Diastolic Left Ventricular Dysfunction : A Clinical Appraisal
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Diastolic left ventricular (LV) distensibility is determined by the material properties of the LV wall and by LV geometry (i.e., LV shape, LV volume and LV wall thickness). These material properties are influenced both by the physical structure of the LV myocardium and by the dynamic process of myocardial relaxation. The material properties of the myocardium dictate the strain that follows a given stress, and determine position and shape of the myocardial stress-strain relationship. The material properties, together with the LV geometry, also determine position and shape of the diastolic LV pressure-volume relationship. Diastolic LV distensibility is best characterized by this diastolic LV pressure-volume relationship. The crucial role of diastolic LV distensibility in relation to the heart failure syndrome are discussed in chapter 2, 3 and 4 of this thesis. Chapter 2 of this thesis discusses diastolic left ventricular dysfunction, characterized by an upward shift of the left ventricular diastolic pressure-volume relationship. Chapter 2.1 describes the effects of myocardial ischemia, either pacing-induced or by coronary occlusion, on the diastolic properties of the same LV anterior wall segment in 12 patients with single-vessel proximal left anterior descending coronary artery stenosis at rest, immediately after 7 ± 1.2 minutes of pacing, and at the end of a 1- minute balloon occlusion of coronary angioplasty (CO). Shifts of the diastolic LV pressure-length relation, derived from simultaneous tip-micromanometer LV pressure recordings and digital subtraction LV angiograms, were used as an index of regional diastolic LV distensibility of the anterior wall segment. The diastolic LV Pressure(P)-Radial Length(RL) plot of the ischemic segment was shifted upward for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. This upward shift at the end of CO was significantly smaller than that immediately after pacing. At the end of CO, a correlation was observed for the ischemic segment between percentage systolic shortening and upward shift of the diastolic LV pressure-radial length plot. The upward shift of the diastolic LV pressure-radial length plot, which was used as an index of decreased regional diastolic LV distensibility, was larger immediately after pacing than at the end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for a decrease in diastolic distensibility of the ischemic segment because of the higher percentage systolic shortening of the ischemic segment immediately after pacing, and because of the correlation at the end of CO between the upward shift of the diastolic LV pressure-radial length plot and percentage systolic shortening of the ischemic segment. Chapter 2.2 describes the different effects of low- flow ischemia, pacing-induced ischemia, and hypoxemic perfusion on LV performance in humans. During the initial phase of an ischemic insult, left ventricular (LV) performance depends on the complex interaction between oxygen deprivation, vascular turgor, and accumulation of metabolites. Summary 205 In experimental preparations, low-flow ischemia decreases systolic shortening and increases diastolic LV distensibility, whereas pacing- induced ischemia or hypoxic perfusion produces smaller decreases in systolic shortening but decreases LV diastolic distensibility. Therefore, the different effects of low-flow ischemia, pacing-induced ischemia, and hypoxemic perfusion on LV performance was studied in 20 patients with a significant stenosis in the left anterior descending coronary artery. Micromanometer-tip LV pressure recordings, LV angiography, and coronary sinus blood sampling were obtained at rest and during pacing-induced ischemia, low-flow ischemia due to balloon coronary occlusion, and hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion. LV stroke work index was lower at the end of balloon coronary occlusion than during pacing-induced ischemia and was lower at the end of balloon coronary occlusion than at the end of hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion. LV end-diastolic pressure rose from 16±5 mm Hg at rest to 23±6 mm Hg at the end of balloon coronary occlusion. However, LV end-diastolic pressure was lower at the end of balloon coronary occlusion than during pacing-induced ischemia and was lower at the end of balloon coronary occlusion than at the end of hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion. LV end-diastolic volume index increased at the end of balloon coronary occlusion. Left ventricular end-diastolic volume index increased to values similar to those for balloon coronary occlusion during pacing-induced ischemia and at the end of hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion. Higher values of LV end-diastolic pressure and unchanged values of LV end-diastolic volume index for pacing-induced ischemia and hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion, compared with balloon coronary occlusion, suggested a lower end- diastolic LV distensibility during pacing-induced ischemia and during hypoxemia, as compared with low-flow ischemia. Upward shifts of individual diastolic LV pressure-volume curves during pacing-induced ischemia (9 of 11 patients) and at the end of hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion (7 of 9 patients), compared with balloon coronary occlusion, were also consistent with lower LV diastolic distensibility during pacing-induced ischemia and during hypoxemia, compared with low-flow ischemia. Coronary sinus lactate, H+, and K+ levels increased after balloon deflation (balloon coronary occlusion and hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion) and during pacing-induced ischemia. Thus, during low-flow ischemia, LV systolic performance was lower and LV diastolic distensibility larger than during pacing-induced ischemia or hypoxemia. The variable response of the human myocardium to different types of ischemia was probably related to the degree of vascular turgor and accumulation of tissue metabolites. Chapter 2.3 covers a pathophysiologic perspective of the comparative effects of ischemia and Chapter 6 206 hypoxemia on left ventricular diastolic function in humans. In Chapter 2.4 the presence of a deficient acceleration of left ventricular relaxation is reported during exercise after heart transplantation. The exercise-induced rise in left ventricular filling pressures after cardiac transplantation is considered to be the result of a blunted heart rate response, of elevated venous return, and of unfavorable passive late-diastolic properties of the cardiac allograft. In contrast to passive late-diastolic left ventricular properties, the effect of left ventricular relaxation on the exercise-induced rise in left ventricular filling pressures of the cardiac allograft has not yet been studied. In the present study, the response of left ventricular relaxation to exercise was investigated in transplant recipients and compared with left ventricular relaxation observed in normal control subjects exercised to the same heart rate. Moreover, the response of left ventricular relaxation of the cardiac allograft to beta-adrenoreceptor stimulation, to reduced left ventricular afterload, and to increased myocardial activator calcium was investigated by infusion of dobutamine and of nitroprusside and by postextrasystolic potentiation. Twenty-seven transplant recipients were studied 1 year (n = 17), 2 years (n = 7), 3 years (n = 2), and 4 years (n = 1) after transplantation. All patients were free of rejection and of significant graft atherosclerosis at the time of study. Tip-micromanometer left ventricular pressure recordings and cardiac hemodynamics were obtained at rest, during supine bicycle exercise stress testing, during dobutamine infusion at a heart rate matching the heart rate at peak exercise, during nitroprusside infusion, and after postextrasystolic potentiation. Tip-micromanometer left ventricular pressure recordings were also obtained in a normal control group at rest and during supine bicycle exercise stress testing to a heart rate, which matched the heart rate of the transplant recipient group at peak exercise. Left ventricular relaxation rate was measured by calculation of a time constant of left ventricular pressure decay (T) derived from an exponential curve fit to the digitized tip-micromanometer left ventricular pressure signal. In the transplant recipients, exercise abbreviated T and caused a rise of left ventricular minimum diastolic pressure. In normal control subjects, exercise induced a larger abbreviation of T and a smaller drop in left ventricular minimum diastolic pressure than was found in the transplant recipients. In the transplant recipients, the change in T from rest to exercise was variable, ranging from an abbreviation, as observed in normal controls, to a prolongation and was significantly correlated with the change in RR interval on the ECG and the change in left ventricular end-diastolic pressure. In a first subset of transplant recipients, dobutamine infusion resulted in a heart rate equal to the heart rate at peak exercise, a left ventricular end-diastolic pressure (lower than at peak exercise) and a T value, which was shorter than both the resting value and the value observed at peak exercise. In a second subset of transplant recipients, nitroprusside infusion and postextrasystolic potentiation resulted in a significant prolongation of T and a characteristic negative dP/dt upstroke pattern with downward convexity as previously observed in left ventricular hypertrophy. Exercise after cardiac transplantation resulted in a smaller acceleration Summary 207 of left ventricular relaxation than in a normal control group exercised to the same heart rate. These transplant recipients, who made the largest use of left ventricular preload reserve during exercise, showed least acceleration of left ventricular relaxation. This association between a rise of left ventricular end-diastolic pressure and slower left ventricular isovolumic relaxation was also evident in the individual transplant recipient from the slower isovolumic relaxation during exercise than during dobutamine infusion despite equal heart rates. After postextrasystolic potentation during nitroprusside infusion, a slow left ventricular relaxation with downward convexity of the dP/dt signal was observed in the cardiac allograft. This finding suggests depressed function of the sarcoplasmic reticulum in left ventricular myocardium after transplantation, which could be related either to decreased adrenergic tone or to preceding ischemic injury during organ retrieval or to hypertrophy caused by cyclosporine induced arterial hypertension. Chapter 3 of this thesis discusses diastolic left ventricular dysfunction, characterized by a lack of rightward shift of the left ventricular diastolic pressure-volume relationship. In chapter 3.1 the functional significance of a modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy. Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies. LV endomyocardial expression of NOS2 was linearly correlated with LV stroke volume, LV ejection fraction, and LV stroke work. In patients with elevated LV end-diastolic pressure, a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume, LV ejection fraction, and LV stroke work. LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume and LV stroke work. To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endothelial release of NO) was infused intracoronarily. In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume and LV stroke work and shifted the LV end-diastolic pressurevolume relation to the right. It is concluded, that in patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve. In Chapter 3.2, because nitric oxide (NO) reduces diastolic LV stiffness, diastolic LV stiffness and LV systolic performance are related to intensity of endomyocardial NO synthase (NOS) gene expression in dilated cardiomyopathy and in athlete's heart. In dilated cardiomyopathy and in athlete's heart, progressive LV dilatation is accompanied by rightward displacement of the diastolic LV pressure-volume relation. In dilated cardiomyopathy, an increase in diastolic LV Chapter 6 208 stiffness can limit this rightward displacement, thereby decreasing LV systolic performance. Microtip LV pressures, conductance-catheter or angiographic LV volumes, echocardiographic LV wall thicknesses and snap-frozen LV endomyocardial biopsies were obtained in 33 patients with dilated cardiomyopathy and in three professional cyclists referred for sustained ventricular tachycardia. Intensity of LV endomyocardial inducible NOS (NOS2) and constitutive NOS (NOS3) gene expression was determined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Dilated cardiomyopathy patients with higher diastolic LV stiffnessmodulus and lower LV stroke work had lower NOS2 and NOS3 gene expression at any given level of LV end-diastolic wall stress. The intensity of NOS2 and NOS3 gene expression observed in athlete's heart was similar to dilated cardiomyopathy with low LV diastolic stiffness-modulus and preserved LV stroke work. High LV endomyocardial NOS gene expression is observed in athlete's heart and in dilated cardiomyopathy with low diastolic LV stiffness and preserved LV stroke work. Favorable effects on the hemodynamic phenotype of high LV endomyocardial NOS gene expression could result from a NO-mediated decrease in diastolic LV stiffness and a concomitant rise in LV preload reserve. In Chapter 3.3 findings from recent experimental and clinical research are covered, which solved some of the controversies with respect to the myocardial contractile effects of NO. These controversies were: (1) does NO exert a contractile effect at baseline? (2) Is NO a positive or a negative inotrope? (3) Are the contractile effects of NO similar when NO is derived from NOdonors or from the different isoforms of NO synthases (NOS)? (4) Does NO exert the same effects in hypertrophied, failing or ischemic myocardium? Transgenic mice with cardioselective overexpression of NOS revealed NO to produce a small reduction in basal developed LV pressure and a LV relaxation-hastening effect mainly through myofilamentary desensitization. Similar findings had previously been reported during intracoronary infusions of NO-donors in isolated rodent hearts and in humans. The LV relaxation hastening effect was accompanied by increased diastolic LV distensibility, which augmented LV preload reserve, especially in heart failure patients. This beneficial effect on diastolic LV function always overrode the small NO-induced attenuation in LV developed pressure in terms of overall LV performance. In most experimental and clinical conditions, contractile effects of NO were similar when NO was derived from NOdonors or produced by the different isoforms of NOS. Because expression of inducible NOS (NOS2) is frequently accompanied by elevated oxidative stress, NO produced by NOS2 can lead to peroxynitrite-induced contractile impairment as observed in ischemic or septic myocardium. Finally, shifts in isoforms or in concentrations of myofilaments can affect NO-mediated myofilamentary desensitization and alter the myocardial contractile effects of NO in hypertrophied or failing myocardium. Chapter 4 of this thesis discusses diastolic left ventricular dysfunction, characterized by a steeper slope of the left ventricular diastolic pressure-volume relationship. The purpose of the study reported in chapter 4.1 was to investigate interactions between myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy. In previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited Summary 209 LV preload reserve. Twenty-eight dilated cardiomyopathy patients underwent LV catheterization, balloon caval occlusions, intracoronary substance P infusion, and procurement of LV endomyocardial biopsies for determinations of collagen volume fraction, of gene expression of NOS2, NOS3, heme oxygenase, and TNF-alpha, and of NOS2 protein. Collagen volume fraction was unrelated to the intensity of NOS2, NOS3, heme oxygenase, or TNF-alpha gene expression or of NOS2 protein expression. Preload recruitable LV stroke work correlated directly with NOS2 gene expression and inversely with collagen volume fraction. High collagen volume fraction (>10%) reduced baseline LV stroke work and preload recruitable LV stroke work at each level of NOS2 gene expression. In dilated cardiomyopathy , myocardial fibrosis is unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (heme oxygenase), or cytokines (TNF-alpha) and blunts NOS2-related recruitment of LV preload reserve. Chapter 4.2 reports on heart failure patients, in which beneficial effects of NO on diastolic LV function always overrides a small NO-induced attenuation of LV developed pressure in terms of overall hemodynamic status, either at baseline or following ß-adrenergic stimulation. The absence of hemodynamic deterioration in transgenic mice over expressing either myocardial NOS2 or NOS3 confirms these clinical observations. In failing myocardium, NO’s correction of diastolic LV dysfunction reinforces NO’s energy sparing effects and the concerted action of NO on both diastolic LV dysfunction and deranged energetics could well be instrumental for preventing relentless deterioration of failing myocardium. Another beneficial effect of high endomyocardial NO activity on diastolic LV distensibility of the cardiomyopathic heart could result not only from NO-induced phosphorylation of troponin I and a concomitant reduction of diastolic crossbridge cycling but also from prevention of endomyocardial fibrosis. Chronic inhibition of NO synthesis has indeed been demonstrated to induce progressive myocardial fibrosis through a signaling cascade involving endothelin, angiotensin II, aldosterone and transforming growth factor ??. Chapter 5 discusses left ventricular dysfunction in relation to different changes in the left ventricular pressure-volume relationships. New, mainly noninvasive observations on diastolic LV dysfunction are confronted in this chapter with the old framework of diastolic LV pressurevolume relations to confirm their validity or to clarify their cause. Some questions recently emerged: 1. Is diastolic LV dysfunction always secondary to systolic LV dysfunction ? 2. Can transient elevations in LV loading induce diastolic LV dysfunction ? 3. Can diastolic LV dysfunction result from heightened active diastolic cardiac muscle tone?
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