Isoproterenol sensitivity of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and heart failure

Rats treated with the alkaloid monocrotaline developed right ventricular hypertrophy with a left:right ventricle weight ratio of 1.35 +/- 0.10 (mean +/- s.e.m., n = 25) compared with 3.83 +/- 0.40 (n = 14) in diet-matched controls (P less than 0.001). Urine volume and sodium content were reduced and body water increased consistent with heart failure. In 10 out of 26 treated rats pleural, pericardial or peritoneal effusions were present. Urine norepinephrine content was significantly raised (P less than 0.02) but epinephrine was unchanged. Plasma norepinephrine levels were raised though not significantly. Myocytes isolated from the right ventricle had a reduced myosin Ca2+-activated ATPase (P less than 0.05) activity and a shift towards slower V2 and V3 myosin isoforms. There was no decrease in maximum contraction amplitude with calcium or isoproterenol in either left or right ventricular cells of treated rats. Right ventricular cells from treated rats showed a reduced rate of contraction in maximum isoproterenol (P less than 0.05) and a significant rightward shift in PD2 (P less than 0.05) representing a two-fold increase in EC50 for isoproterenol compared with right ventricular cells from control animals. There was no shift in EC50 for isoproterenol in left ventricle cells. In parallel experiments, myocytes isolated from both ventricles of rats treated with isoproterenol for one week showed a rightward shift of more than 50-fold in the isoproterenol concentration-response curve and a depressed response to maximum isoproterenol. In the rat monocrotaline model of right-sided cardiac hypertrophy and failure, changes in sensitivity to beta-adrenoceptor agonists are slight, and present only in the right ventricle. The lack of change in the left ventricle seems to suggest that this functional desensitisation is not a consequence of raised circulating catecholamines.     

An inhibitor of nitric oxide synthase does not increase contraction or beta-adrenoceptor sensitivity of ventricular myocytes from failing human heart

OBJECTIVE: Nitric oxide (NO) has been implicated in the depression of cardiac function in human heart failure. Some reports have identified iNOS (inducible nitric oxide synthase) within the myocyte component of the failing human heart, and NO is known to decrease the contraction amplitude of isolated ventricular myocytes. We have treated myocytes from failing human ventricle with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA), in an attempt to restore contractile function. METHODS AND RESULTS: Myocytes were isolated from failing and non-failing human ventricles and their contraction amplitude was measured during superfusion (32 degrees C, 1-2 mmol/l Ca2+) and electrical stimulation (0.1-2 Hz). The contraction amplitude of myocytes from failing hearts was depressed in a frequency-dependent manner. At 1 Hz, the contraction amplitude of cells from non-failing heart was 4.70 +/- 0.53% cell shortening (mean +/- SEM, n = 13 subjects), compared with 2.18 +/- 0.27% (P < 0.01, 11 patients) from patients with ischaemic heart disease (IHD) or 2.56 +/- 0.74% (P < 0.02, six patients) with dilated cardiomyopathy (DCM). Superfusion with 0.1 mmol/l L-NMMA did not increase contraction amplitude in myocytes from failing heart at either 0.2 Hz (n = 11) or 1 Hz (n = 7). Responses to beta-adrenoceptor stimulation were reduced in myocytes from failing human heart, with contraction amplitude in maximum isoprenaline 0.47 +/- 0.11 of that in high Ca2+ in the same cell (n = 6), compared to 0.99 +/- 0.07 in non-failing heart (n = 14, P < 0.01). The presence of 0.1 mmol/l L-NMMA did not increase the isoprenaline/Ca2+ ratio in myocytes from failing heart (0.40 +/- 0.09, P = NS). CONCLUSION: These results do not suggest a functional role for tonic NO production in the frequency-dependent depression of contraction or beta-adrenoceptor desensitisation in myocytes from failing human ventricle.     

Beta-adrenoceptors and adenylate cyclase activity in hypertrophied and failing rabbit left ventricle.

Beta-adrenoceptor density and affinity, studied by H3-CGP 12177 binding, and adenylate cyclase activity were measured in 12 left ventricles of rabbits with heart failure and compared to 13 left ventricles of control (C) rabbits. Heart failure (HF) was induced by a double volume (aortic insufficiency) plus pressure (aortic stenosis 14 days later) overload. Left ventricular mass was increased in HF by 67% above C. Saturation curves with CGP 12177 showed a 36% decrease in beta-adrenoceptor density (C = 61.5 +/- 5.4 fmol/mg prot., P less than 0.05) but competition curves with isoproterenol were not different in HF and C. Basal and Gpp(NH)p stimulated adenylate cyclase activity were decreased by 36% and 22% respectively in rabbits with heart failure as compared with control animals and cAMP production was significantly smaller in failing left ventricles than in control left ventricles both after NaF stimulation (C: 161.3 +/- 24.9 pmols/mg/min; HF: 98.8 +/- 7.0 pmols/mg/min; P less than 0.05) and even more after forskolin stimulation (C: 159.1 +/- 23.9 and HF: 60.8 +/- 7.3 pmols/mg/min; P less than 0.01). Although isoproterenol stimulated ACA was smaller in HF than in C, EC50 was similar in both groups (1.6 x 10(-7) M). We conclude that in the early stage of heart failure in the rabbit, although adrenoceptor density is decreased, there are no changes of affinity of beta-adrenoceptors for isoproterenol and the major alteration of cAMP production appears to lie down-stream the receptor level with a markedly impaired stimulation of adenylate cyclase activity by forskolin.     

Assessment of left atrial function in patients with hypertensive heart disease

Left atrial function in patients with hypertensive heart disease was compared with that in control subjects. In patients with hypertensive heart disease, the time constant of left ventricular relaxation was significantly greater than that in controls (54 +/- 18 vs 31 +/- 16 msec; p less than 0.01). The ratio of left ventricular filling volume before atrial contraction (left atrial reservoir volume/left atrial emptying volume before atrial contraction, and conduit volume/flow volume from the pulmonary vein into the left ventricle) to left ventricular stroke volume was significantly smaller than that in controls (65 +/- 13 vs 76 +/- 7%; p less than 0.05). In patients with hypertensive heart disease, the ratio of reservoir volume to stroke volume was not significantly different from that in controls, while the ratio of conduit volume to stroke volume was significantly smaller than that in controls (43 +/- 13 vs 57 +/- 9%; p less than 0.05). The latter ratio was inversely correlated with the time constant of left ventricular relaxation (r = -0.05, p less than 0.05). In patients with hypertensive heart disease, the ratio of left ventricular filling volume during atrial contraction to stroke volume was significantly larger than that in controls (35 +/- 13 vs 24 +/- 7%; p less than 0.05). The ratio of left ventricular filling volume during atrial contraction to stroke volume had a significant inverse correlation with the ratio of conduit volume to stroke volume (r = -0.84, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of left ventricular function and severity of coronary artery disease on exercise-induced pulmonary thallium-201 uptake

Pulmonary uptake of thallium-201 during exercise was measured in 58 patients with coronary artery disease and compared with the results from 21 patients with normal coronary arteries and 5 normal volunteers. A quantitative method was used to assess the pulmonary thallium uptake relative to cardiac activity (heart/lung ratio). This ratio was calculated for exercise and for redistribution imaging. The mean exercise heart/lung ratio for the group with coronary artery disease was 1.43 +/- 0.36 SD (n = 58); and for the "normal" group was 2.76 +/- 0.41 (n = 26) (P less than 0.001). Increased pulmonary uptake after exercise in the coronary disease group was reversible (mean redistribution heart/lung = 1.96 +/- 0.37 SD; P less than 0.001). The exercise heart/lung ratio differed significantly between groups with single-, two- and three-vessel disease; patients with and without prior infarction; and patients with exercise-induced ST segment depression and elevation. Linear regression analysis between ejection fraction calculated from equilibrium radionuclide angiography at rest and the exercise heart/lung ratio in the coronary artery disease group gave the equation: exercise heart/lung = 0.857 +/- 0.014 ejection fraction for n = 58; r = 0.695; P less than 0.001. It would appear that the exercise heart/lung ratio is a simple and valuable non-invasive index which should be used as part of routine thallium scan interpretation to provide additional information on left ventricular function after exercise and as an indicator of the severity of obstructive coronary artery disease.     

Dependence of peak dP/dt and mean ejection rate on load and effect of inotropic agents on the relationship between peak dP/dt and left ventricular developed pressure--assessed in the isolated working rat heart and cardiac muscles.

To examine the effects of preload (mean left atrial pressure) and afterload on two so-called "contractility indices" and the effects of inotropic agents (isoproterenol and calcium) on the relationship between left ventricular developed pressure and peak dP/dt when afterload was increased, we used a modified working rat heart preparation (perfused with Krebs-Henseleit solution bubbled with a 95% O2 -5% CO2 gas mixture at 37 degrees C). The atrium was stimulated at a rate of 240/min. An increase in preload from 5 to 15 mmHg caused an increase in peak dP/dt from 1,711 +/- 293 mmHg/s to 1,971 +/- 387 mmHg/s (p less than 0.001, n = 15), and an increase in the mean systolic ejection rate from 1.28 +/- 0.31 ml/s to 2.74 +/- 0.80 ml/s (p less than 0.001). An increase in afterload (left ventricular developed pressure) from 66 to 97 mmHg produced by elevating aortic pressure caused an increase in peak dP/dt from 1,829 +/- 222 mmHg/s to 2,449 +/- 254 mmHg/s (p less than 0.001, n = 7), and a decrease in the mean systolic ejection rate from 2.12 +/- 0.36 ml/s to 1.95 +/- 0.33 ml/s (p less than 0.001). Studies using isolated rat papillary muscles ruled out the contribution of an increase in myocardial perfusion to the increase in peak dP/dt, since the maximum rate of rise in tension (dT/dt) increased with an increase in afterload during afterloaded isotonic contraction. Peak dP/dt showed a linear relationship to left ventricular developed pressure when the latter was increased by elevating the aortic reservoir and then clamping the aortic outflow tube (n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical factors influencing survival and adequacy of revascularization after coronary bypass operation

We retrospectively analyzed the clinical data on 3479 consecutive patients having coronary bypass surgery. Patients with triple vessel and left main coronary disease had a greater frequency of inotropic requirements than did patients with single or double vessel disease (7.9% and 8.6% versus 3.8% and 4.2%; P less than 0.001). Presence of previous myocardial infarction, heart failure, or left ventricular contraction abnormalities significantly decreased the ability to achieve complete revascularization with bypass grafting. Hospital mortality since 1976 has been 0.8% (25/3040). Hospital mortality was significantly increased by history of myocardial infarction (P less than 0.001), hypertension (P less than 0.05), heart failure (P less than 0.01), extent of anatomic disease (P less than 0.005), presence of preoperative ST-T wave changes (P less than 0.001), and severe abnormalities of left ventricular function (P less than 0.001). Anginal pattern, history of hypertension, previous myocardial infarction, preoperative heart failure but not perioperative myocardial infarction significantly affected long-term survival. Patients with normal left ventricular function had excellent 42-month survival regardless of vessel disease. Inability to achieve complete revascularization did not adversely affect hospital mortality, but did significantly reduce late survival. Although bypass grafting improves survival in patients with multivessel disease and left ventricular dysfunction, the benefits appear to be significantly reduced when left ventricular damage has occurred.     

Myocardial changes in pressure overload-induced left ventricular hypertrophy. A study on tissue composition, polyploidization and multinucleation.

Morphological changes in human myocardium associated with pressure overload-induced left ventricular hypertrophy were studied in 22 normal and 21 hypertrophic hearts obtained at autopsy. Samples were obtained from the left lateral ventricular wall, half way between the apex and the base. Myocyte dimensions, polyploidization, multinucleation and relative volume fractions were studied. Regression analysis in relation to indexed heart weight yielded statistically significant correlation coefficients for myocyte volume: r = 0.69 (P less than 0.001), for degree of polyploidization: r = 0.77 (P less than 0.001), for number of nuclei per myocyte: r = 0.47 (P less than 0.01) and for volume fraction of myocytes: r = 0.32 (P less than 0.05). Approximate numbers of myocytes and connective tissue cells per left ventricle were calculated. Correlation coefficients related to indexed heart weight were r = 0.34 (P less than 0.05) for the number of myocytes and r = 0.76 (P less than 0.001) for the number of connective tissue cells. Based on regression analysis in relation to indexed heart weight, we calculated that a doubling of indexed heart weight was associated with an increase in mean myocyte volume by 65%, degree of polyploidization by 24%, multinucleation by 7%, number of myocytes by 20% and number of connective tissue cells by 141%. The volume percentage of myocytes decreased by 6% in favour of the connective tissue fraction. These changes in myocardial composition indicate that the term 'hypertrophy' inadequately describes the actual myocardial changes in response to pressure overload.     

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.     

Hemodynamic effects of intravenous metoprolol.

The hemodynamic effects of the cardioselective beta adrenergic blocking agent metoprolol, at a dose of 0.1 mg/kg body weight administered intravenously, were studied in 10 patients undergoing routine cardiac catheterization. The beta adrenergic blocking effect of the drug was confirmed by a highly significant reduction (53 percent, P less than 0.001) in the mean heart rate response to a challenge with isoproterenol, and by a mean heart rate rssponse to a challenge with isoproterenol, and by a highly significant reduction (73 percent, P less than 0.001) in the isoproterenol-induced increase in the first derivative of left ventricular pressure (dP/dt). An intrinsic negative inotropic effect was shown by a 43 percent reduction (P less than 0.05) in the response of mean left ventricular dP/dt when the heart rate was fixed by atrial pacing alone. With the combination of atrial pacing and isoproterenol, metoprolol produced a 48 percent reduction (P less than 0.01) in the response of mean left ventricular dP/dt, resulting from both the intrinsic depressor effect and the beta adrenergic blocking effect on the rate-independent beta agonist activity of isoproterenol. There was no significant change in right atrial, femoral arterial or left ventricular end-diastolic pressure; analysis of left ventricular angiograms performed during atrial pacing before and after metoprolol revealed no significant effect on angiographic ejection fraction, pressure-volume loops or diastolic compliance. In two patients improvement in segmental wall motion was noted, and no deterioration was seen in any patient. Metoprolol is an effective cardioselective beta adrenergic blocking agent that, under these conditions, reduces catecholamine-induced increases in heart rate and left ventricular dP/dt without significant alteration in ejection fraction, preload or afterload.     

Diastolic blood pressure as a determinant of Doppler left ventricular filling indexes in normotensive adolescents

Alterations in left ventricular filling can occur with aging and in patients with hypertension, ischemic heart disease, congestive and hypertrophic cardiomyopathy and congenital heart disease. This study examines the effects of blood pressure on left ventricular diastolic filling indexes measured by Doppler ultrasound technique in 47 young normotensive adolescents (mean age 13 years). Left ventricular filling was assessed by Doppler peak early and late diastolic transmitral flow velocities, early and late diastolic flow velocity integrals and early diastolic deceleration. Systolic blood pressure did not correlate with any of the Doppler filling indexes, although it was related to echocardiographic left ventricular mass (r = 0.44, p less than 0.005). Diastolic blood pressure did not correlate with left ventricular mass; however, it was inversely related to peak early diastolic flow velocity (r = -0.44, p less than 0.005), early diastolic flow velocity integral (r = -0.40, p less than 0.01) and early diastolic deceleration (r = -0.32, p less than 0.05). The ratio of late to early peak filling (A/E) was directly related to diastolic blood pressure (r = 0.48, p less than 0.001). Examination of electrocardiograms showed that there was a stronger correlation between A/E ratio and diastolic blood pressure (r = 0.63) in 22 subjects with bimodal P waves in lead V1 than in subjects with unimodal P waves (r = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)     

Minimum left ventricular pressure during beta-adrenergic stimulation in human subjects. Evidence for elastic recoil and diastolic "suction" in the normal heart

The influence of elastic recoil and restoring forces on diastolic left ventricular pressure decay and minimum left ventricular pressures has been demonstrated in animal models but has not been studied in the human heart. To investigate this issue in the normal human left ventricle, we studied eight patients with chest pain and normal coronary arteries with simultaneous measurement of left ventricular volume (by radionuclide angiography) and pressure (by micromanometer catheter) and coronary sinus blood flow. Electrocardiographic-gated data were obtained in the basal state, during rapid atrial pacing, and during isoproterenol infusion to a similar heart rate. Compared with pacing, isoproterenol increased ejection fraction and reduced end-systolic volume (p less than 0.005), end-systolic pressure (p less than 0.005), and the half-time of pressure decline after peak negative dP/dt (T1/2) (p less than 0.001). Negative diastolic pressure developed in seven of eight patients during isoproterenol (range, -0.5 to -2.4 mm Hg) but in only one of eight during pacing (-0.2 mm Hg). These reduced diastolic pressures during isoproterenol were accompanied by increased stroke volume (reflecting increased transmitral flow) and diminished pulmonary wedge pressure (reflecting left atrial pressure). The magnitude of reduction in minimum diastolic pressure during pacing and isoproterenol was related to the change in end-systolic volume (r = 0.79, p less than 0.001), ejection fraction (r = -0.74, p less than 0.001), T1/2 (r = -0.57, p less than 0.02), and coronary sinus flow (r = 0.73, p less than 0.005). Stronger correlations were observed in analyzing changes during isoproterenol alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The aging of the heart: weight and structural changes in the left ventricle with age]

Structural alterations of the cardiovascular system with aging are difficult to differentiate from superimposed pathologic processes. To determine whether aging "per se" affects the dimension of the heart, the weight of the heart, and the left ventricle and their rations to body weight, left ventricle wall thickness, the number of myocyte nuclei in the ventricle and the myocyte cell volume per nucleus were measured in 67 autopsies of subjects, 45 males and 22 females, who died from causes independent of cardiovascular diseases, from 17 to 90 years old. With aging, total heart weight increased slightly, while left ventricular and interventricular septum weights after dissection of the subepicardial fat decreased significantly (r = 0.44; p less than 0.001). Although left ventricular wall thickness remained constant with time, left ventricular weight to body weight ratio decreased progressively. At the structural level the number of myocyte nuclei within the left ventricle decreased (r = 0.45; p less than 0.001), whereas myocyte cell volume per nucleus increased (r = 0.30; p greater than 0.05) with age. Thus, the aging process of the heart is associated with a reduction in volume of the myocardial mass resulting from myocyte cell loss and reactive hypertrophy of the spared myocytes.     

Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger

Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to isoproterenol in adult rat ventricular myocytes. Responses to isoproterenol were largely mediated through the beta1AR in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the isoproterenol concentration-response curve. Responses to isoproterenol could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling. Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that beta2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart.     

Evaluation of left ventricular filling dynamics by pulsed Doppler echocardiography during afterload stress in ischemic heart disease using angiotensin II infusion

To evaluate cardiac reserve in ischemic heart disease, we simultaneously investigated left ventricular filling parameters using pulsed Doppler echocardiography (PDE) and catheter-obtained hemodynamics before and during afterload stress (angiotensin II test) in 14 patients with ischemic heart disease. The patients were divided into two groups according to their left ventricular function, i.e., mean left ventricular ejection fraction (mLVEF): Group I (n = 7, mLVEF = 65%) and Group II (n = 7, mLVEF = 43%). The peak velocity of rapid filling (R), the peak velocity of atrial contraction (A), the ratio of the two peak velocities (A/R), flow velocity integrals of the rapid filling phase (IR) and atrial contraction phase (IA) were obtained by PDE. Results were as follows: 1. During afterload stress, blood pressure, pulmonary artery wedge pressure, and left ventricular end-diastolic pressures (LVEDP) were elevated in both groups (p less than 0.01). The stroke work index (SWI) increased (p less than 0.01) and the time constant of left ventricular isovolumic pressure decay (T) was unchanged in Group I. SWI did not increase and T was prolonged in Group II (p less than 0.05). delta SWI/delta LVEDP, the ratio of the SWI change to the LVEDP change, during afterload stress was larger in Group I than in Group II (p less than 0.02). 2. Before the infusion of angiotensin II, R and IR were larger in Group I than in Group II. The A/R in Group I was less than that in Group II (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered calcium handling in left ventricular pressure-overload hypertrophy as detected with aequorin in the isolated, perfused ferret heart.

The purpose of this study was to test the hypothesis that systolic and diastolic dysfunction in left ventricular pressure-overload hypertrophy is caused by abnormal intracellular calcium handling. Experiments were performed with intact, buffer-perfused, isovolumic ferret hearts (n = 9 hypertrophied, n = 9 control) that were loaded with the bioluminescent indicator aequorin to monitor changes in cytoplasmic calcium. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Compared with their age-matched controls, significant hypertrophy of the left ventricle developed 4 weeks after postvalvular aortic banding; at the time the animals were killed, the left ventricular weight/body weight ratio was increased in the banded animals (5.3 x 10(-3) versus 3.6 x 10(-3), p less than 0.001). As indicated by the diastolic pressure-volume relation, left ventricular distensibility was significantly diminished in the hypertrophied hearts. In comparison to the controls, the hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 278 +/- 5.4 versus 247 +/- 10.2 msec, p less than 0.05), but a marked decrease in peak systolic midwall stress (22.4 +/- 5.0 versus 38.6 +/- 5.7 g/cm2, p less than 0.05). The increased duration of isovolumic contraction correlated with a similar prolongation of the calcium transient (time to 90% decline from peak: 245 +/- 19.5 versus 127 +/- 13.2 msec, p less than 0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

绝对不应期电刺激对心力衰竭豚鼠心室肌细胞钙离子流的影响

目的探讨绝对不应期电刺激(ARPES)对心力衰竭(简称心衰)心室肌细胞收缩和钙离子流的作用。方法应用单细胞收缩动缘检测仪,在单纯基础刺激和一定延时后同时给予ARPES,观察细胞收缩并测定以F360/F380反映细胞内钙瞬变。应用膜片钳技术中记录单纯基础刺激和ARPES(延迟后10ms刺激)所诱发动作电位(APSA1,APARPES),并比较动作电位时程(APD)。分别以APSA1和APARPES为测试电压,记录AP电压钳下的细胞膜L型钙通道电流(ICa-L)。结果①ARPES使单个心衰心室肌细胞收缩幅值增高15.53%±5.31%(P<0.05),收缩和舒张速度峰值均增加(分别增加10.60%±3.02%,23.2%±8.26%,P<0.05或0.01,n=6);F360/F380幅值增加16.82%±7.03%(P<0.01,n=6)。②ARPES延长动作APD。③与APSA1电压钳记录的ICa-L相比,APARPES电压钳记录的ICa-L减弱程度明显减少,其单位膜电容下的电流强度的整合值增加(P<0.01)。结论ARPES提高衰竭心肌收缩力与增强单个心室肌细胞钙瞬变相关。     

Angiotensin II-forming pathways in normal and failing human hearts

Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang II on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring the conversion of [125I]angiotensin I (Ang I) to [125I]Ang II. LV [125I]Ang II-forming activity in normal hearts (35.5 +/- 2.7 fmol/min/mg, n = 8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5 +/- 2.9 fmol/min/mg, n = 9) and was 48% lower (p less than 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5 +/- 1.9 fmol/min/mg, n = 15).(ABSTRACT TRUNCATED AT 250 WORDS)     

Left ventricular function under stress before and after myocardial revascularization.

To compare left ventricular responses to stress during exercise-induced myocardial ischemia and after myocardial revascularization, 35 patients (mean age 55 +/- 7 years, class III angina) with three-vessel coronary artery disease underwent a rest and exercise initial-transit radionuclide angiocardiography before aortocoronary bypass grafting. Left ventricular ejection fraction decreased during exercise (p less than 0.01), but cardiac output was augmented with an increased heart rate (p less than 0.0001) and left ventricular end-diastolic volume (p less than 0.001). Group A (n = 15) underwent six serial resting studies at different volume loads during the first 24 hours after operation while heart rate and blood pressure were held constant. These data revealed no significant change in left ventricular ejection fraction, but preload varied in all patients because of bleeding and fluid administration, with a mean end-diastolic volume change of 115 to 176 ml. This range of end-diastolic volume was similar to that defined with rest and exercise testing before operation. Group B (n = 20) underwent a repeat rest and exercise test 3 months after operation that demonstrated no change in resting function. However, exercise ejection fraction and peak systolic pressure/end-systolic volume ratio increased (p less than 0.001 and p less than 0.05, respectively) while end-diastolic volume decreased (p less than 0.05) compared with the values before operation. These data indicate that patients with coronary artery disease have chronically adapted cardiac function that makes use of both rapid heart rate and a wide range in preload to augment cardiac function under stress.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asynchronous (segmental early) relaxation impairs left ventricular filling in patients with coronary artery disease and normal systolic function

Asynchronous segmental early relaxation, defined as a localized early segmental outward motion of the left ventricular endocardium during isovolumetric relaxation, has been associated with an altered left ventricular relaxation rate. To determine whether asynchronous segmental early relaxation also results in impaired left ventricular filling, early diastolic ventricular wall motion and Doppler-derived left ventricular filling indexes were examined in 25 patients with documented coronary artery disease and normal systolic function. Patients were further classified into two groups according to the presence (n = 15, group 1) or absence (n = 10, group 2) of asynchronous early relaxation at left ventriculography. A third group of 10 age-matched normal subjects served as a control group. No differences were observed between the two patient groups with coronary artery disease with respect to age, gender distribution, heart rate, left ventricular systolic and diastolic pressures or extent and severity of coronary artery disease. No differences in transmitral filling dynamics were observed between group 2 patients and age-matched control subjects. Conversely, group 1 patients had significantly lower peak early filling velocities (44 +/- 11 vs. 58 +/- 11 cm/s, p less than 0.01), larger atrial filling fraction (45 +/- 4% vs. 38 +/- 4%, p less than 0.001), lower ratio of early to late transmitral filling velocities (0.6 +/- 0.08 vs. 0.99 +/- 0.18, p less than 0.001) and a longer isovolumetric relaxation period (114 +/- 12 vs. 90 +/- 6 ms, p less than 0.001) compared with group 2 patients and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)