient's sensory evoked potential did not allow us to predict their subsequent performance on the discrimination task.

Calcium antagonists and left ventricular function.

Calcium antagonists impede the entry of calcium into myocytes and inhibit myocardial contraction. Calcium antagonists differ in their relative negative inotropic potency and can provoke baroreceptor stimulation that modulates left ventricular (LV) performance. Calcium antagonists are uniformly well tolerated in patients with normal LV function. Use of these agents in patients with suspected LV function impairment has yielded results ranging from hemodynamic improvement to clinical deterioration and increased mortality. Reports of clinical deterioration when calcium antagonists were combined with beta blockers underscore the importance of reflex adrenergic support for the myocardium. Although calcium antagonists are potent vasodilators and produce short-term hemodynamic improvement, they are not useful as primary treatment in patients with congestive heart failure (CHF). They may have a place in the treatment of coexistent problems in patients with LV dysfunction. Short-term use of calcium antagonists for myocardial ischemia or rapid atrial fibrillation is probably safe in the presence of LV dysfunction and overt CHF. Calcium antagonists appear to have a role in the treatment of patients with diastolic dysfunction of diverse etiologies.

A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study.

The safety and efficacy of a 10- to 15-mg/h continuous infusion of intravenous diltiazem were evaluated in 47 patients with atrial fibrillation or flutter who first responded to 20 mg or 20 mg followed by one or more 25-mg bolus doses of open label intravenous diltiazem. Of the 47 patients, 44 responded to the bolus injection and were randomized under double-blind conditions to receive either a continuous infusion of intravenous diltiazem (10 to 15 mg/h) (23 patients) or placebo (21 patients) for up to 24 h. Seventeen (74%) of the 23 patients receiving diltiazem infusion and none of the 21 with placebo infusion maintained a therapeutic response for 24 h (p less than 0.001). Over 24 h, patients receiving diltiazem infusion lost response significantly more slowly than did those receiving placebo infusion (p less than 0.001). Nonresponders to the double-blind infusion were given an additional bolus injection of open label intravenous diltiazem and administered an open label 24-h intravenous diltiazem infusion. The overall proportion of patients maintaining a response to a 24-h infusion of intravenous diltiazem under double-blind or open label conditions combined was 83% (34 of 41). Efficacy of the 24-h infusion of intravenous diltiazem was similar in elderly versus young patients, those who did versus those who did not receive digoxin and those weighing less than 84 versus greater than or equal to 84 kg. However, intravenous diltiazem appeared to be more effective in atrial fibrillation than in atrial flutter. No significant untoward effects were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of left ventricular systolic wall thickness by digital subtraction angiography.

The accuracy of digital subtraction angiography (DSA) for determination of left ventricular (LV) systolic wall thickness and muscle mass was evaluated in 20 patients (mean age 50 +/- 11 years). Conventional LV angiograms were digitized and subtracted using a combined subtraction mode ('mask mode' and 'time interval difference' subtraction). Wall thickness and muscle mass were determined at end-diastole, after the first- and second-third of systole and at end-systole. M-mode echocardiography (Echo), which was obtained from beam selection of the two-dimensional echocardiogram and conventional angiography (LVA), served as reference techniques. Angiographic LV wall thickness and muscle mass were determined according to the technique of Rackley in both, right (RAO) and left (LAO) anterior oblique projections, whereas echocardiographic wall thickness was measured just below the mitral valve orthogonal to the posterior wall (= LAO equivalent). Percent wall thickening was calculated in all patients. LV end-diastolic wall thickness and muscle mass correlated well between DSA and LVA (LV end-diastolic wall thickness in LAO projection r = 0.72, biplane LV end-diastolic muscle mass r = 0.83), LV end-systolic wall thickness (1.44 vs 1.33 cm, P less than 0.05) and percent wall thickening (52 vs 42%, P less than 0.05) compared favourably between echocardiography and DSA but was significantly larger when echocardiographically measured than with DSA (LAO projection). DSA and echocardiography showed a good correlation in regard to LV end-diastolic and end-systolic wall thickness (correlation coefficient r = 0.89, standard error of estimate SEE = 0.15 cm or 13% of the mean value).(ABSTRACT TRUNCATED AT 250 WORDS)

Right ventricular systolic function during exercise with and without significant coronary artery disease.

To evaluate the effects of exercise and coronary artery disease on right ventricular (RV) systolic function, rest and exercise biplane RV angiograms were recorded in 20 patients undergoing diagnostic cardiac catheterization. Thirteen patients had exercise angiograms of sufficient quality to undergo analysis and were classified into 2 groups. Group 1 had no or only mild coronary artery disease; group 2 had significant coronary artery disease as manifested by new, exercise-induced, left ventricular regional wall motion abnormalities. RV systolic pressure increased in both groups during exercise: 33 to 57 mm Hg in group 1 (p = 0.0002) and 33 to 55 mm Hg in group 2 (p = 0.0004). Pulmonary resistance did not change in group 1 during exercise but increased in group 2 (3.2 to 4.8 Wood units, p = 0.04). RV ejection fraction increased slightly, but not significantly, during exercise in group 1, but decreased in group 2 (73 vs 58% with exercise [p = 0.01]). The change in RV ejection fraction from rest to exercise correlated closely with the change in pulmonary resistance from rest to exercise (r = -0.89, p less than 0.0001). RV regional wall motion analysis demonstrated a generalized decline in regional ejection fraction in group 2 during exercise, even in patients without right coronary artery disease. In conclusion, there is a decline in RV ejection fraction during exercise in patients with significant coronary artery disease. The generalized reduction in regional RV ejection fraction coupled with the close correlation with the change in pulmonary resistance suggests that increased afterload, rather than RV ischemia, is the cause.

Right ventricular diastolic function during exercise: effect of ischemia.

The effects of exercise on right ventricular diastolic function were evaluated in 14 patients who underwent supine rest and exercise right ventricular angiography. On the basis of coronary anatomy and exercise left ventricular regional wall motion analysis, these patients were classified into two groups: Group 1 (n = 7) had no or only mild coronary artery disease and Group 2 (n = 7) had significant coronary disease and exercise-induced left ventricular wall motion abnormalities suggesting ischemia. Chamber stiffness at rest was higher in Group 2 (48 x 10(-3) ml-1/m2) than in Group 1 (18 x 10(-3) ml-1/m2, p = 0.006). During exercise, right ventricular filling rate in the second half of diastole was significantly lower in Group 2 (126 versus 276 ml/m2 per s, p less than 0.03). The time constant of right ventricular pressure decay decreased significantly in both groups with exercise; however, both groups displayed a parallel upward shift of the pressure-volume curve with exercise. Because ischemia could not be demonstrated in Group 1, it is an unlikely explanation for this shift. Septal shifting was not a significant factor with exercise. Because of an increase in left ventricular end-diastolic volume with exercise and a close correlation between right and left ventricular end-diastolic pressures (r = 0.96 for Group 1 and r = 0.76 for Group 2), pericardial constraint is the most likely cause for this upward shift of the pressure-volume curve. Therefore, an increase in right ventricular end-diastolic pressure may not be a reliable indicator of ischemia during exercise because this pressure is coupled to changes in left ventricular volume and pericardial constraint.