Bruno Villari

Influence of collagen network on left ventricular systolic and diastolic function in aortic valve disease.

OBJECTIVESnThe purpose of this study was to evaluate left ventricular structure-function interplay in aortic valve disease.nnnBACKGROUNDnAn increase in myocardial fibrosis has been demonstrated in aortic valve disease, but changes in the collagen network and their effect on ventricular function have not been defined.nnnMETHODSnLeft ventricular structure was assessed from left ventricular endomyocardial biopsy specimens obtained in 32 patients with aortic valve disease (aortic stenosis in 25, aortic regurgitation in 7). Total collagen volume fraction, orthogonal collagen fiber meshwork (cross-hatching), endocardial fibrosis, muscle fiber diameter and volume fraction of myofibrils were determined by morphologic-morphometric evaluation. Control biopsy data were obtained from six donor hearts before transplantation. Eleven other patients with normal left ventricular function served as hemodynamic status control subjects. Left ventricular biplane cineangiography and high fidelity pressure measurements were carried out in all patients. Systolic function was assessed from ejection fraction. Diastolic function was evaluated by the time constant of relaxation, early and late peak filling rates and the constant of passive myocardial stiffness. Patients were assigned to three groups according to increasing severity of nonmyocyte tissue alterations. Group 1 comprised 10 patients with elevated total collagen volume fraction. Group 2 comprised 6 patients with normal total collagen volume fraction and the presence of increased cross-hatching or endocardial fibrosis, or both. Group 3 comprised 16 patients with elevated total collagen volume fraction and the presence of cross-hatching or endocardial fibrosis, or both.nnnRESULTSnMuscle fiber diameter was increased in the three groups with aortic valve disease, whereas the volume fraction of myofibrils was comparable in all four study groups. Ejection fraction was depressed in groups 2 and 3 compared with the control group. The time constant of relaxation was prolonged in the three groups with aortic valve disease. No differences in early and late peak filling rate were observed in the four study groups, but the constant of myocardial stiffness increased in groups 2 and 3.nnnCONCLUSIONSnIn aortic valve disease, changes in collagen architecture are associated with altered systolic function and passive diastolic properties. The sole increase in total collagen volume fraction without a change in architecture leaves systolic and passive diastolic function unaltered.

Angina Pectoris in Patients With Aortic Stenosis and Normal Coronary Arteries Mechanisms and Pathophysiological Concepts

BACKGROUNDnThe incidence of angina pectoris (AP) in patients with severe aortic stenosis (AS) and normal coronary arteries has been reported to be 30% to 40%. The exact pathophysiological mechanism, however, is not known. The purpose of this work was to evaluate the various hemodynamic and angiographic determinants of myocardial perfusion in 61 patients with severe AS.nnnMETHODS AND RESULTSnIn a retrospective analysis, 61 patients with severe AS and without significant coronary artery disease were studied. Thirty-three patients with atypical chest pain and angiographically normal arteries served as control subjects. Patients were divided into two groups: 32 with AP and 29 without AP. Quantitative coronary angiography was performed in 59 patients and 22 control subjects. Coronary flow reserve was determined in 29 patients and 7 control subjects by use of coronary sinus thermodilution technique. Patients with AP had a lower left ventricular (LV) muscle mass, an increased LV peak systolic pressure, and increased wall stress than those without AP. Vessels of the left coronary artery were smaller and coronary flow reserve was lower in patients with AP than in those without. Inadequate L V hypertrophy with an increased wall stress was found in patients with AP but not in patients without AP.nnnCONCLUSIONSnMyocardial ischemia in patients with severe AS can occur in the absence of coronary artery disease and appears to be due to inadequate LV hypertrophy with high systolic and diastolic wall stresses and a reduced coronary flow reserve. The cause of inadequate LV hypertrophy, however, remains unclear.

Effect of aortic valve stenosis (pressure overload) and regurgitation (volume overload) on left ventricular systolic and diastolic function

In secondary hypertrophy from chronic pressure or volume overload, or both, systolic as well as diastolic abnormalities of left ventricular (LV) function have been described, but their relation has not been defined. In 58 patients with aortic valve disease (28 with aortic valve stenosis, and 30 with aortic regurgitation) and in 11 control subjects, LV biplane cineangiography was performed simultaneously with LV high-fidelity pressure measurements. LV ejection performance was assessed by ejection fraction, and diastolic function by the time constant of LV pressure decay, the early and late peak filling rates, and the constants of chamber (pressure-volume relation) and myocardial stiffness (stress-strain relation). In the entire cohort (n = 69), ejection fraction was inversely related to the time constant of LV relaxation (r = -0.58, p less than 0.001) and to the constant of myocardial stiffness (r = -0.62, p less than 0.001). Despite preserved systolic contractile function (as evaluated from the ejection fraction-mean systolic stress relation), abnormalities in LV diastolic function were present in 9 of 18 patients with pressure overload and 20 of 22 with volume overload. None of the 58 patients with aortic valve disease had a reduced early peak filling rate, whereas a reduction in late peak filling rate was observed in 3 with aortic stenosis, but in none with aortic regurgitation. This, it appears that abnormalities of relaxation and passive diastolic myocardial stiffness precede alterations in myocardial contractility. Assessment of peak filling rates is not helpful to detect diastolic dysfunction in patients with aortic valve disease.

Normalization of left ventricular nonuniformity late after valve replacement for aortic stenosis

The aim of the present study was to evaluate nonuniformity in pressure overload hypertrophy due to aortic stenosis. Twenty patients were included in the present analysis. Ten patients with severe aortic stenosis were studied preoperatively as well as early (21 +/- 8 months) and (89 +/- 21 months) after aortic valve replacement (AVR) using left ventricular biplane angiograms, high-fidelity pressure measurements and endomyocardial biopsies. Ten normal subjects served as controls. LV systolic function was assessed from biplane ejection fraction, and diastolic function from the time constant of relaxation, the peak filling rate and the constant of myocardial stiffness. Nonuniformity was evaluated from the coefficient of variation of the time to end-systole (systolic asynchrony) and peak filling rate (diastolic asynchrony) of 12 regions in right anterior oblique and left anterior oblique projection. Ejection fraction was comparable in patients with aortic stenosis and in controls, whereas preoperatively diastolic dysfunction with prolonged relaxation and increased stiffness was present in patients with aortic stenosis and was normalized late after AVR. LV systolic asynchrony was present (>25D of controls) in 7 and diastolic asynchrony in 10 of 10 patients with aortic stenosis. Early as well as late after AVR systolic asynchrony was normalized in 9 of 10 patients. Diastolic asynchrony was present early AVR in all but one patient, although there was a significant improvement with respect to the preoperative evaluation. Late after AVR there was a normalization of diastolic asynchrony in 9 of 10 patients with aortic stenosis. Thus, it is concluded that systolic asynchrony is normalized early after AVR probably due to its load-sensitivity, whereas diastolic asynchrony persists probably due to residual LV hypertrophy with increased interstitial fibrosis and myocardial stiffness. Late after AVR, diastolic asynchrony is normalized due to structural remodeling with regression of both myocardial hypertrophy and interstitial fibrosis.

Regression of coronary artery dimensions after successful aortic valve replacement.

BackgroundThe effect of regression of myocardial hypertrophy on coronary artery dimensions was evaluated in patients with aortic valve disease who underwent valve replacement. Methods and ResultsCross-sectional area (CSA) of the three major coronary arteries (left anterior descending [LAD], left circumflex [LCx], and right coronary artery) was determined by quantitative coronary arteriography in 15 patients with aortic valve disease before and 38 months (range, 14–113 months) after successful aortic valve replacement. Twelve normal subjects served as controls. Left ventricular (LV) angiographic mass was calculated according to the method of Rackley. CSA of the left coronary artery was larger in aortic valve disease than in controls (LAD, 15 versus 8 mm2, p<00.001; LCx, 14 versus 6 mm2, p<0.001). After valve replacement, CSA of the left coronary artery decreased (LAD, 12 mm2 p<0.05 versus before surgery; LCx, 11 mm2, p<0.05 versus before surgery) but remained significantly larger than in controls. CSA of the right coronary artery in patients with aortic valve disease was not different from controls. LV muscle mass was significantly increased in aortic valve disease patients before (364 g) and after (250 g) valve replacement compared with controls (135 g). The appropriateness of coronary artery size with respect to muscle mass was evaluated by normalizing CSA of the left coronary artery (LAD+LCx) per 100 g of LV muscle mass (mm2/100 g). This index amounted to 11 mm2/100 g in controls, to 8 mm2/100 g in preoperative patients (p<0.05 versus controls), and to 10 mm2/100 g in postoperative patients with aortic valve disease (p = NS versus controls). ConclusionsIn patients with aortic valve disease, CSA of the proximal LAD and LCx is increased, but this increase is not sufficient to keep CSA per 100 g of LV mass within normal limits. The postoperative decrease in muscle mass is associated with a decrease in the size of LAD and LCx, whereas the size of the right coronary artery remains unchanged. In contrast to the preoperative state, the residually hypertrophied LV myocardium after aortic valve replacement is supplied by an enlarged but adequately sized LAD and LCx.

Effect of progression of left ventricular hypertrophy on coronary artery dimensions in aortic valve disease

OBJECTIVESnThe effect of progression of left ventricular hypertrophy on coronary artery dimensions was studied in patients with aortic valve disease.nnnMETHODSnCross-sectional area of the left and right coronary arteries was determined by quantitative coronary arteriography in 12 control subjects and in 10 patients with aortic valve disease at baseline and after a follow-up period of 66 months.nnnRESULTSnThe cross-sectional area of the left coronary artery was larger in patients with aortic valve disease than in control subjects (left anterior descending artery 13 vs. 8 mm2, p < 0.001; left circumflex artery 13 vs. 6 mm2, p < 0.001). At the follow-up examination, cross-sectional area of the left coronary artery increased (left anterior descending artery 17 mm2, p < 0.01 vs. baseline; left circumflex artery 15 mm2, p < 0.01 vs. baseline). The cross-sectional area of the right coronary artery was not different in patients with aortic valve disease from that in control subjects. Left ventricular muscle mass was larger in patients with aortic valve disease both at baseline (269 g, p < 0.001) and after follow-up examination (339 g, p < 0.001) than in control subjects (136 g). The appropriateness of coronary artery size with respect to muscle mass was evaluated by normalizing cross-sectional area of the left coronary artery (left anterior descending plus left circumflex artery) per 100 g of left ventricular muscle mass (mm2/100 g). This index was 10.9 mm2/100 g in control subjects, and decreased in subjects with aortic valve disease from 10.3 mm2/100 g at baseline to 8.6 mm2/100 g at the follow-up measurement (p < 0.05 vs. control values).nnnCONCLUSIONSnIn patients with aortic valve disease, the progression of left ventricular hypertrophy is associated with an increase in left anterior descending and left circumflex coronary artery dimensions, whereas the size of the right coronary artery remains unchanged. Despite the enlargement of the left coronary artery, the cross-sectional area of the left coronary artery per 100 g of left ventricular muscle mass decreased. Hence, the increase in coronary artery size appears to be inadequate when the severity of left ventricular hypertrophy increases.

Persistent Diastolic Dysfunction Late After Valve Replacement in Severe Aortic Regurgitation

Background— Regression of left ventricular (LV) hypertrophy with normalization of diastolic function has been reported in patients with aortic stenosis late after aortic valve replacement (AVR). The purpose of the present study was to evaluate the effect of AVR on LV function and structure in chronic aortic regurgitation early and late after AVR. Methods and Results— Twenty-six patients were included in the present analysis. Eleven patients with severe aortic regurgitation were studied before, early (21 months) and late (89 months) after AVR through the use of LV biplane angiograms, high-fidelity pressure measurements, and LV endomyocardial biopsies. Fifteen healthy subjects were used as controls. LV systolic function was determined from biplane ejection fraction and midwall fractional shortening. LV diastolic function was calculated from the time constant of LV relaxation, peak filling rates, and myocardial stiffness constant. LV structure was assessed from muscle fiber diameter, interstitial fibrosis, and fibrous content. LV muscle mass decreased significantly by 38% early and 55% late after surgery. Ejection fraction was significantly reduced preoperatively and did not change after AVR (P=NS). LV relaxation was significantly prolonged before surgery (89±28 ms) but was normalized late after AVR (42±14 ms). Early and late peak filling rates were increased preoperatively but normalized postoperatively. Diastolic stiffness constant was increased before surgery (22±6 versus 9±3 in control subjects; P=0.0003) and remained elevated early and late after AVR (23±4; P=0.002). Muscle fiber diameter decreased significantly after AVR but remained increased at late follow-up. Interstitial fibrosis was increased preoperatively and increased even further early but decreased late after AVR. Fibrosis was positively linearly correlated to myocardial stiffness and inversely correlated to LV ejection fraction. Conclusions— Patients with aortic regurgitation show normalization of macroscopic LV hypertrophy late after AVR, although fiber hypertrophy persists. These changes in LV myocardial structure late after AVR are accompanied by a change in passive elastic properties with persistent diastolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrial.gov. Unique identifier: NCT00976625.

Reduced Epicardial Coronary Vasodilator Capacity in Patients With Left Ventricular Hypertrophy

BACKGROUNDnEnlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow.nnnMETHODS AND RESULTSnVasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 micrograms intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2 +/- 2.2 mm) than in control subjects (8.6 +/- 1.5 mm; P < .001); after 100 micrograms intracoronary nitroglycerin, it increased to 12.9 +/- 2.2 mm (6 +/- 5%) in those with LV hypertrophy and to 10.3 +/- 1.5 mm (21 +/- 8%; P < .001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (r = -.71, P < .001).nnnCONCLUSIONSnVasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.

Coronary artery size in mitral regurgitation and its regression after mitral valve surgery.

The relationship between coronary artery size and left ventricular (LV) muscle mass was studied in 10 control subjects and in 10 patients with chronic mitral regurgitation before and 28 +/- 15 months after mitral valve surgery. Left and right coronary artery size was determined by quantitative coronary arteriography. Left coronary artery size was significantly increased before surgery (26 mm2) and decreased after operation (23 mm2), but was still larger than in control subjects (14 mm2). The right coronary artery was also enlarged preoperatively (13 mm2; controls = 9 mm2), but was normalized after surgery (11 mm2). A linear correlation was found between LV muscle mass and left (r = 0.88, p < 0.001) and right coronary artery size (r = 0.84, p < 0.001) as well as between right coronary artery size and mean pulmonary artery pressure (r = 0.56, p < 0.01). Thus in chronic mitral regurgitation the enlargement of the left and right coronary artery is proportional to the degree of LV hypertrophy. The increase in right coronary artery size is probably the result of right ventricular pressure overload. Postoperatively there is only partial regression of left coronary artery size but normalization of right coronary artery size.

Zeitlicher Verlauf von myokardialen Umbauprozessen nach Herzklappenersatz bei chronischer Druck- und Volumenbelastung

Die Vorgange im Zusammenhang mit der Ruckbildung einer Myokardhypertrophie sind vielfaltig und spielen sich auf molekularer, zellularer, struktureller und hamodynamischer Ebene ab. Dieser Ruckbildungsprozess geht ausserdem mit Veranderungen der kardialen Geometrie (= ventrikulares Remodeling) einher. Bei Vorliegen einer physiologischen Hypertrophie, z.B. bei Sportlern, ist dieser Ruckbildungsprozess vollstandig ohne strukturelle Restveranderungen, wahrend bei pathologischer Hypertrophie dieser Umbauprozess unvollstandig und meistens mit einer funktionellen Einschrankung verbunden ist (4). Mon-rad et al. konnten zeigen, dass bei einem Drittel der Patienten 10 Jahre nach erfolgreichem Aortenklappenersatz eine diastolische Dysfunktion persistiert, die nur unter korperlicher Belastung mit einem pathologischen Anstieg des Lungenkapillardrucks zum Ausdruck kommt (17). Dies weist darauf hin, dass strukturelle Umbauprozesse auch 10 Jahre nach erfolgreichem Klappenersatz nicht abgeschlossen sind und eine isolierte Storung der diastolischen Ventrikelfunktion bewirken konnen. Heute versucht man, durch den Einsatz verschiedener therapeutischer Massnahmen diesen Umbauprozess zu beschleunigen und die negativen Auswirkungen des strukturellen Remodelings zu minimieren. In der folgenden Ubersicht soll der zeitliche Ablauf dieser myokardialen Umbauprozesse nach Herzklappenersatz bei chronischer Druck- und Volumenbelastung naher beleuchtet werden und am Beispiel von Patienten mit praoperativerAortenstenose bzw. Aorteninsuffizienz dargestellt werden.