Yoichi Goto

Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin Infusion in Patients With Congestive Heart Failure

BACKGROUNDnExperimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown.nnnMETHODS AND RESULTSnHemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo.nnnCONCLUSIONSnIntravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Assessment of coronary artery distensibility by intravascular ultrasound. Application of simultaneous measurements of luminal area and pressure.

BACKGROUNDnAtherosclerotic change in the coronary artery is associated with an impaired vessel wall distensibility. However, there are few data regarding the relation between vessel wall morphology and distensibility. Therefore, with intravascular ultrasound, we assessed coronary artery distensibility in angiographically normal coronary segments of humans.nnnMETHODS AND RESULTSnData were analyzed at 35 angiographically normal coronary sites where circumferential or noncircumferential lesions were demonstrated by ultrasound in 22 patients (mean age, 55 years). After intracoronary injection of 500 micrograms nitroglycerin (NTG), coronary luminal area was measured with intravascular ultrasound (30 MHz, 3.5F to 4.3F, 1800 rpm). Intracoronary pressure was simultaneously measured with a 2F micromanometer-tipped catheter located at the left main coronary artery. The coronary distensibility index was calculated as 10-fold the ratio of luminal area change to intracoronary pressure change during a cardiac cycle. Another pressure-independent vascular stiffness index, beta, was derived by the following formula: beta = [ln(SBP/DBP)]/(dD/diastolic mean diameter), where SBP is systolic intracoronary pressure, DBP is diastolic intracoronary pressure, and dD is the difference between systolic and diastolic diameters. At the sites where luminal areas were measured, thickness of intima-media complex, defined as the distance between the intimal leading edge and the adventitial leading edge, was determined as an index of the severity of atherosclerosis. In seven segments, distensibility index was determined before and after NTG injection to examine the effect of NTG on coronary distensibility. In all examined sites, including circumferential and noncircumferential lesions, the luminal area was 12.6 +/- 5.0 mm2 during systole and 11.6 +/- 4.6 mm2 during diastole, and the calculated coronary distensibility index ranged from 0 to 0.83 mm2/mm Hg. The thickness of the intima-media complex ranged from 0.12 to 1.30 mm, suggesting the presence of various grades of atherosclerosis even in the absence of angiographic lesions. There was a poor inverse correlation between thickness of the intima-media complex and distensibility index (r = .19, y = -0.17x + 0.41, P = .29). However, when noncircumferential lesions were excluded for evaluation, there was a significant inverse correlation between them (r = .58, y = -0.50x + 0.72, P < .01). Under these conditions, the thickness of the intima-media complex also correlated with the value of beta (X10(-1), which ranged from 0.28 to 3.99 (r = .70). After NTG injection, coronary distensibility increased by an average of 71% in the segments with a thin intima-media complex, whereas it did not substantially change in those with a relatively thick intima-media complex.nnnCONCLUSIONSnThese results suggest that coronary distensibility is impaired in the coronary sites accompanying occult atherosclerosis, none of which can be detected by the conventional angiography. NTG can augment coronary distensibility in the segments without a markedly thickened intima-media complex. We suggest that thickness of the intima-media complex can contribute to determining the coronary distensibility in clinical settings.

Increased plasma adrenomedullin levels in patients with acute myocardial infarction in proportion to the clinical severity

Objectives To investigate the pathophysiological role of adrenomedullin in myocardial infarction. Patients and design Plasma concentrations of adrenomedullin, atrial natriuretic factor, and brain natriuretic peptide were measured by radioimmunoassay in 31 patients with acute myocardial infarction over four weeks, and in 44 normal subjects. Results In patients with acute myocardial infarction, plasma adrenomedullin reached a peak of (mean (SD) 14.0u2009(9.0)u2009pmol/l at 24 hours after the onset of symptoms and remained increased at all sampling points except the four week point compared with the value in normal subjects (5.0u2009(2.0)u2009pmol/l). Adrenomedullin concentrations on admission were higher in patients from Killip class II, III, and IV than class I, and correlated positively with peak plasma creatine kinase and left ventricular end diastolic volume index, and negatively with left ventricular ejection fraction. The values from 12 to 48 hours were negatively correlated with systemic vascular resistance index. During the time course studied, adrenomedullin concentrations were positively correlated with atrial natriuretic factor (ru2009=u20090.40, pu2009<u20090.001) and brain natriuretic peptide (ru2009=u20090.53, pu2009<u20090.001). Conclusions Plasma adrenomedullin concentrations increased in the acute phase of myocardial infarction in proportion with clinical severity, suggesting that adrenomedullin may play an important role in the pathophysiology of myocardial infarction.

Plasma adrenomedullin as an indicator of prognosis after acute myocardial infarction

OBJECTIVE To elucidate whether prognosis after acute myocardial infarction can be predicted by measuring plasma adrenomedullin, a novel vasorelaxant peptide. PATIENTS AND DESIGN Plasma adrenomedullin concentrations on day 2 after myocardial infarction were measured in 113 patients with myocardial infarction with other clinical and haemodynamic variables related to mortality. RESULTS During a mean follow up period of 25 months, 16 patients died of cardiac causes. Plasma adrenomedullin concentrations on day 2 increased significantly in patients with myocardial infarction compared with controls (mean (SD), 12.3 (8.8) v 4.9 (1.0) pmol/l, pu2009<u20090.001). Plasma adrenomedullin correlated negatively with left ventricular ejection fraction on admission (ru2009=u2009−0.47, pu2009<u20090.001), although it did not significantly correlate with any other haemodynamic variable. By univariate Cox proportional hazards analysis, plasma adrenomedullin, age, coronary reperfusion, maximum creatine kinase concentrations, pulmonary congestion, pulmonary capillary wedge pressure, cardiac index, and left ventricular ejection fraction were all significantly related to mortality. Among the non-invasive variables, only plasma adrenomedullin was an independent predictor of mortality after myocardial infarction (pu2009<u20090.05). The Kaplan–Meier survival curves based on the median plasma adrenomedullin concentration (10.3 pmol/l) showed that patients with high plasma adrenomedullin had a higher mortality than those with low plasma adrenomedullin (pu2009<u20090.01). CONCLUSIONS Plasma adrenomedullin on day 2 after myocardial infarction is strongly associated with long term mortality, and thus may complement standard prognostic indicators.

Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension

OBJECTIVE To assess acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN Cardiopulmonary exercise testing was performed in 20 patients with CTEPH before thromboendarterectomy (baseline), one month after (early phase), and four months after (late phase). Peak oxygen uptake (peakV˙o 2) and the ventilatory response to carbon dioxide production (V˙e-V˙co 2 slope) were measured for assessment of exercise capacity and ventilatory efficiency. Right heart catheterisation was performed in all patients before and one month after surgery. RESULTS Baseline peakV˙o 2 decreased andV˙e-V˙co 2 slope increased along with the increase in pulmonary vascular resistance in patients with CTEPH. After thromboendarterectomy, theV˙e-V˙co 2 slope decreased greatly from baseline to the early phase (mean (SD), 50 (9) to 37 (7), pu2009<u20090.05) and reached a steady level thereafter. In contrast, a continued increase in peak V˙o 2 was noted from the early to the late phase (16.9 (4.1) to 21.1 (5.0)u2009ml/kg/min, pu2009<u20090.05). The decrease in theV˙e-V˙co 2 slope from baseline to the early phase, but not the increase in peakV˙o 2, correlated strongly with the decrease in pulmonary vascular resistance after surgery (ru2009=u20090.75, pu2009<u20090.01). CONCLUSIONS Thromboendarterectomy may cause an immediate improvement in ventilatory efficiency, possibly through its beneficial haemodynamic effects. In contrast, exercise capacity may continue to improve towards the late phase, reflecting peripheral adaptation to exercise.

Intravenous adrenomedullin in myocardial function and energy metabolism in patients after myocardial infarction

This study investigated the effects of adrenomedullin on left ventricular myocardial contraction and relaxation, coronary blood flow, and myocardial oxygen consumption in comparison with those of atrial natriuretic peptide (ANP). Fourteen patients who had had myocardial infarctions were randomly assigned to receive IV infusion of adrenomedullin (0.05 &mgr;g/kg/min) or ANP (0.05 &mgr;g/kg/min). Both adrenomedullin and ANP significantly decreased left ventricular systolic pressure (−17 mm Hg, −13 mm Hg, respectively, both p < 0.05). The increase in cardiac index by adrenomedullin (+31%) was significantly greater than that by ANP (+16%). Adrenomedullin significantly increased an index of myocardial contractility, Emax (2.5 ± 0.3 mm Hg–3.7 ± 0.3 mm Hg/ml, p < 0.05) and shortened an index of myocardial relaxation, Tau (52 ± 5 ms–48 ± 4 ms, p < 0.05). In contrast, ANP did not significantly alter either parameter. In addition, adrenomedullin, but not ANP, significantly increased coronary sinus blood flow (73 ± 10 ml/min–86 ± 10 ml/min, p < 0.05). Adrenomedullin did not increase myocardial oxygen consumption. Unlike ANP, IV administration of adrenomedullin enhanced left ventricular myocardial contraction and improved left ventricular relaxation without increasing myocardial oxygen consumption in patients who had had a myocardial infarction.

Impact of Left Ventricular End-Diastolic Wall Stress on Plasma B-Type Natriuretic Peptide in Heart Failure with Chronic Kidney Disease and End-Stage Renal Disease

BACKGROUNDnPlasma B-type natriuretic peptide (BNP) is a diagnostic and prognostic marker in heart failure (HF). Although renal function is reported as an important clinical determinant, precise evaluations of the relationships of renal function with hemodynamic factors in determining BNP have not been performed. Therefore, we evaluated the association of plasma BNP concentrations with LV end-diastolic wall stress (EDWS) in a broad range of HF patients including those with chronic kidney disease (CKD) and end-stage renal disease (ESRD).nnnMETHODSnIn 156 consecutive HF patients including those with CKD and ESRD, we measured plasma BNP and performed echocardiography and cardiac catheterization. LV EDWS was calculated as a crucial hemodynamic determinant of BNP.nnnRESULTSnPlasma BNP concentrations increased progressively with decreasing renal function across the groups (P < 0.01) and were correlated with LV EDWS (r = 0.47) in the HF patients overall. This relationship was also present when patients were subdivided into systolic and diastolic HF (P < 0.01). In multivariable analysis, higher EDWS was associated with increased BNP concentration independently of renal dysfunction (P < 0.01). Anemia, systolic HF, and decreased BMI also contributed to increased BNP concentrations.nnnCONCLUSIONSnThese results suggest that LV EDWS is a strong determinant of BNP even in patients with CKD and ESRD. Anemia, obesity, and HF type (systolic or diastolic) should also be considered in interpreting plasma BNP concentrations in HF patients. These findings may contribute to the clinical management of HF patients, especially those complicated with CKD and ESRD.

Is preinfarction angina related to the presence or absence of coronary plaque rupture

OBJECTIVE To analyse the prodrome of acute myocardial infarction in relation to the plaque morphology underlying the infarct. DESIGN A retrospective investigation of the relation between rupture and erosion of coronary atheromatous plaques and the clinical characteristics of acute myocardial infarction. The coronary arteries of 100 patients who died from acute myocardial infarction were cut transversely at 3 mm intervals. Segments with a stenosis were examined microscopically at 5 μm intervals. The clinical features of the infarction were obtained from the medical records. RESULTS A deep intimal rupture was encountered in 81 plaques, whereas 19 had superficial erosions only. There were no differences in the location of infarction, the incidence of hypertension, diabetes mellitus, or hyperlipidaemia, diameter stenosis of the infarcted related artery, Killip class, Forresters haemodynamic subset, or peak creatine kinase between plaque rupture and plaque erosion groups. The presence of plaque rupture was associated with significantly greater incidences of leucocytosis, current smoking, and sudden or unstable onset of acute coronary syndrome. In patients with unstable preinfarction angina, new onset rest angina rather than worsening angina tended to develop more often in the plaque rupture group than in the plaque erosion group (pu2009=u20090.08). CONCLUSIONS Plaque rupture causes the sudden onset of acute myocardial infarction or unstable preinfarction angina, which may be aggravated by smoking and inflammation.

Attenuation of hypercapnic carbon dioxide chemosensitivity after postinfarction exercise training: possible contribution to the improvement in exercise hyperventilation.

Objective: To elucidate the responsible mechanisms of increased slope of minute ventilation relative to carbon dioxide production (V̇E/V̇co2) during exercise after acute myocardial infarction without overt signs of heart failure, patients who had an acute myocardial infarction were examined after participating in a three month supervised exercise training programme. Design: Exercise testing, hypercapnic CO2 chemosensitivity measurement (rebreathing method), and pulmonary function test were repeated at entry and after three months in 50 acute myocardial infarction patients with neither symptoms nor signs of heart failure who completed the training programme. Ten patients who performed initial inhospital training served as controls. Results: Age, peak oxygen uptake, left ventricular ejection fraction, CO2 chemosensitivity, respiratory parameters (percentage of predicted normal vital capacity (%VC), forced expiratory volume in one second, and carbon monoxide transfer factor (%Tlco)) were all significantly correlated with V̇E/V̇co2 slope. Multivariate regression analysis showed that age (β = 0.29, p = 0.01), %Tlco (β = −0.27, p = 0.01), and CO2 chemosensitivity (β = 0.49, p < 0.001) were independent determinants of V̇E/V̇co2 slope. After three months, there was no significant change in these parameters in the control group. Peak oxygen uptake, %Tlco, and %VC and attenuation in CO2 chemosensitivity increased significantly in the training group. The V̇E/V̇co2 slope decreased marginally (p = 0.11). The changes in V̇E/V̇co2 slope were correlated only with those in CO2 chemosensitivity (r = 0.50, p < 0.001). Conclusion: After acute myocardial infarction, exercise hyperventilation is seen in association with aging, enhanced hypercapnic CO2 chemosensitivity, and reduced Tlco, even in the absence of overt heart failure. The correlation of V̇E/V̇co2 attenuation after training with the reduction in CO2 chemosensitivity suggests that exercise training may reduce increased V̇E/V̇co2 slope, at least partially by reducing CO2 chemosensitivity.

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

AbstractTo investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G(−273)C (P=0.0074), C(−297)T (P=0.0195), and IMS-JST071749 (P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G(−273)C genotype was influential in another set of subjects (P=0.0310, n=743). However, the distribution of the ABCA1 G(−273)C genotype in subjects with MI (n=598) was not different from that in the control population (n=801). These results indicate that ABCA1 G(−273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.