Left Ventricular Function In Humans Research Articles

Abstract 12001: Atrial Fibrillation Induces Ventricular Dysfunction via Altered Ca 2+ Handling and Oxidative CaMKII Activation in the Human Heart

Introduction: The effects of atrial fibrillation (AF) on left ventricular (LV) function are poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to LV dysfunction. This study investigated the effects of AF on the human LV. Methods and Results: LV myocardium from patients with preserved LV function (EF>50%) with sinus rhythm (SR, n=31) or rate-controlled AF (n=24) obtained during surgery for aortic stenosis was studied. Clinical data were mostly balanced without changes in LV function and remodeling. LV myocardium from SR and AF patients showed no changes in fibrosis. In functional studies, systolic Ca 2+ transient amplitude of human LV cardiomyocytes (CM) was reduced in AF patients, while diastolic Ca 2+ levels and Ca 2+ transient kinetics were unaltered. These results were confirmed in LV CM from non-failing donors with AF (n=4) vs. SR (n=8). In addition, normofrequent AF was simulated in vitro using arrhythmic or rhythmic electrical culture pacing (both at 60 bpm). After 24h of AF-simulation, human LV CM from non-failing donors (n=9) showed also an impaired Ca 2+ transient amplitude. For a standardized chronic AF-simulation, human iPSC-CM (n=22 differentiations/5 individuals) were tested. 7 days of AF-simulation caused reduced systolic Ca 2+ transient amplitude and sarcoplasmic reticulum Ca 2+ load, which could be explained by an increased diastolic Ca 2+ leak. Mechanistically, oxidative stress markers were higher in the LV of AF patients. Ca 2+ /calmodulin-dependent protein kinase IIδ (CaMKII) was found to be more oxidized at Met281/282 in the LV of AF patients leading to an increased CaMKII activity. Thus, RyR2 phosphorylation was elevated, which likely underlies the depression of LV Ca 2+ handling in AF. In translational contractility experiments of human ventricular trabecula from patients with heart failure (n=8), in vitro AF-simulation for 8h worsened systolic and diastolic contractile function. Conclusions: Here we could firstly show that AF impairs human LV function via increased oxidative stress and CaMKII activity in different patient populations and models. Thus, this translational study demonstrates the detrimental effects and mechanisms of AF in the absence of tachycardia on the human LV.

Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function.

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7–26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.

The Impact Of Lifelong Physical Activity And Myocardial Infarction On Left Ventricular Function

Physical activity (PA) protects against future cardiovascular events. Nonetheless, myocardial infarction (MI) has been reported in lifelong athletes. MI typically reduces left ventricular function (LVF), but animal studies suggest that regular PA can reduce the ischemic effects of a MI and therefore preserve LVF. PURPOSE: To examine the impact of lifelong physical activity and myocardial infarction on left ventricular function. METHODS: 68 male subjects (45-75 yrs) were included and divided over four groups: 1) lifelong athletes (>3 h/week PA for>20 years) with a history of MI (active-MI, n=16), 2) lifelong athletes without a history of MI (active-CON, n=17), 3) sedentary subjects (<1 h/week PA for>20 years) with a history of MI (inactive-MI, n=16), and 4) sedentary subject without a history of MI (inactive-CON, n=19). Physical fitness was assessed by a cardio-pulmonary exercise test, while ejection fraction (EF), E/A ratio, and circumferential wall deformation (CWD) of the left ventricle were measured by echocardiography. RESULTS: VO2max was significantly higher (P<0.05) in the active-MI (40.6±6.7 mL/min/kg) and active-CON group (46.0±9.0 mL/min/kg) versus the inactive-MI (28.9±6.6 mL/min/kg) and inactive-CON group (33.6±4.9 mL/min/kg). Active-MI (59.1±5.9%) and active-CON subjects (60.3±5.8%) demonstrated a significantly higher EF compared to inactive-MI subjects (50.8±8.4%, P<0.05), whereas the EF of the active-MI subjects was not different compared to the inactive-CON subjects (56.3±5.0%; P>0.05). The E/A ratio was not different across groups (P>0.05). Active-MI (-17.8±3.3%) and active-CON subjects (-19.2±2.5%) demonstrated a better CWD compared to inactive-MI (-13.2±3.6%) (P<0.05), while the CWD in the active-MI group was not different compared to the inactive-CON subjects (-15.6±2.6%) (P>0.05). CONCLUSION: Active-MI subjects demonstrate EF and CWD values comparable to active-CON and inactive-CON subjects, while these values are significantly better than those in inactive-MI subjects. These findings suggest that lifelong physical activity may reduce the detrimental effect of myocardial infarction-induced ischemia on left ventricular function in humans.

Quantitative assessment of left ventricular function in humans at 7 T

The purpose of this study was to determine the ability of 7 T cardiac magnetic resonance imaging (MRI) to quantitatively assess left ventricular volumes, mass, and function from cine short-axis series and left ventricular diastolic filling from velocity-encoded MRI in 10 healthy volunteers. As comparative "gold standard," the corresponding measures obtained at 1.5 T were taken. Left ventricular volumes, function, and mass were obtained by manual image segmentation. Trans-mitral flow graphs were obtained from 2D one-directional through-plane velocity-encoded MRI planned at the mitral valve in end-systole. Imaging at 7 T MRI was successful in 80% of the examinations. Assessment of left ventricular volumes, function, and mass at 7 T showed good agreement with 1.5 T (no significant differences between variables describing volumes, function, and mass with intraclass correlation coefficients ranging from 0.77 to 0.96). Trans-mitral stroke volume and the ratio between early and atrial peak filling rate showed strong agreement at both field strengths (no significant differences between stroke volumes and filling ratios with intraclass correlation coefficients 0.92 for stroke volumes and 0.77 for peak filling ratios). In conclusion, this study shows that assessing left ventricular volumes, function, and flow is feasible at 7 T MRI and that standardized MRI protocols provide similar quantitative results when compared with 1.5 T MRI.

Arterial Stiffness Is Associated With Regional Ventricular Systolic and Diastolic Dysfunction

The pathophysiology of left ventricular (LV) dysfunction, particularly in the setting of a preserved ejection fraction (EF), remains unclear. Few studies have investigated the relationship between arterial compliance and LV function in humans, and none used cardiovascular MRI. We sought to determine whether arterial compliance is related to regional myocardial function among participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Arterial compliance was assessed using carotid ultrasound measurements to calculate the distensibility coefficient (DC) and Young's modulus (YM). Circumferential systolic (SR(S)) and diastolic (SR(E)) strain rates were calculated by harmonic phase (HARP) from tagged MRI. Associations between arterial compliance and indices of ventricular function were adjusted for cardiovascular risk factors. We found a significant association between arterial compliance and SR(S) in all myocardial regions (P<0.05); arterial compliance was also associated with SR(E) in the lateral and septal wall regions (P<0.05). Multiple linear regression analyses demonstrated a direct linear relationship between the carotid artery DC and SR(S) across all LV segments and slices, even after adjustment for cardiovascular risk factors and LV mass. In regression analyses, a significant relationship between arterial compliance and SR(E) in the septal and antero-apical walls was also found and remained significant after multivariable adjustment. Arterial stiffness is associated with early and asymptomatic impairment of systolic as well as diastolic myocardial function. Further studies are needed to elucidate role of vascular compliance in the development of ventricular dysfunction and failure.

Sex differences in basal hemodynamics and left ventricular function in humans with and without heart failure

Women with systolic heart failure (HF) demonstrate better survival than men. Whether sex differences occur in hemodynamics or measures of left ventricular (LV) function is not well understood. We retrospectively analyzed a cohort who underwent evaluation by right heart catheterization +/- micromanometer-tipped catheterization of the LV. Two groups, defined at the time of catheterization, were studied: normal LV (NLV) function or HF (LV ejection fraction <35%, New York Heart Association II-III symptoms). For each female, we identified 2 male controls matched for age and LV ejection fraction in the HF group. In the NLV group, we matched 73 men (56 +/- 10 years) to 39 women (56 +/- 10 years). In the HF group, we matched 71 men (57 +/- 10 years) to 36 women (57 +/- 10 years). In the NLV group, women had higher heart rate and lower right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure. Left ventricular peak systolic pressure was higher, and LV end-diastolic pressure was lower in women. In the HF group, no sex differences were observed in any hemodynamic measurement. In both groups, no sex differences were observed in isovolumic contractility or relaxation. Sex differences in hemodynamics are observed in patients with NLV function but not with HF. The intrinsic or extrinsic factors responsible for sex differences observed in patients with NLV function may be eclipsed by the HF disease state or its treatment.

The effect of acute hypoxia on left ventricular function during exercise

The effect of acute hypoxia on the human left ventricular function during exercise was evaluated by 2D and Doppler echocardiography on 11 healthy male college students. Each subject completed 6-min moderate intensity (100 W) supine cycling exercises in normoxia and hypoxia, respectively. The concentration of inspired O(2) was adjusted to keep arterial hemoglobin O(2) concentration (SpO(2)) at 88-92% during hypoxia. Doppler indices obtained were compared between normoxia and hypoxia. The left ventricular myocardial diastolic function was increased during exercise in hypoxia compared with normoxia. The peak velocity of early filling wave increased at rest (P < 0.05) and during exercise (P < 0.05 at second minute, and P < 0.01 at sixth minute) in hypoxia. The heart rate (P < 0.01) and cardiac output (P < 0.001) were elevated markedly at rest during hypoxia. The left ventricular systolic function variables, such as stroke volume, ejection fraction, and end-systolic volume were relatively unaltered during hypoxia compared with normoxia. The results suggest that acute hypoxia increases the left ventricular myocardial diastolic function during moderate intensity supine cycling exercise without affecting the systolic function.

Positive effects of nitric oxide on left ventricular function in humans

The myocardial effect of tonically released nitric oxide (NO) in humans is still not known. We tested the hypothesis that low-dose NO exerts positive effects on left ventricular (LV) function. Twelve healthy volunteers, 26+/-4 years, were enrolled in this study. Magnetic resonance imaging was used to precisely measure the direct effects of NO on stroke volume index (SVI). The NO pool was monitored by chemiluminescence. We reduced endogenous NO levels with intravenous infusion of the NO synthase-inhibitor N(G)-monomethyl-l-arginine. Replenishment of the NO pool was achieved with the NO donor S-nitrosoglutathione (GSNO) (0.5 micromol iv). To differentiate load-dependent from the direct effects of NO on LV function, changes in SVI in response to GSNO were compared with changes in the NO-independent vasodilator dihydralazine (2.5 mg iv) at matched arterial pressure and heart rate. Inhibition of NO synthesis was followed by reduction in SVI. Subsequent replenishment of the circulating NO with GSNO significantly increased SVI (39+/-8 to 54+/-7 mL m(-2); P=0.001), whereas no significant changes were observed with the NO-independent vasodilator dihydralazine (39+/-8 to 46+/-8 mL m(-2); P=0.0626). Inhibition of endogenous NO release reduces, whereas replenishment with exogenous NO increases LV function, pointing towards a positive effect of tonically released NO on LV function in healthy humans.

Relationship Between Early Diastolic Intraventricular Pressure Gradients, an Index of Elastic Recoil, and Improvements in Systolic and Diastolic Function

Background Early diastolic intraventricular pressure gradients (IVPGs) have been proposed to relate to left ventricular (LV) elastic recoil and early ventricular “suction.” Animal studies have demonstrated relationships between IVPGs and systolic and diastolic indices during acute ischemia. However, data on the effects of improvements in LV function in humans and the relationship to IVPGs are lacking. Methods and Results Eight patients undergoing CABG and/or infarct exclusion surgery had a triple-sensor high-fidelity catheter placed across the mitral valve intraoperatively for simultaneous recording of left atrial (LA), basal LV, and apical LV pressures. Hemodynamic data obtained before bypass were compared with those with similar LA pressures and heart rates obtained after bypass. From each LV waveform, the time constant of LV relaxation (τ), +dP/dt max , and −dP/dt max were determined. Transesophageal echocardiography was used to determined end-diastolic (EDV) and end-systolic (ESV) volumes and ejection fractions (EF). At similar LA pressures and heart rates, IVPG increased after bypass (before bypass 1.64±0.79 mm Hg; after bypass 2.67±1.25 mm Hg; P &lt;0.01). Significant improvements were observed in ESV, as well as in apical and basal +dP/dt max , −dP/dt max , and τ (each P &lt;0.05). Overall, IVPGs correlated inversely with both ESV (IVPG=−0.027[ESV]+3.46, r =−0.64) and EDV (IVPG=−0.027[EDV]+4.30, r =−0.70). Improvements in IVPGs correlated with improvements in apical τ (Δτ =5.93[ΔIVPG]+4.76, r =0.91) and basal τ (Δτ =2.41[ΔIVPG]+5.13, r =−0.67). Relative changes in IVPGs correlated with changes in ESV (ΔESV=−0.97[%ΔIVPG]+23.34, r =−0.79), EDV (ΔEDV=−1.16[%ΔIVPG]+34.92, r =−0.84), and EF (ΔEF=0.38[%ΔIVPG]−8.39, r =0.85). Conclusions Improvements in LV function also increase IVPGs. These changes in IVPGs, suggestive of increases in LV suction and elastic recoil, correlate directly with improvements in LV relaxation and ESV.

Electromechanical mapping of regional left ventricular function in humans: Comparison with echocardiography

A catheter-based method of mapping left ventricular electromechanical regional function may be used to optimize application of local myocardial therapies by demarcating zones of ischemia or infarction. We thus performed a detailed comparison between electromechanical parameters and segmental function as assessed by echocardiography in 10 patients (3 with normal ventricles and 7 with old infarcts). Using a 16-segment model, unipolar voltage and local shortening were significantly and independently related to echo score by multivariate analysis, having a concordance with echo score of 73% for shortening and 79% for voltage. Area under ROC curves, expressing the ability to differentiate normal from abnormal segments, had values of 0.75 and 0.81 for local shortening and unipolar voltage, respectively. In conclusion, automatic assessment of regional ventricular function can be achieved independently by electrical and mechanical parameters, compared with echocardiography, permitting an integrated approach to the evaluation of ventricular function and aiding localization of catheter-based therapies. Cathet. Cardiovasc. Intervent. 50:10–18, 2000. © 2000 Wiley-Liss, Inc.

Critical importance of myocardial salvage: Relationship with the choice of reperfusion strategies

Clinical trials have left little doubt that in patients with symptoms of acute myocardial infarction, early reperfusion achieved with coronary thrombolytic therapy is beneficial in limiting infarct size [ 1 Koren G. Weiss A.T. Hasin Y. et al. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Eng J Med. 1985; 313: 1384-1389 Google Scholar , 2 Hasche E.T. Fernandes C. Freedman S.B. Jeremy R.W. Relation between ischemia time, infarct size and left ventricular function in humans. Circulation. 1995; 92: 710-719 Google Scholar , 3 Raitt M.H. Maynard C. Wagner G.S. Cerqueira M.D. Silvester R.H. Weaver W.D. Relation between symptom duration before thrombolytic therapy and final myocardial infarct size. Circulation. 1996; 93: 48-53 Google Scholar , 4 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349–360. Google Scholar ].

Paracrine Coronary Endothelial Control of Left Ventricular Function in Humans

Similar to endothelial modulation of vascular tone, myocardial contraction may be modulated by cardioactive agents released from the coronary endothelium. To investigate such modulation in humans, we performed invasive assessment of left ventricular (LV) function before, during, and after bicoronary infusion of substance P, which releases nitric oxide from the endothelium. Eight healthy subjects were investigated during diagnostic coronary angiography and eight transplant recipients during annual catheterization. Tip-micromanometer LV pressure was recorded before, during, and after bicoronary (n = 16) and right atrial (n = 14) infusion of substance P (20 pmol/min). LV angiograms (n = 11) were obtained before and at the end of the substance P infusion. At the end of the intracoronary substance P infusion, we observed (1) a fall in LV peak systolic pressure from 147 +/- 16 to 139 +/- 15 mm Hg (P < .01) in healthy subjects and from 147 +/- 25 to 141 +/- 22 mmHg (P < .05) in transplant recipients; (2) a downward and rightward shift of the average LV end-systolic pressure-volume point consistent with depressed systolic performance; and (3) a rise in LV end-diastolic volume at comparable end-diastolic pressure, consistent with increased end-diastolic distensibility. Five minutes after the substance P infusion, LV peak systolic pressure was higher than at baseline in healthy subjects (154 +/- 18 mm Hg; P < .05). Right atrial infusion of substance P did not reproduce these changes. Bicoronary infusion of substance P modulates LV function in humans, probably through paracrine myocardial action of cardioactive agents released from the coronary endothelium.

Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: Retrospective clinical evidence of “preconditioning”

We examined whether angina pectoris occurring shortly before the onset of acute myocardial infarction can actually preserve postischemic left ventricular function in humans. Experimental studies indicate that brief, transient episodes of ischemia render the heart very resistant to infarction from a subsequent sustained ischemic insult, an effect termed ischemic preconditioning. However, no clinical data are available concerning the implications of angina pectoris shortly before the onset of infarction in humans. We studied 84 patients with an acute anterior myocardial infarction. All patients had total occlusion of the proximal or medial portion of the left anterior descending coronary artery and achieved reflow within 6 h of onset. Patients were classified into three groups on the basis of duration of antecedent angina pectoris: group 1 = no angina (37 patients); group 2 = new angina pectoris occurring < or = 7 days of onset of infarction (22 patients); group 3 = angina pectoris beginning > 7 days before onset of infarction (25 patients). All patients underwent left ventriculography on the day of, and 28 days after, onset of infarction to determine ejection fraction and regional wall motion in the territory of the left anterior descending coronary artery by the centerline method. Angiographic collateral flow grade was higher in group 3 than in groups 1 and 2 ([mean +/- SD] group 1 = 0.08 +/- 0.7, group 2 = 0.7 +/- 0.7, group 3 = 1.5 +/- 0.8). Although there were no differences in baseline ejection fraction and regional wall motion among the three groups, the degree of improvement was significantly greater in groups 2 and 3 than in group 1 (late minus baseline ejection fraction: group 1 = 0 +/- 8%, group 2 = 7 +/- 10% group 3 = 6 +/- 10% [p < 0.05 group 1 vs. groups 2 and 3]; late minus baseline regional wall motion: group 1 = 0.2 +/- 0.4, group 2 = 0.6 +/- 0.5, group 3 = 0.5 +/- 0.6 SD/chord [p < 0.05, group 1 vs. group 2]). When the study was limited to those patients with no or poor collateral flow (31 in group 1, 19 in group 2, 10 in group 3), only group 2 patients had a significant improvement in wall motion. Angina pectoris within 24 h before onset of infarction was more frequent in group 2 (82%) than group 3 (28%, p < 0.05). Episodes of angina pectoris occurring shortly before the onset of infarction may preserve myocardial contractile function in reperfused myocardial infarction despite less support from collateral flow channels, although these are suggestive results in a limited number of patients.

Transcatheter Endocardial Ablation: Acute Effects of Direct Current Countershock on Regional Myocardial Blood Flow

Effect of DC Shock Ablation on Myocardial Blood Flow. Introduction: High energy direct current ablative shocks delivered through endocardial electrode catheters have been used as a treatment for various cardiac arrhythmias including ventricular tachycardia. Frequently, these shocks result in depression of myocardial function, at least transiently. Methods and Results: This study assessed the effect of a 200‐joule direct current shock delivered endocardially to the apex of the heart in ten adult mongrel dogs. Arterial blood pressures were monitored continuously. Myocardial contraction was monitored via two‐dimensional echocardiography. Regional myocardial blood flows were measured using radionuclide labeled microspheres before delivery of the shock, 30 seconds after delivery of the shock, and at 5 and 10 minutes after the shock. The results of the study demonstrated that there was a marked drop in arterial blood pressure immediately after the shock that gradually recovered over a 20‐minute period. Regional myocardial blood flow at the site of catheter ablation was severely depressed immediately after the shock. The degree of myocardial blood flow depression was inversely related to the distance from the site of ablation. At 5–10 minutes after ablation there was a marked hyperemic response in areas that suffered from depressed flow immediately after the shock. Two‐ dimensional echocardiography demonstrated depressed contractile function immediately after the shock with gradual recovery over a 10‐ to 20‐minute period. The catheter shock also generated prominent echo densities within the myocardium surrounding the ablative site. In contrast to the intracavitary echo densities that cleared quickly, the intramyocardial densities cleared much more slowly. Conclusion: The results of the study confirm the clinical observation that human left ventricular function is depressed acutely following a high‐energy ablative shock delivered to the left ventricular endocardium. Our results also demonstrated for the flrst time the effect of such ablative shocks on regional myocardial blood flow. Such depressions of blood flow may help explain the sudden drop in contractile function of the heart. The persistent intramyocardial echoes seen after the shock probably represented generation of intramyocardial bubbles that could obstruct arterial flow as well as disrupt cellular function. (J Cardiovasc Electrophysiol, Vol. 3, pp. 40–47, February 1992)

A comparison of traditional wall motion assessment and quantitative shape analysis: A new method for characterizing left ventricular function in humans

To forego the need to arbitrarily choose coordinate, reference, and indexing systems and to make other assumptions mandated by traditional methods of measuring walf motion, a technique of regional function analysis based on shape characteristics and pattern recognition was developed. The method is based on curvature analysis, a fundamental shape parameter, and is adaptive to the complex geometry of cineangiographic ventricular images. Quantitative shape parameters were compared to a standard method of regional function analysis (center-line method) in 130 patients. Quantitative shape and wall motion indexes showed a positive correlation over a broad range of normal and abnormal function ( r = 0.748, p < 0.001). Overall sensitivity and specificity for categorization of regional function were not statistically different for either technique. Within regions, however, shape criteria were more specific in categorizing inferior zones than anterior zones and were more often abnormal in the presence of mild regional abnormalities that were not located in the apical region. In conclusion, shape analysis and pattern recognition techniques can be used to forego dependence on the numerous assumptions and approximations required by traditional wall motion techniques, while providing performance characteristics that are similar to, and in some instances better than, traditional approaches. Incorporation of shape information in assessments of regional function provides a more comprehensive evaluation that includes the important visual cues used by experienced observers or “experts.”