Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchyma characterized by a chronic inflammatory cellular infiltration and varying degrees of interstitial fibrosis. Current data indicate that the severity of fibrosis and the degree of cellularity determine, in part, the prognosis of IPF and the response to therapy. Whereas lung biopsy gives the best assessement of fibrosis and cellularity, physiologic studies are used to stage and monitor the disease process. To determine which physiologic studies correlate best with severity of fibrosis and degree of cellularity, these parameters were graded in lung biopsies of 23 patients with IPF and compared with a variety of physiologic studies. Although vital capacity, total lung capacity, and diffusing capacity are commonly used as objective monitors of the disease process, none of these parameters correlated with either the severity of fibrosis or the degree of cellularity in biopsy specimens. In contrast, almost all parameters of lung distensibility correlated with the morphologic assessment of degree of fibrosis; compliance had the best correlation. Parameters of distensibility, however, correlated poorly with the degree of cellularity. In comparison, gas exchange during exercise correlated with both morphologic parameters; the exercise-induced changes in arterial oxygen pressure per liter of oxygen consumed had a high correlation with the degree of fibrosis (r = 0.89; P less than 0.001) and correlated to a lesser extent with the degree of cellularity (r = 0.56; P = 0.009). In contrast, neither the resting arterial oxygen tension nor the arterial oxygen tension at maximal exercise correlated with the morphologic assessment of degree of fibrosis or the degree of cellularity. These morphologic-physiologic comparisons suggest that (a) lung volumes and diffusing capacity are poor monitors of both the degree of fibrosis and the degree of cellularity; (b) the fibrotic process contributes, at least in part, to parameters of lung distensibility, and both fibrosis and cellularity contribute to gas exchange alterations during exercise; and (c) parameters of lung distensibility and exercise-induced gas exchange alterations may be useful in staging the severity of disease in IPF.

Small airways in idiopathic pulmonary fibrosis. Comparison of morphologic and physiologic observations.

18 patients with idiopathic pulmonary fibrosis were studied to determine if they had morphologic evidence of small airways disease and if physiologic testing could predict morphologic findings. In the presence of normal airway function by standard physiologic studies (forced expiratory volume in 1 s/forced vital capacity and airway resistance by plethysmography), dynamic compliance, maximum expiratory flow-volume curves, and maximum flowstatic recoil curves were measured to detect physiologic alterations consistent with small airways abnormalities. These physiologic data were then compared with estimates of small airways diameter made in lung biopsy specimens.94% (17 of 18) of the patients had peribronchiolar fibrosis or peribronchiolar inflammation or bronchiolitis. 67% (12 of 18) had an overall estimate of small airways diameter of "narrowed," whereas 33% (6 of 18) had airways that overall were "not narrowed." 59% (10 of 17) had frequency-dependent dynamic compliance, 50% (9 of 18) had abnormal maximum expiratory flow-volume curves, and 39% (7 of 18) had abnormal maximum flow-static recoil curves. Comparisons between morphologic and physiologic data revealed a significant correlation between the results of dynamic compliance and the overall estimate of small airways diameter (P = 0.001), and the results of maximum flow-volume curves and the overall estimate of small airways diameter (P = 0.009); there was no significant correlation between the results of maximum flow-static recoil curves and the overall estimate of small airways diameter (P = 0.1). THE RESULTS OF THIS STUDY SUGGEST THAT: (a) idiopathic pulmonary fibrosis is a disease of small airways as well as alveoli; (b) dynamic compliance and the maximum expiratory flow-volume curve can predict the overall status of small airways diameter in idiopathic pulmonary fibrosis; and (c) whereas the maximum flowstatic recoil curve predicts the overall estimate of small airways diameter in most patients with this disease, it is the least sensitive of these three monitors of small airways.

Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

To evaluate cellular and protein components in the lower respiratory tract of patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP), limited broncho-alveolar lavage was done in 58 patients (19 IPF, 7 CHP, and 32 controls). Analysis of the cells and protein in the lavage fluids from patients with IPF revealed an inflammatory and eosinophilic response and a significant elevation of IgG in the lungs. With corticosteroid therapy, inflammation diminished but eosinophils remained. Lavage fluid from patients with CHP also had eosinophils and elevated levels of IgG. However, in contrast to IPF, lavage fluid from CHP patients contained IgM, fewer inflammatory cells, and a strikingly increased number (38-74%) of lymphocytes. Identification of lavage lymphocytes in CHP showed that T lymphocytes were significantly elevated and B lymphocytes were decreased compared to peripheral blood. These studies suggest nthat the lung in IPF and CHP may function as a relatively independent immune organ, and that analysis of cells and proteins in broncho-alveolar lavage fluid may be of diagnostic, therapeutic, and investigative value in evaluating patients with fibrotic lung disease.

Clinical, electrocardiographic and morphologic features of massive fatty deposits ("lipomatous hypertrophy") in the atrial septum.

OBJECTIVES: This study examined the morphologic features and the clinical significance of massive fatty deposits in the atrial septum of the heart. BACKGROUND: Large deposits of adipose tissue in the atrial septum were first described in 1964 and have been referred to as "lipomatous hypertrophy" of the atrial septum. A relation between these fatty deposits and atrial arrhythmias has been suggested. METHODS: The thickness of the atrial septum cephalad to the fossa ovalis ranged from 1.5 to 6 cm in 91 patients and was > or = 2 cm in 80 patients. This report focuses primarily on the latter 80 patients. RESULTS: The thickness of the atrial septum in the 80 patients correlated with body weight and the thickness of the adipose tissue in the atrioventricular groove and that covering the right ventricle. In 53 patients (67%), one or more of the four major epicardial coronary arteries were narrowed > 75% in cross-sectional area by atherosclerotic plaque. Atrial arrhythmias were present in 31 patients (40%). Patients with larger deposits of fat (atrial septal thickness > or = 3 cm) had a higher frequency of atrial arrhythmias (60% vs. 34%, p < 0.01). The atrial septum was significantly thicker in patients with atrial arrhythmia compared with those without atrial arrhythmias (2.9 vs. 2.3 cm, p < 0.01). Of the 28 patients with available electrocardiograms, 20 (71%) showed atrial arrhythmias (nine atrial premature complexes, seven atrial fibrillation, three atrial tachycardia, one ectopic atrial rhythm and one junctional rhythm). CONCLUSIONS: Massive fatty deposits in the atrial septum are associated with large deposits of fat elsewhere in the body and other parts of the heart. They are frequently associated with atrial arrhythmias and atherosclerotic coronary artery disease.

Dissection of the aorta associated with congenital malformation of the aortic valve.

The association of congenital aortic valve malformation and aortic dissection is analyzed. Over a 30 year period, 186 patients with non-iatrogenic aortic dissection were studied at necropsy. The aortic valve was tricuspid in 170 (91.4%), bicuspid in 14 (7.5%) and unicuspid in 2 (1.1%). Among the 16 patients with aortic dissection and a congenitally malformed valve, the age at death ranged from 17 to 82 years (mean 52) and 13 (81%) were men. The entrance tear of the aortic dissection was located in the ascending aorta in all 16 patients with a malformed valve but in only 68% of those with a tricuspid aortic valve. The aortic valve was stenotic in 6 of the 16 patients with a congenitally malformed valve. Fatal rupture of the false channel occurred after acute ascending aortic dissection in each of the 11 patients (none with healed dissection) who did not have operative therapy for the dissection. Two of the 16 patients with a malformed valve compared with no patient with a tricuspid aortic valve had aortic isthmic coarctation. Histologic sections of aorta from 10 patients disclosed severe degeneration of the elastic fibers of the media in 9 patients. Thus, a congenitally malformed aortic valve appears to be present at least 5 times more frequently in adults with than in those without aortic dissection, and in our patients the entrance tear was always in the ascending aorta, which usually had severe loss of elastic fibers in its media.

Morphologic comparison of patients with mitral valve prolapse who died suddenly with patients who died from severe valvular dysfunction or other conditions.

Clinical and necropsy findings are described in 56 patients with mitral valve prolapse: 15 patients, aged 16 to 69 years (mean 39), died suddenly and mitral valve prolapse was the only cardiac condition found at necropsy (hereafter called isolated mitral valve prolapse); the remaining 41 patients had other conditions that were capable of being fatal. Of the latter 41 patients, 7, aged 17 to 59 years (mean 45), had associated congenital heart disease, and 34 patients, aged 17 to 70 years (mean 52), had no associated congenital cardiac abnormalities. Compared with the 34 patients without associated congenital heart disease and with nonmitral valve prolapse conditions capable in themselves of being fatal, the 15 patients who died suddenly with isolated mitral valve prolapse were younger (mean age 39 +/- 17 versus 52 +/- 15 years; p = 0.01), more often women (67% versus 26%; p = 0.008) and had a lower frequency of mitral regurgitation (7% versus 38%; p = 0.02). The 15 patients dying suddenly with isolated mitral valve prolapse also were less likely to have evidence of ruptured chordae tendineae (29% versus 67%; p = 0.04). The frequency of increased heart weight (67% versus 59%), a dilated mitral valve anulus (80% versus 81%), a dilated tricuspid valve anulus (17% versus 17%), an elongated anterior mitral leaflet (86% versus 54%), an elongated posterior mitral leaflet (79% versus 77%) and fibrous endocardial plaque under the posterior mitral leaflet (73% versus 63%) was similar between the two groups. The severity of the prolapse (mild 20% versus 11%; moderate 27% versus 58%; severe 53% versus 32%) also was similar between the two groups. Thus, persons with mitral valve prolapse dying suddenly without another recognized condition tend to be relatively young women without mitral regurgitation.

Rupture of a left ventricular papillary muscle during acute myocardial infarction: analysis of 22 necropsy patients.

Certain clinical and cardiac morphologic findings are described in 22 patients, aged 45 to 80 years (mean 64) (15 men [68%]), in whom rupture of a papillary muscle occurred during acute myocardial infarction. In most, the acute infarction associated with papillary muscle rupture was a first coronary event (only 18% had a myocardial scar consistent with prior infarction and 29% had angina pectoris). The posteromedial papillary muscle, presumably because of its more tenuous blood supply, ruptured almost three times more frequently than the anterolateral one (73 and 27%, respectively). Quantitative examination of the amounts of narrowing by atherosclerotic plaque in each of the four major epicardial coronary arteries (right, left main, left anterior descending and left circumflex) disclosed less narrowing in the patients with rupture than in the patients with fatal acute myocardial infarction unassociated with rupture. Of the 519 five mm sections of coronary artery examined (11 patients), only 68 sections (13%) were narrowed greater than 75% in cross-sectional area compared with 34% of 1,403 sections from 27 patients with fatal myocardial infarction without rupture.

Left main coronary artery originating from the right sinus of Valsalva and coursing between the aorta and pulmonary trunk.

Findings are described in five patients who at necropsy were found to have origin of the left main coronary artery from the right sinus of Valsalva and coursing of the anomalously arising artery between aorta and pulmonary trunk to reach the left side of the heart. Three of the five patients were boys and died suddenly at ages 13, 14 and 19 years, respectively: two of them had had one or more episodes of syncope and the third had an abnormal electrocardiogram. The fourth patient, a 64 year old woman, died of chronic congestive heart failure 1 year after an acute myocardial infarction. She had insignificant coronary atherosclerosis. The fifth patient, an 81 year old man, died of chronic alcoholism, having been free of symptoms of cardiac dysfunction during life. Additionally, clinical and necropsy findings are summarized in 38 previously reported necropsy patients with the coronary anomaly. Of these 38 (34 male [89%]), 23 (61%) died suddenly in the first two decades of life; death in 6 others (16%) appears to have been related to coronary atherosclerosis and 9 patients (24%) died from noncoronary causes. Thus, this anomaly is life-threatening. Why it frequently causes fatal cardiac arrest in some young individuals and allows a normal life span in others remains unclear.

Tetralogy of Fallot, truncus arteriosus, abnormal myocardial architecture and anomalies of the aortic arch system induced by bis-diamine in rat fetuses.

OBJECTIVES: The aim of this study was to analyze the relation between anomalies of the heart and aortic arch arteries in near-term rat fetuses exposed to the chemical bis-diamine. BACKGROUND: Bis-diamine is known to induce cardiovascular anomalies. METHODS: Bis-diamine was given orally to normal pregnant rats, and the 65 fetuses were examined under a dissecting microscope after formalin fixation. RESULTS: There were 26 rat fetuses (40%) with a ventricular septal defect in the perimembranous portion, of which 14 (22%) had tetralogy of Fallot, 4 (6%) had truncus arteriosus and 8 (12%) had a relatively small defect with no other major anomalies. In 44 fetuses (68%) the middle latitudinal muscle bundle of the ventricular septum was continuous with the right ventricular free wall. There were, isolated or in association, a double- or right aortic arch in 6 fetuses (9%), aberrant subclavian arteries in 9 (14%), right ductus arteriosus in 12 (18%) and agenetic ductus in 4 (6%). The cross-sectional area of the ductus, as corrected by that of the aortic isthmus, was abnormally small in 47 rats (72%). The rat fetuses with a septal defect or abnormal myocardial architecture, or both, usually had a small ductus; it was very small or absent in those fetuses with tetralogy of Fallot. Of the four fetuses with truncus arteriosus, two had a vestigial vasculature on the truncus root and three had a rudimentary infundibulum. CONCLUSIONS: The cardinal defect may be the anomalous and reduced development of the sixth arch arteries, which by imposing pressure overload on the fetal right ventricle, may have led to either or both the persistence of ventricular septal defect as a vent or the formation of myocardial architecture favorable for the generation of pressure in the right ventricle.

Solitary coronary ostium in the aorta in the absence of other major congenital cardiovascular anomalies.

OBJECTIVES: This study examines the distribution patterns and the clinical significance of the "solitary coronary ostium" in the aorta in the absence of other major congenital cardiovascular anomalies. BACKGROUND: Ogden in 1970 classified "single coronary artery" into 14 basic distribution patterns. Since then, other patterns of distribution of single coronary artery have been recognized. Distinction has also been made between the cases with and without other major congenital cardiovascular anomalies or coronary artery atresia and those without these additional abnormalities. Single coronary artery has been generally considered to be a benign clinical entity. METHODS: This study describes 10 cases of single coronary artery at necropsy and reviews 87 previously reported cases, 35 diagnosed at necropsy and 52 by coronary angiography. RESULTS: We classified single coronary artery into 20 categories on the basis of the location of the solitary coronary ostium, the presence or absence of an aberrant-coursing coronary artery and the course taken by the aberrant-coursing coronary artery. When atherosclerotic coronary artery disease was absent, 15% (8 of 53) of the patients reviewed with single coronary artery had myocardial ischemia as a direct consequence of the coronary anomaly. CONCLUSIONS: The anatomic classification presented is useful from both clinical and surgical viewpoints. This comprehensive classification of this rare anomaly facilitates description of the various distribution patterns of single coronary artery and their clinical significance.

Morphologic features of fossa ovalis membrane aneurysm in the adult and its clinical significance.

OBJECTIVES: This study evaluated morphologic features of fossa ovalis membrane aneurysm and associated cardiac abnormalities that may predispose to systemic embolism. BACKGROUND: An increasing number of fossa ovalis membrane aneurysms are diagnosed by echocardiography. Higher frequencies of such aneurysms have been reported in patients with embolic stroke. METHODS: The hearts of 20 adults with fossa ovalis membrane aneurysms (mean [ +/- SD] age 62 +/- 19 years, range 24 to 87; 12 women [60%], 8 men [40%]) were examined. The areas of excised atrial septum, fossa ovalis membrane and fossa ovalis were measured. An aneurysm was defined as the ratio of the fossa ovalis membrane to fossa ovalis area > or = 1.5. RESULTS: Compared with a control group of 20 adults (mean age 58 +/- 21 years, range 18 to 86; 12 women [60%], 8 men [40%]), the 20 patients with fossa ovalis membrane aneurysm had larger (711 +/- 240 vs. 203 +/- 105 mm2, p < 0.0001) and thinner fossa ovalis membranes (0.6 +/- 0.1 vs. 1.9 +/- 0.9 mm2, p < 0.0001). The mean ratio of the fossa ovalis membrane to fossa ovalis area was 2.1 +/- 0.4 in patients with and 1.2 +/- 0.1 in those without fossa ovalis membrane aneurysm. Patent foramen ovale was seen in 14 (70%) of 20 patients with fossa ovalis membrane aneurysm and in 4 (20%) of 20 control subjects (p = 0.0005). CONCLUSIONS: Fossa ovalis membrane aneurysm is characterized by thinning and marked redundancy without adherent thrombi or fibrin tags. Mitral valve prolapse, dilated atria, intracardiac thrombi and patent foramen ovale are frequently seen in association with fossa ovalis membrane aneurysm and may explain the increased frequency of embolic stroke in patients with such aneurysms.

Morphologic comparison of frequency and types of acute lesions in the major epicardial coronary arteries in unstable angina pectoris, sudden coronary death and acute myocardial infarction.

The frequency and type of acute lesions in the four major (right, left main, left anterior descending, left circumflex) epicardial coronary arteries were examined at necropsy in 14 patients with unstable angina pectoris, 21 patients with sudden coronary death and 32 patients with a fatal first acute myocardial infarction. None of the 67 patients had a grossly visible left ventricular scar (healed myocardial infarct) and only the group with acute myocardial infarction had left ventricular myocardial necrosis. Although the frequency of intraluminal thrombus was similar in patients with unstable angina (29%) and sudden death (29%) and significantly lower than in those with acute infarction (69%) (p = 0.02), the thrombus in the patients with unstable angina and sudden death consisted almost entirely of platelets and was nonocclusive, whereas the thrombus in the group with acute infarction consisted almost entirely of fibrin and was occlusive. The frequency of plaque rupture was insignificantly different in the groups with unstable angina (36%) and sudden death (19%), and was significantly lower than in the group with acute infarction (75%) (p = 0.02). The frequency of plaque hemorrhage was insignificantly different in the groups with unstable angina (64%) and sudden death (38%) and was significantly lower than in the group with acute infarction (90%) (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Causes of sudden death in competitive athletes.

Cardiovascular diseases responsible for sudden unexpected death in highly conditioned athletes are largely related to the age of the patient. In most young competitive athletes (less than 35 years of age) sudden death is due to congenital cardiovascular disease. Hypertrophic cardiomyopathy appears to be the most common cause of such deaths, accounting for about half of the sudden deaths in young athletes. Other cardiovascular abnormalities that appear to be less frequent but important causes of sudden death in young athletes include congenital coronary artery anomalies, ruptured aorta (due to cystic medial necrosis), idiopathic left ventricular hypertrophy and coronary artery atherosclerosis. Diseases that appear to be very uncommon causes of sudden death include myocarditis, mitral valve prolapse, aortic valve stenosis and sarcoidosis. Cardiovascular disease in young athletes is usually unsuspected during life, and most athletes who die suddenly have experienced no cardiac symptoms. In only about 25% of those competitive athletes who die suddenly is underlying cardiovascular disease detected or suspected before participation and rarely is the correct clinical diagnosis made. In contrast, in older athletes (greater than or equal to 35 years of age) sudden death is usually due to coronary artery disease, and rarely results from congenital heart disease.

Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy.

Many patients with hypertrophic cardiomyopathy have signs and symptoms of myocardial ischemia and dysfunction. Although hypertrophy and increased left ventricular pressure can account for such abnormalities, altered small intramural coronary arteries have also been described in such patients. To determine the prevalence and extent as well as the clinical relevance of abnormal intramural coronary arteries, a histologic analysis of left ventricular myocardium obtained at necropsy was performed in 48 patients with hypertrophic cardiomyopathy (but without atherosclerosis of the extramural coronary arteries) and in 68 control patients with either a normal heart or acquired heart disease. In hypertrophic cardiomyopathy, abnormal intramural coronary arteries were characterized by thickening of the vessel wall and a decrease in luminal size. The wall thickening was due to proliferation of medial or intimal components, or both, particularly smooth muscle cells and collagen. Of the 48 patients with hypertrophic cardiomyopathy, 40 (83%) had abnormalities of intramural coronary arteries located in the ventricular septum (33 patients), anterior left ventricular free wall (20 patients) or posterior free wall (9 patients); an average of 3.0 +/- 0.7 abnormal arteries were identified per tissue section. Altered intramural coronary arteries were also significantly more common in tissue sections having considerable myocardial fibrosis (31 [74%] of 42) than in those with no or mild fibrosis (31 [30%] of 102; p less than 0.001). Abnormal intramural coronary arteries were also identified in three of eight infants who died of hypertrophic cardiomyopathy before 1 year of age. In contrast, only rare altered intramural coronary arteries were identified in 6 (9%) of the 68 control patients (0.1 +/- 0.05 abnormal arteries per section; p less than 0.001) and those arteries showed only mild thickening of the wall and minimal luminal narrowing. Moreover, of those patients with abnormal intramural coronary arteries, such vessels were about 20 times more frequent in patients with hypertrophic cardiomyopathy (0.9 +/- 0.2/cm2 myocardium) than in control patients (0.04 +/- 0.02/cm2 myocardium). Hence, abnormal intramural coronary arteries with markedly thickened walls and narrowed lumens are present in increased numbers in most patients with hypertrophic cardiomyopathy studied at necropsy and may represent a congenital component of the underlying cardiomyopathic process.(ABSTRACT TRUNCATED AT 400 WORDS)

Coexistence of sudden cardiac death and end-stage heart failure in familial hypertrophic cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine the occurrence of sudden cardiac death or end-stage heart failure, two phases of the natural history of hypertrophic cardiomyopathy, in closely related relatives. BACKGROUND: Hypertrophic cardiomyopathy is a genetically transmitted cardiac disease with a particularly diverse clinical and morphologic spectrum. Premature death usually occurs either suddenly or as a result of progressive congestive heart failure. METHODS: We describe seven families with genetically transmitted hypertrophic cardiomyopathy that were studied with echocardiography or necropsy, or both, and were selected because they were known to include relatives who had incurred either premature sudden cardiac death or the end-stage phase of the disease. RESULTS: The seven families comprised 128 relatives; 26 died suddenly, and 9 developed end-stage heart failure (including 2 with heart transplantation) associated with left ventricular cavity enlargement, wall thinning or decreased contractility, alone or in combination, as well as loss of outflow obstruction. Patients who died suddenly did so at younger ages (23 +/- 10 years) than did patients who died or required heart transplantation in the end-stage phase of hypertrophic cardiomyopathy (42 +/- 8 years, p < 0.001). CONCLUSIONS: This study demonstrates that family members with hypertrophic cardiomyopathy, despite a common genetic substrate, may exhibit markedly diverse and distinct expressions of the natural history of their disease, which occur at widely separated periods of life.

Comparison in women versus men of composition of atherosclerotic plaques in native coronary arteries and in saphenous veins used as aortocoronary conduits.

OBJECTIVES: This study quantifies and compares the components of atherosclerotic plaques in native coronary arteries and in saphenous vein grafts used for aortocoronary bypass surgery in women versus those in men. BACKGROUND: Plaque composition has been described in various manifestations of fatal coronary artery disease and after the bypass operation, but no reports have investigated this composition according to gender. METHODS: A total of 979 5-mm segments of native coronary arteries and 842 5-mm segments of saphenous vein grafts were examined by computerized planimetric technique in 11 women and 11 men who were matched for survival time after the bypass operation. RESULTS: Comparison of the plaque components revealed that atherosclerotic plaques in women, compared with those in men, contained significantly more cellular fibrous tissue, both in native coronary arteries (mean 38% vs. 4%, p < 0.001) and in saphenous vein grafts (mean 70% vs. 36%, p < 0.05). In contrast, the proportion of dense fibrous tissue was significantly less in the atherosclerotic plaques of women than in those of men, both in native coronary arteries (mean 50% vs. 85%, p < 0.001) and in saphenous vein grafts (mean 25% vs. 57%, p < 0.05). CONCLUSIONS: Cellular fibrous tissue is often found at an early stage of plaque development, whereas dense fibrous tissue is a major component in later stages. Thus, the plaque composition of the native coronary arteries and saphenous venous conduits differed in men and women, with the plaques of the women appearing younger than those of the men.

Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a diverse clinical spectrum, in which many of the abnormal structural and pathophysiologic features are consequences of inappropriate left ventricular hypertrophy. METHODS: We analyzed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly. The morphologic appearance and volume fractions of interstitial (matrix) and perivascular (adventitial) collagen were analyzed with polarization microscopy and computerized videodensitometry in picrosirius red-stained sections. Findings were compared with 16 structurally normal hearts, 5 with systemic hypertension and 6 infants who died of HCM. RESULTS: Adults and young children with HCM had an eightfold greater amount of matrix collagen compared with normal controls (14.1 +/- 8.8% vs. 1.8 +/- 1% of the tissue section; p < 0.0001), and a threefold increase compared with patients with systemic hypertension (4.5 +/- 1.3%; p < 0.001) and infants with HCM (4.0 +/- 2.4%; p < 0.001). Compared with normal controls and hypertensives, adults and young children (and infants) with HCM showed increased numbers and thickness of each collagen fiber component of the matrix (perimysial coils, pericellular weaves and struts), which were often arranged in disorganized patterns. In HCM patients, the amount of collagen was not a consequence of other clinical, demographic and morphologic disease variables. CONCLUSIONS: Left ventricular collagen matrix in young, previously asymptomatic patients with HCM who died suddenly is morphologically abnormal and substantially increased in size. The enlarged matrix collagen compartment is present in HCM at an early age, further expands during growth, is partially responsible for increased ventricular septal thickness and likely represents a primary morphologic abnormality in this disease. These findings support the view that the complex HCM disease process is not confined to sarcomere protein abnormalities, but also involves connective tissue elements.

Mode of death, frequency of healed and acute myocardial infarction, number of major epicardial coronary arteries severely narrowed by atherosclerotic plaque, and heart weight in fatal atherosclerotic coronary artery disease: analysis of 889 patients studied at necropsy.

Mode of death, frequency of a healed or an acute myocardial infarct, or both, number of major epicardial coronary arteries severely narrowed by atherosclerotic plaque, and heart weight were studied at necropsy in 889 patients 30 years of age or older with fatal atherosclerotic coronary artery disease. No patient had had a coronary bypass operation or coronary angioplasty. The 889 patients were classified into four major groups and each major group was classified into two subgroups: 1) acute myocardial infarct without (306 patients) or with (119 patients) a healed myocardial infarct; 2) sudden out of hospital death without (121 patients) or with (118 patients) a healed myocardial infarct; 3) chronic congestive heart failure with a healed myocardial infarct without (137 patients) or with (33 patients) a left ventricular aneurysm; and 4) sudden in-hospital death without (20 patients) or with (35 patients) unstable angina pectoris. The mean age of the 687 men (77%) was 60 +/- 11 years, and of the 202 women (23%), 68 +/- 13 years (p = 0.0001). Although men included 77% of all patients, they made up approximately 90% of the out of hospital (nonangina) sudden death group. The frequency of systemic hypertension and angina pectoris was similar in each of the four major groups. The frequency of diabetes mellitus was least in the sudden out of hospital death group and similar in the other three major groups. The mean heart weight and the percent of patients with a heart of increased weight were highest in the chronic congestive heart failure group; values were lower and similar in the other three major groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe mitral or aortic valve regurgitation, or both, requiring valve replacement for infective endocarditis complicating hypertrophic cardiomyopathy.

Certain clinical and morphologic findings are described in 11 patients with hypertrophic cardiomyopathy complicated by infective endocarditis that produced severe mitral or aortic valve regurgitation, or both, necessitating valve replacement. All 11 patients had changes in the operatively excised valve or valves characteristic of healed infective endocarditis. The infection involved only the mitral valve in seven patients, only the aortic valve in three patients and both valves in one patient. Study of the operatively excised mitral valves indicated that the healed vegetations were located most commonly on the left ventricular aspects of the anterior mitral leaflet, indicating that vegetation had formed at contact points of this leaflet with mural endocardium of the left ventricular outflow tract. In all 11 patients, the infective endocarditis either worsened preexisting valve regurgitation or initiated valve regurgitation and led to worsened signs and symptoms of cardiac dysfunction, necessitating valve replacement. Functional class improved in the nine patients who survived 7 to 101 months after valve replacement. Hypertrophic cardiomyopathy appears to be a factor predisposing to infective endocarditis. Patients with hypertrophic cardiomyopathy should receive prophylactic antibiotic therapy during procedures that predispose to infective endocarditis.

Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy.

OBJECTIVES: The present study examined whether sudden death in patients with hypertrophic cardiomyopathy occurred with a particular pattern of frequency throughout the day. BACKGROUND: Previous investigators have shown a circadian distribution in the occurrence of sudden death and other cardiovascular events in patients with atherosclerotic coronary artery disease. Sudden death is also an important feature of the natural history of patients with hypertrophic cardiomyopathy. METHODS: The study group comprised 94 patients with a time of death (or cardiac arrest) that could be ascertained accurately to the nearest hour. This hourly distribution was analyzed by harmonic regression. RESULTS: Sudden death did not occur uniformly or randomly throughout the day. Rather, it was distributed in a bimodal pattern that conformed to a two-harmonic regression model. A disproportionate number of sudden deaths (43 [46%] of 94) occurred in the first peak in midmorning between 7 AM and 1 PM. The second peak of sudden death was less distinct but was in the early evening, between 8 PM and 10 PM. This periodicity in occurrence of sudden cardiac death was not evident for the days of the week or months of the year and, furthermore, did not appear to be influenced by other clinical variables, such as age, gender, severity of symptoms, subaortic gradient or left ventricular wall thickness. Sudden death occurred most commonly during periods of severe exertion (37 [39%] of 94). CONCLUSIONS: Sudden death in hypertrophic cardiomyopathy demonstrates a bimodal pattern of circadian variability over the 24-h day, with a prominent midmorning peak similar to that described in patients with coronary artery disease, and a less striking early-evening peak of occurrence. These findings suggest that temporally related physiologic changes, possibly in the electrical vulnerability of the myocardial substrate, may play a role in the sudden death of patients with hypertrophic cardiomyopathy.