Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function

Objective—±Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.Design—This was a single blind, randomised comparison of ±candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of ±candoxatrilat and two placebo doses on four consecutive days.Setting—A teaching hospital department of cardiology.Patients—Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37·5% and mean peak oxygen consumption was 20·4 ml/min/kg.Main outcome measures—Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after ±candoxatrilat and placebo.Results—±Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0·005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6·7 to 4·7 mm Hg (NS) and pulmonary artery wedge pressure fell from 9·2 to 6·7 mm Hg (p < 0·05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39·5 to 34·2 cm/s (p < 0·05), along with a non-significant rise in peak atrial filling velocity from 39·7–41·6 cm/s after ±candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1·04 to 0·87 (p < 0·05).Conclusions—±Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.     

Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function

Objective—±Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.     

Left ventricular diastolic function in PTCA: a Doppler echocardiographic study

The measurement of left ventricular inflow by Doppler echocardiography provides a continuous, non-invasive assessment of parameters of diastolic function. We studied changes in left ventricular diastolic function during percutaneous transluminal coronary angioplasty (PTCA) of the left anterior descending coronary artery (LAD). In ten patients, the diastolic flow velocity profile across the mitral valve was measured by Doppler echocardiography, before and 60 s after inflation and 60 s after deflation of the balloon. The peak velocity of early diastolic filling (VE) significantly decreased during angioplasty, from 68 +/- 12 to 56 +/- 10 cm/s (p less than 0.001), while the peak velocity of late diastolic filling caused by atrial contraction (VA) showed no change. This resulted in a significant decline in the diastolic velocity ratio (VE/VA) from 1.11 +/- 0.47 to 0.92 +/- 0.35 (p less than 0.01). The total area under the diastolic flow velocity profile representing the total filling volume fell from 14.3 +/- 4.1 to 10.9 +/- 3.6 cm (p less than 0.001). The early diastolic filling fraction decreased from 68 +/- 5% to 64 +/- 7%, in favor of the filling fraction due to atrial contraction, which increased from 32 +/- 5%, to 36 +/- 7% (p less than 0.01). 60 s after deflation of the balloon, the parameters of diastolic filling returned to baseline values. We conclude from our results that diastolic dysfunction caused by angioplasty of the LAD results in a decrease in early diastolic left ventricular filling, which is completely reversible after 60 s.     

Response of atrial natriuretic factor to acute and chronic increases of atrial pressures in experimental heart failure in dogs. Role of changes in heart rate, atrial dimension, and cardiac tissue concentration.

BACKGROUND. This study evaluated the role of changes in heart rate, atrial pressure, volume, and cardiac tissue atrial natriuretic factor (ANF) concentration in the modulation of plasma ANF concentration in a model of pacing-induced heart failure. METHODS AND RESULTS. The effects of acute right ventricular pacing (250 beats/min), acute volume expansion (35 ml/min), and volume expansion after 1 week of right ventricular pacing on plasma ANF concentration were compared in eight dogs (group 1). As shown during right ventricular pacing previously, volume expansion produced significant increases in cardiac filling pressures and left atrial volume. Right ventricular pacing and volume expansion produced similar increments in plasma ANF concentration: from 32 +/- 12 to 168 +/- 153 pg/ml (p less than 0.05) and from 32 +/- 9 to 137 +/- 113 pg/ml (p less than 0.05), respectively. When pacing was initiated after volume expansion, plasma ANF concentration increased further to 462 +/- 295 pg/ml (p less than 0.05) despite little change in filling pressures and left atrial volume. With repeated volume expansion after 1 week of pacing, there were no significant further increases in left atrial volume and plasma ANF concentrations (from 332 +/- 121 to 407 +/- 113 pg/ml) despite significant increases in filling pressures. Atrial and ventricular tissue samples were also obtained from 21 dogs paced to severe heart failure (group 2) and from 14 normal dogs (controls). In all groups, atrial ANF was higher than ventricular ANF concentration. At 1 week (group 1), left atrial appendage ANF concentration (6.2 +/- 2.5 versus 16.1 +/- 10.3 ng/mg) was reduced, whereas left ventricular free wall ANF concentration (0.62 +/- 0.31 versus 0.24 +/- 0.16 pg/mg) was increased compared with that of controls (both p less than 0.001). At severe heart failure (group 2), atrial ANF remained low, whereas ventricular ANF concentration was similar to that of the controls. CONCLUSIONS. These data indicate that in pacing-induced heart failure, changes in heart rate, atrial pressure, and volume all contribute to the increased plasma ANF concentration. However, by 1 week (early heart failure), ANF release is attenuated, perhaps because of the inability of the atria to be stretched further and because of reduced atrial ANF concentration. In addition, the ventricle may be an additional source of ANF.     

Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major

The consequences of transfusional iron overload on left ventricular diastolic filling have never been investigated systematically in patients with thalassemia major. In the present study, the pattern of left ventricular filling was assessed by Doppler echocardiography in 32 patients with thalassemia major (age, 17 +/- 5 years) who had not experienced symptoms of heart failure and had normal left ventricular systolic function. Data were compared with those obtained in 32 age-matched and sex-matched normal subjects. An abnormal Doppler pattern of left ventricular filling with increased flow velocity at mitral valve opening followed by an abrupt and premature decrease of flow velocity in early diastole was identified in the patients with thalassemia. Peak flow velocity in early diastole was increased in patients compared with controls (90 +/- 10 vs. 81 +/- 15 cm/sec; p less than 0.01), and rate of deceleration of flow velocity after the early diastolic peak and the ratio between the early and late (atrial) peaks of flow velocity were also increased (1,050 +/- 325 vs. 762 +/- 193 cm/sec2 and 2.7 +/- 0.7 vs. 2.2 +/- 0.5, respectively; p less than 0.001), whereas flow velocity deceleration time was reduced (97 +/- 22 vs. 119 +/- 19 msec; p less than 0.001). This Doppler pattern of diastolic filling is usually described as "restrictive" and reflects a decrease in left ventricular chamber compliance. A restrictive pattern of left ventricular filling was also identified in the subgroup of 16 study patients who had undergone optimal iron chelation therapy with deferoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Left ventricular diastolic dysfunction in patients with COPD in the presence and absence of elevated pulmonary arterial pressure

BACKGROUND: Increased right ventricular afterload leads to left ventricular diastolic dysfunction due to ventricular interdependence. Increased right ventricular afterload is frequently present in patients with COPD. The purpose of this study was to determine whether left ventricular diastolic dysfunction could be detected in COPD patients with normal or elevated pulmonary artery pressure (PAP). METHODS: Twenty-two patients with COPD and 22 matched control subjects underwent pulsed Doppler echocardiography. Left ventricular systolic dysfunction and other causes of left ventricular diastolic dysfunction (eg, coronary artery disease) were excluded in all patients and control subjects. PAP was measured invasively in 13 patients with COPD. RESULTS: The maximal atrial filling velocity was increased and the early filling velocity was decreased in patients with COPD compared to control subjects. The early flow velocity peak/late flow velocity peak (E/A) ratio was markedly decreased in patients with COPD compared to control subjects (0.79 +/- 0.035 vs 1.38 +/- 0.069, respectively; p < 0.0001), indicating the presence of left ventricular diastolic dysfunction. The atrial contribution to total left diastolic filling was increased in patients with COPD. This was also observed in COPD patients with normal PAP, as ascertained using a right heart catheter. The atrial contribution to total left diastolic filling was further increased in COPD patients with PAP. PAP correlated with the E/A ratio (r = -0.85; p < 0.0001). CONCLUSIONS: Left ventricular diastolic dysfunction is present in COPD patients with normal PAP and increases with right ventricular afterload.     

Reduced atrial contribution to left ventricular filling in patients with severe tricuspid regurgitation after tricuspid valvulectomy: a Doppler echocardiographic study

Patients undergoing valvulectomy for isolated tricuspid valve endocarditis offer the unique opportunity to study the effects of acquired right ventricular volume overload on left ventricular filling in persons free of pulmonary hypertension and preexisting left heart disease. Eleven patients who had undergone total or partial removal of the tricuspid valve were compared with 11 age-matched control subjects; Doppler echocardiographic techniques were used to quantify changes in left ventricular filling and to relate them to changes in left ventricular and left atrial geometry caused by right ventricular and right atrial distension. The late diastolic fractional transmitral flow velocity integral, a measure of the left atrial contribution to left ventricular filling, was significantly decreased in patients undergoing tricuspid valvulectomy compared with control subjects (0.22 +/- 0.11 versus 0.32 +/- 0.09; p less than 0.04). Severe tricuspid regurgitation in these patients resulted in marked right atrial distension, reversal of the normal interatrial septal curvature and compression of the left atrium such that left atrial area was significantly smaller than in control subjects (5.9 +/- 2.2 versus 8.6 +/- 1.2 cm2/m2; p less than 0.005). Acting as a receiving chamber, the left ventricle was maximally compressed by the volume-overloaded right ventricle in late diastole, coincident with the timing of atrial systole, resulting in a significant increase in the left ventricular eccentricity index compared with that in control subjects (1.35 +/- 0.14 versus 1.03 +/- 0.1; p less than 0.001). Thus, right ventricular volume overload due to severe tricuspid regurgitation results in left heart geometric alterations that decrease left atrial preload, impair left ventricular receiving chamber characteristics and reduce the atrial contribution to total left ventricular filling.     

High levels of plasma atrial natriuretic factor and impaired left ventricular diastolic function in hypertensives without left ventricular hypertrophy.

OBJECTIVE: To seek possible correlations between plasma atrial natriuretic factor (ANF) and left ventricular diastolic function (LVDF) in hypertensive patients. DESIGN: Since LVDF abnormalities can be detected in patients with normal left ventricular mass, we studied a group of hypertensive patients without left ventricular hypertrophy. METHODS: Untreated hypertensive patients (n = 23) and normotensive control subjects (n = 19) were studied. LVDF indices were obtained by M-mode and pulsed Doppler echocardiography. Blood samples for plasma ANF were taken in the recumbent position from subjects on normal-sodium intake. RESULTS: Plasma ANF levels were significantly higher in hypertensive patients than in normotensive subjects. All indices for systolic function were normal in both normotensive subjects and hypertensive patients. Left atrial diameter was significantly higher for hypertensive patients than for normotensive subjects. Considering LVDF, all indices for ventricular filling were found to be altered, on average, in hypertensive patients, the only exception being peak early velocity. In addition, significant correlations were found between plasma ANF and the pulsed Doppler parameters of left ventricular filling, peak atrial velocity and the peak early:peak atrial velocity ratio. Overall correlations between plasma ANF and left atrial diameter, and between left atrial diameter and left ventricular mass index were also observed. CONCLUSIONS: The high levels of plasma ANF observed in our hypertensive patients and their correlation with the LVDF indices (which mainly reflect the atrial contribution to ventricular filling) could be the result of an increased atrial stretch due to diastolic ventricular dysfunction. This may exist in hypertensive patients before the development of ventricular hypertrophy.     

Serial assessment of left and right ventricular filling in patients with congestive heart failure

Serial changes in the diastolic filling of both ventricles were studied using Doppler echocardiography in 19 patients with congestive heart failure from the acute to the convalescent stage. During the acute stage, left ventricular early filling velocity (E) was high (88 +/- 17 cm/s) and atrial filling velocity (A) was low (44 +/- 23 cm/s), whereas the right ventricular E was depressed (17 +/- 8 cm/s) and A was enhanced (40 +/- 9 cm/s). As the condition improved, left ventricular E decreased (43 +/- 11 cm/s, p < 0.01) and A increased (59 +/- 24 cm/s, p < 0.01) along with a decrease in the left ventricular and atrial dimensions. In contrast to the changes in left ventricular filling, right ventricular E increased (31 +/- 10 cm/s, p < 0.01) and A decreased (32 +/- 5 cm/s, p < 0.05). There are opposite directional changes in left and right ventricular filling with clinical improvement from the acute to the convalescent stage of congestive heart failure, which suggest that the changes are related to improvement of the hemodynamic conditions of both ventricles. The changes in the right ventricular filling pattern was likely to be related to changes in right ventricular afterload, ventricular interaction and external constraint rather than a change in right ventricular filling pressure.     

Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone

To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased (+ 18%; p less than .01) and T decreased (-30%; p less than .01), while heart rate increased by only 8% (87 +/- 12 to 94 +/- 15 beats/min; p less than .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p less than .01). Left ventricular peak filling rate increased (1.2 +/- 0.6 to 1.7 +/- 0.7 end-diastolic volumes/sec; p less than or equal to .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 +/- 7 to 18 +/- 9 mm Hg; p less than .01). There was a fall in left ventricular end-diastolic pressure (28.6 +/- 6 to 19 +/- 7 mm Hg; p less than or equal to .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure.

BACKGROUND. The purpose of this study was to investigate the therapeutic potential of prolonged inhibition of atrial natriuretic factor (ANF) degradation in patients with severe chronic heart failure. METHODS AND RESULTS. The effects of repeated doses of the endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05). Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma norepinephrine and epinephrine levels decreased significantly after candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma vasopressin, aldosterone levels, and plasma renin activity. Hematocrit, total protein content, and plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred. CONCLUSIONS. 1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.     

Age-related alterations of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading conditions

The purpose of this study was to determine whether age-related alterations in Doppler diastolic filling indexes occur independent of cardiovascular disease and confounding physiologic variables. Ten old (62 to 73 years) and 10 young (21 to 32 years) healthy male volunteers were rigorously screened for cardiovascular disease and underwent comprehensive Doppler echocardiography, radionuclide ventriculography and invasive measurements of right heart and left atrial pressures. There were no differences between the two groups in the physiologic variables of left ventricular mass, volumes, ejection fraction, end-systolic wall stress, left atrial size, heart rate and right atrial, pulmonary artery, pulmonary capillary wedge and systemic arterial pressures. However, there were marked differences in Doppler left ventricular filling indexes. Compared with the young group, the old group had reduced peak early diastolic flow velocity (56 +/- 13 vs. 82 +/- 12 cm/s, p = 0.0002) and increased atrial diastolic flow velocity (59 +/- 14 vs. 43 +/- 10 cm/s, p = 0.009) and had a peak atrial/early flow velocity (A/E) ratio twice that of the young group (1.09 +/- 0.29 vs. 0.54 +/- 0.15, p less than 0.0001). Similar results were obtained for the time-velocity integrals of the peaks. Subjects in the old group also had a markedly reduced peak filling rate (274 +/- 62 vs. 448 +/- 152 ml/s, p = 0.004). In univariate and multivariate regression analyses, peak early and atrial flow velocities were not related to any of the physiologic variables measured once age was accounted for, although peak filling rate, a volumetric measure flow, was related to body surface area as well as age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of alteration in preload on the pattern of left ventricular diastolic filling as assessed by Doppler echocardiography in humans

We examined the influence of alterations in preload on pulsed Doppler indexes of left ventricular diastolic function in 50 patients including 12 without cardiovascular disease, 29 with coronary artery disease, and nine with critical aortic stenosis. Micromanometer left ventricular pressure was recorded simultaneously with pulsed Doppler echocardiography of left ventricular inflow and M-mode echocardiography of left ventricular diameter. Chamber stiffness constants, kd and kv, were obtained from the diastolic pressure-diameter and pressure-volume relations, respectively. Relaxation was measured by the isovolumic relaxation time constants, TL and TD, derived from the exponential left ventricular pressure decay and maximum negative dP/dt. In 41 patients after nitroglycerin treatment, left ventricular end-diastolic pressure decreased from 18 +/- 5 to 13 +/- 4 mm Hg (p less than 0.001). The ratio of peak early to peak atrial filling velocities and time-velocity integral ratios decreased from 1.08 +/- 0.57 to 0.90 +/- 0.42 (p less than 0.001) and from 1.77 +/- 0.95 to 1.41 +/- 0.71 (p less than 0.001), respectively. The peak early filling velocity and time-velocity integral decreased from 56.1 +/- 15.7 to 49.9 +/- 14.5 cm/sec (p less than 0.001) and from 7.9 +/- 2.7 to 6.8 +/- 2.8 cm (p less than 0.001), respectively. Relaxation (TL, TD, and maximum negative dP/dt) and chamber stiffness (kd and kv) were not impaired after nitroglycerin administration. In 48 patients after ventriculography, left ventricular end-diastolic pressure increased from 18 +/- 6 to 22 +/- 8 mm Hg (p less than 0.001). The peak early and peak atrial filling velocities increased from 57.4 +/- 15.2 to 68.3 +/- 19.7 cm/sec (p less than 0.001) and from 61.0 +/- 22.7 to 69.4 +/- 23.2 cm/sec (p less than 0.01), respectively. As a result, the ratio of peak early to peak atrial filling velocity was unchanged. However, in the aortic stenosis group, the ratio of peak early to peak atrial filling velocity increased from 0.95 +/- 0.64 to 1.10 +/- 0.72 (p less than 0.02). Relaxation and chamber stiffness were unchanged. Thus, a reduction or increase in preload may induce a diastolic filling pattern that mimics or masks diastolic dysfunction, respectively. Preload conditions need to be accounted for when the status of diastolic function is extrapolated from the pulsed Doppler mitral inflow velocity profile.     

Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography

Indexes of left ventricular diastolic filling were measured by pulsed Doppler echocardiography in 21 insulin-dependent diabetic patients and 21 control subjects without clinical evidence of heart disease. No patient had chest pain or electrocardiographic changes during exercise testing. The mean age of patients was 32 years. All patients had a normal ejection fraction. Six (29%) of the 21 diabetic patients had evidence of diastolic dysfunction as assessed by the presence of at least two abnormal variables of mitral inflow velocity. The ratio of peak early to peak late (atrial) filling velocity was significantly decreased in diabetic compared with control subjects (1.24 +/- 0.21 versus 1.66 +/- 0.30, p. less than 0.001). Atrial filling velocity was significantly increased in diabetic patients (74.3 +/- 16.7 versus 60.3 +/- 12.2 cm/s, p less than 0.004), whereas early filling velocity was reduced by a nearly significant degree (88.8 +/- 12.6 versus 98.5 +/- 18.8 cm/s, p less than 0.057). The atrial contribution to stroke volume as assessed by area under the late diastolic filling envelope compared to total diastolic area was also significantly increased in diabetic compared with control subjects (35 versus 27%, p less than 0.001). Left ventricular diastolic filling abnormalities in diabetic patients did not correlate with duration of diabetes, retinopathy, nephropathy or peripheral neuropathy. These data suggest that approximately one-third of such patients have subclinical myocardial dysfunction unrelated to accelerated atherosclerosis. Doppler echocardiography may offer a reliable noninvasive means to assess diastolic function and to follow up diabetic patients serially for any deterioration in cardiac status before the appearance of clinical symptoms.     

Hemodynamic study during 48 hours of delayed-release isosorbide dinitrate (repeated oral administration) in the acute phase of myocardial infarction complicated by left ventricular insufficiency

The aim of this study was to evaluate the haemodynamic effects of slow release isosorbide dinitrate (IDN) 40 mg oral preparation over a 48 hour period in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (8 male, 6 female) were treated by repeat dose ISD (8 hourly) and the haemodynamic changes were recorded at 1 hr, 2 hrs, 6 hrs, 12 hrs, 24 hrs, and 48 hrs. After 48 hours treatment the heart rate was unchanged; mean arterial blood pressure fell from 109.5 +/- 5.6 mmHg to 93.5 +/- 6.2 mmHg (-15%) (p less than 0.01). Cardiac index rose from 2.4 +/- 0.57 1/min/m2 to 2.8 +/- 0.65 1/min/m2 (+16%) (NS); diastolic pulmonary artery pressure fell from 22.5 +/- 7.07 mmHg to 13.7 +/- 4.5 mmHg (-39%) (p less than 0.003); systolic pulmonary artery pressure fell from 40.5 +/- 12.2 mmHg to 28.6 +/- 11.6 mmHg (-30%) (NS). Systemic vascular resistance fell from 2 095.2 +/- 63 dynes/s/cm5 to 1 537 +/- 60 dynes/s/cm5 (-22.3%) (NS). Finally, total pulmonary resistance fell from 561.9 +/- 15 dynes/s/cm5 to 301.9 +/- 14.5 dynes/s/cm5 (-47%) (p less than 0.003). The most valuable effect was therefore the reduction in left ventricular filling pressures which was maximal after about 48 hours. Two groups of patients were identified according to the clinical outcome. The patients in Group I (11 cases) were improved by the fall in diastolic pulmonary artery pressure, the rise in cardiac index and the reduction of systemic valvular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005). CONCLUSIONS: Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.     

Noninvasive assessment of diastolic and systolic properties of ibopamine in patients with congestive heart failure

The acute effect of a single oral 100 mg dose of ibopamine on systolic and diastolic left ventricular function in nine patients with congestive heart failure was assessed by quantitative M-mode and pulsed Doppler echocardiography. Echocardiography was performed at baseline and 30, 60, and 120 minutes after ingestion of drug. Indices of systolic and diastolic left ventricular function were derived from digitized tracings of the septal and posterior endocardial surfaces and transmitral and aortic valve velocity profiles. Ibopamine significantly improved systolic function as reflected by a decrease in the preejection period to left ventricular ejection time ratio from 0.57 +/- 0.16 at baseline to 0.47 +/- 0.15 (p less than 0.05) 30 minutes after ingestion of drug. The maximum improvements in stroke volume and cardiac output after ibopamine were from 63 +/- 35 to 72 +/- 40 ml (p less than 0.05) and 4.6 +/- 1.7 to 5.4 +/- 2.1 L/min (p = 0.05), respectively. The contribution of atrial systole to total diastolic filling increased from 32 +/- 10% at baseline to 37 +/- 12% (p less than 0.05) after 30 minutes and persisted for at least 120 minutes. The distribution of diastolic filling was significantly altered after ingestion of ibopamine as reflected by a decrease in the ratio of the time-velocity integrals of left ventricular filling during early diastole and atrial systole (Ei/Ai) from 2.44 +/- 1.08 at baseline to 1.98 +/- 0.97 (p less than 0.05) 30 minutes after drug. The decrease in the Ei/Ai persisted for at least 120 minutes. The duration of the effect of ibopamine on diastolic filling persisted longer than its effect on augmenting systolic function. The positive effect of ibopamine on systolic function makes it a promising drug in the treatment of congestive heart failure.     

Vasodilator therapy in acute myocardial infarction. Use of sublingual isosorbide dinitrate.

The haemodynamic effect of a long-acting vasodilator isosorbide dinitrate has been studied in 10 patients after an acute myocardial infarct, all of whom had evidence of left ventricular failure. Left ventricular filling pressure measured as the mean pulmonary artery wedge pressure was raised in all patients and fell significantly from 20+/-6 to 13+/-5 mmHg (P less than 0-001) within 10 minutes of sublingual isosorbide dinitrate. This 35 per cent fall in left ventricular preload was accompanied by significant fall in mean pulmonary artery pressure from 30+/-7 to 20+/-4 mmHg (P +less than 0-001) and mean right atrial pressure from 11+/-3 to 6+/-2 mmHg but cardiac output measured by thermodilution was unchanged. Mean systemic blood pressure was also significantly reduced. This improvement in left ventricular performance resulting from a reduction in left ventricular filling pressure and systemic blood pressure indicates that there may be a place for long-acting vasodilator in the treatment of acute myocardial infarction.     

Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a primary myocardial disease in which symptoms may frequently result from impaired left ventricular relaxation, filling and compliance. In the present investigation, Doppler echocardiography was utilized to measure transmitral flow velocity and thereby assess left ventricular diastolic performance noninvasively in a group of 111 patients representative of the broad clinical spectrum of hypertrophic cardiomyopathy. In patients with hypertrophic cardiomyopathy, all Doppler indexes of diastolic relaxation and filling differed significantly (p less than 0.001) from those obtained in 86 control subjects without heart disease, namely, prolongation of isovolumic relaxation (94 +/- 24 versus 78 +/- 12 ms) and of the early diastolic peak of flow velocity (244 +/- 55 versus 220 +/- 28 ms), as well as slower deceleration (3.4 +/- 1.4 versus 4.9 +/- 1.3 m/s2) and reduced maximal flow velocity in early diastole (0.5 +/- 0.2 versus 0.6 +/- 0.1 m/s). As an apparent compensation for impaired relaxation and early diastolic filling, the atrial contribution to left ventricular filling was increased, as shown by increased late diastolic flow velocity (0.4 +/- 0.3 versus 0.3 +/- 0.1 m/s) and reduced ratio of maximal flow velocity in early diastole to that in late diastole (1.4 +/- 0.8 versus 2.1 +/- 0.9). The vast majority of patients with hypertrophic cardiomyopathy (91 [82%] of 111) showed evidence of impaired left ventricular diastolic performance, as assessed from the Doppler waveform. Abnormal Doppler diastolic indexes were identified with similar frequency in patients with (78%) or without (83%) left ventricular outflow obstruction, as well as in patients with (84%) or without (80%) cardiac symptoms. However, patients with nonobstructive hypertrophic cardiomyopathy showed more severe alterations in the Doppler indexes of diastolic function than did patients with obstruction. Thus, abnormal diastolic performance as assessed by Doppler echocardiography was apparent in the vast majority of the study patients with hypertrophic cardiomyopathy, independent of the presence or absence of cardiac symptoms or a subaortic pressure gradient. The high frequency with which diastolic abnormalities are identified in asymptomatic patients with hypertrophic cardiomyopathy suggests that impaired diastolic performance may be present at a time in the natural history of the disease when functional limitation is not yet evident.     

Doppler-echo evaluation of left ventricular diastolic filling in patient with mixed connective tissue disease

Left ventricular diastolic function was assessed in 17 patients (2 males and 15 females; mean age 44 +/- 9 years) with mixed connective tissue disease (MCTD) and 18 sex- and age-matched healthy control subjects (2 males and 16 females; mean age 44 +/- 8 years) by means of M-mode and pulsed Doppler echocardiography. None had clinical evidence of overt myocardial disease or abnormal left ventricular systolic function. Compared with the control group, patients with MCTD had a significantly longer isovolumic relaxation time (IVRT) (59 +/- 7 versus 70 +/- 12 ms; p less than 0.01), a lower peak early diastolic flow velocity (E) (0.79 +/- 0.10 versus 0.70 +/- 0.07 m/s; p less than 0.005), a higher peak late diastolic flow velocity due to atrial contraction (A) (0.47 +/- 0.08 versus 0.54 +/- 0.08 m/s; p less than 0.05) and a reduced E/A ratio (1.72 +/- 0.37 versus 1.33 +/- 0.26; p less than 0.005). Although there was no significant correlation of left ventricular diastolic filling indexes with age, heart rate, left ventricular end-diastolic and end-systolic dimensions, interventricular septal and left ventricular posterior wall thickness, and fractional shortening, the duration of illness was significantly related to IVRT (r = 0.62; p less than 0.01), peak A (r = 0.79; p less than 0.001) and velocity half-time (r = 0.54; p less than 0.05). The results suggest the presence of an abnormal left ventricular diastolic filling pattern in patients with MCTD and may represent myocardial involvement in this disease.