Gerhard Mall

Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms.

Hemodynamic and metabolic studies were performed in 15 patients without heart disease (controls, group A), in 21 patients with typical stress-induced anginal pain but normal coronary and left ventricular angiograms (angina pectoris with normal arteriogram, group B), and in 10 patients with angiographically proved coronary artery disease (CAD, group C). Coronary dilatory capacity, determined by measuring total myocardial blood flow at rest and during maximal coronary vasodilatation (dipyridamole, 0.5 mg/kg i.v.), was markedly reduced in group B and C patients. In group B patients, left ventricular catheter biopsy specimens revealed no evidence of small-vessel disease, but did show histologic alterations of mitochondria. During atrial pacing, the control subjects showed no changes in myocardial lactate uptake, whereas in group B patients, myocardial lactate production occurred. In contrast to controls, patients in group B showed a significant decline in ejection fraction and circumferential fiber shortening during isometric exercise. These findings suggest that myocardial ischemia is the cause of angina pectoris in patients who have angina but normal coronary arteriograms.

Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries.

The pathogenesis of angina pectoris in patients with left ventricular hypertrophy secondary to arterial hypertension and with normal coronary arteries remains uncertain. We measured coronary blood flow (argon method) in 12 control subjects and in 16 patients with arterial hypertension at rest and after intravenous administration of dipyridamole (0.5 mg/kg). In the patients with arterial hypertension, coronary blood flow response to dipyridamole was markedly reduced (p less than .001 as compared with control values). During coronary vasodilation there was a linear correlation between coronary resistance and left ventricular end-diastolic pressure (r = .67, p less than .001). Left ventricular catheter biopsy specimens did not reveal alterations in myocardial microvasculature. These findings suggest that reduction of coronary reserve may be an important contributor to the pathogenesis of angina pectoris in these patients.

Estimation of surface area and length with the orientator

The orientator is a new technique for the estimation of length and surface density and other stereological parameters using isotropic sections. It is an unbiased, design‐based approach to the quantitative study of anisotropic structures such as muscle, myocardium, bone and cartilage. A simple method for the practical generation of such isotropic planes in biological specimens is described. No special technical equipment is necessary. Knowledge of an axis of anisotropy can be exploited to optimize the efficiency. To randomize directions in space, points are selected with uniform probability in a square using various combinations of simple random, stratified random, and systematic random sampling. The point patterns thus produced are mapped onto the surface of a hemisphere. The mapped points define directions of sectional planes in space. The mapping algorithm ensures that these planes arc isotropic, hence unbiased estimates of surface and length density can be obtained via the classical stereological formulae. Various implementations of the orientator are outlined: the prototype version, the orientator‐gencrated ortrip, two systematic versions, and the smooth version. Orientator sections can be generated without difficulty in large specimens; we investigated human skeletal muscle, myocardium, placenta, and gut tissue. Slight practical modifications extend the applicability of the method to smaller organs like rat hearts. At the ultrastructural level, a correction procedure for the loss of anisotropic mitochondrial membranes due to oblique orientation relative to the electron beam is suggested. Other potential applications of the orientator in anisotropic structures include the estimation of individual particle surface area with isotropic nucleators, the determination of the connectivity of branching networks with isotropic disectors, and generation of isotropic sections for second‐order stereology (three‐dimensional pattern analysis).

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

OBJECTIVES The purpose of this study was to evaluate left ventricular structure-function interplay in aortic valve disease. BACKGROUND An 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. METHODS Left 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. RESULTS Muscle 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. CONCLUSIONS In 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.

Determinants of survival in patients with congestive cardiomyopathy: quantitative morphologic findings and left ventricular hemodynamics.

We analyzed data from 68 consecutive patients with congestive cardiomyopathy to evaluate the prognostic significance of quantitative morphologic findings in left ventricular myocardium as compared with the prognostic significance of left ventricular hemodynamics. Left ventricular endomyocardial biopsy specimens were obtained from all patients during diagnostic heart catheterization. Myocardial fiber diameter, volume fraction of interstitial fibrosis, and intracellular volume fraction of myofibrils were determined by light-microscopic morphometry. All patients had normal coronary arteriograms, but reduced left ventricular ejection fractions. There were 23 deaths during a mean follow-up period of 1124 days. Multivariate regression analysis (Cox model) revealed that left ventricular ejection fraction (p less than .00001) and left ventricular systolic pressure (p less than .01), but not morphometric findings in biopsy specimens, were independent predictors of cardiac death. Thus, morphologic findings in the left ventricular myocardium do not contribute significantly to the prognostic evaluation in patients with congestive cardiomyopathy studied by hemodynamic and angiographic methods.

Cardiac Involvement in Churg-strauss Syndrome: Impact of Endomyocarditis

Cardiac disease is a major contributor to disease-related death in Churg-Strauss syndrome (CSS). We conducted the current study to determine the prevalence and clinical impact of cardiac involvement in CSS patients. We performed a multicenter, cross-sectional analysis of patients diagnosed with CSS. Cardiac workup included electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), and endomyocardial biopsy. We analyzed 49 patients with CSS: 22 patients had clinical evidence of cardiac involvement. A negative antineutrophil cytoplasmic antibodies (ANCA) test and much higher eosinophil counts (9947 vs. 3657/&mgr;L, respectively, p < 0.001) distinguished patients with cardiac involvement from those without. Impaired left ventricular function (50%), mild to severe valvular insufficiencies (73%), and pericardial effusions (41%) were common findings in these patients. Endomyocarditis was found in 13 patients (59%) as detected by cardiac MRI, cardiac thrombus formation, and endomyocardial biopsy, and was associated with impaired cardiac function. After a mean follow-up of 47 months, most patients had regained or maintained good cardiac function. However, patients with endomyocarditis had a more severe outcome. Two patients died (61 and 99 mo after diagnosis, respectively), both due to severe cardiomyopathy and heart failure. Cardiac involvement is common in patients with CSS and is associated with the absence of ANCA and high eosinophil counts. Endomyocarditis may represent the most severe manifestation eventually causing fatal outcome. A structured clinical assessment incorporating cardiac imaging with echocardiography and MRI can identify impaired cardiac function and endomyocardial abnormalities. Abbreviations: ANCA = antineutrophil cytoplasmic antibodies, CSS = Churg-Strauss syndrome, ECG = electrocardiography, FFS = Five Factor Score, IgE = immunoglobulin, LVEF = left ventricular ejection fraction, MRI = magnetic resonance imaging.

Blockade of Bradykinin B2 Receptors Prevents the Increase in Capillary Density Induced by Chronic Angiotensin-Converting Enzyme Inhibitor Treatment in Stroke-Prone Spontaneously Hypertensive Rats

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Quantitative morphologic findings of the myocardium in idiopathic dilated cardiomyopathy

This study assesses the relation between quantitative morphologic findings and left ventricular contractile function in patients with idiopathic dilated cardiomyopathy. Left ventricular endomyocardial catheter biopsy specimens were obtained from 73 patients during diagnostic heart catheterization. All patients had normal coronary arteriograms but abnormal electrocardiograms. Twenty-six patients had normal left ventricular function (ejection fraction greater than or equal to 55%), whereas 47 patients had contractile dysfunction (ejection fraction less than or equal to 54%). Myocardial fiber diameter, volume fraction of interstitial fibrosis, and intracellular volume fraction of myofibrils were determined by light microscopic morphometry. Results of light microscopic morphometry were confirmed by electron microscopic morphometry in 12 patients. The coefficient of variation (analysis of several biopsies from the same patient) was 6% for determination of fiber diameter, 43% for interstitial fibrosis, and 3% for volume fraction of myofibrils. Fiber diameter (r = -0.32, p less than 0.01) and fibrosis (r = -0.47, p less than 0.001) showed a negative correlation, the volume fraction of myofibrils (r = 0.55, p less than 0.001) and calculated myofibrillar mass per 100 g of myocardium (r = 0.64, p less than 0.001) a positive correlation with the ejection fraction. Thus, (1) sampling error is low for determination of fiber diameter and myofibrils but high for evaluation of fibrosis, and (2) a reduction in the volume fraction of myofibrils and an increase in fibrosis are morphologic correlates of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy.

Effect of early onset angiotensin converting enzyme inhibition on myocardial capillaries.

We investigated the preventive effects of long-term treatment with the angiotensin converting enzyme inhibitor ramipril on myocardial left ventricular hypertrophy and capillary length density in spontaneously hypertensive rats. Rats were treated in utero and subsequently up to 20 weeks of age with a high dose (1 mg/kg per day) or with a low dose (0.01 mg/kg per day) of ramipril. Animals given a high dose of ramipril remained normotensive, whereas those given a low dose developed hypertension in parallel to vehicle-treated controls. At the end of the treatment period, converting enzyme activity in heart tissue was inhibited dose-dependently in the treated groups. Both groups revealed an increase in myocardial capillary length density together with increased myocardial glycogen and reduced citric acid concentrations. Left ventricular mass was reduced only in high dose- but not in low dose-treated animals. Our results demonstrate that early onset treatment with a converting enzyme inhibitor can induce myocardial capillary proliferation, even at doses too low to antagonize the development of hypertension or left ventricular hypertrophy. We hypothesize that potentiation of kinins is responsible for this effect, probably by augmenting myocardial blood flow, which is a well-known trigger mechanism of angiogenesis in the heart.

Coronary dilatory capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients.

Hemodynamic function and overall coronary blood flow (argon technique) were measured in 16 patients with idiopathic dilated cardiomyopathy (IDC) and in 12 patients without detectable heart disease (control subjects) referred for precordial pain. In patients with IDC, coronary blood flow was normal at rest (78 +/- 17 ml/100 g-min versus 78 +/- 9 in control subjects). During maximal inducible coronary vasodilation (dipyridamole, 0.5 mg/kg), coronary blood flow was significantly reduced (142 +/- 38 ml/100 g.min versus 301 +/- 64 in control subjects; p less than 0.001). Consequently, obtainable minimal coronary resistance was increased in IDC (0.54 +/- 0.20 mm Hg/ml/100 g.min versus 0.23 +/- 0.04 in control subjects; p less than 0.001). In patients with IDC, left ventricular (LV) end-diastolic pressure was significantly increased (19 +/- 11 mm Hg versus 6 +/- 3 in control subjects; p less than 0.005), and the LV ejection fraction was diminished (36 +/- 11% versus 72 +/- 3% in control subjects; p less than 0.001). In patients with IDC, LV end-diastolic pressure correlated significantly with the obtained minimal coronary resistance after application of dipyridamole (r = 0.85; p less than 0.001). LV catheter biopsy specimens revealed no alterations in myocardial microvasculature. Thus, coronary dilatory capacity is impaired in patients with IDC, due partially to an increase in extravascular component of coronary resistance.