5-hydroxytryptamine: a cytospecific growth stimulator of cultured fibroblasts.

5-Hydroxytryptamine (serotonin) in micromolar amounts increased the growth of fibroblasts in culture while not affecting five other cell lines. Serotonin appeared to shorten the lag phase of cell growth. The effect was less when serotonin was added to the fibroblast culture after the initial 24-hour period. The two functional groups of the serotonin molecule were required for growth enhancement. Serotonin in millimolar concentrations was toxic to fibroblasts.

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Experimental diabetes mellitus and age-simulated changes in intact rat dermal collagen.

Alterations in the physical properties of dermal collagen by streptozotocin-induced diabetes mellitus were investigated in young adult Lewis rats by mounting standardized rings of tail skin on an Instron Universal Testing Apparatus and measuring the thermally induced isometric contraction and stress at rupture of the tissue. Diabetes significantly increased the maximum tension (Tmax) of the contraction and raised the temperature for the Tmax while the stress at rupture (TR) was unaffected when compared with values for controls fed ad libitum and controls fed restricted diets for weight loss equivalence. The diabetes-mediated changes in thermal contractility appeared to be independent of the collagen concentration or negative caloric balance and resembled the reported age-related change in rat skin collagen.

Effects of methoxamine and phenylephrine on left ventricular contractility in rabbits.

The end-systolic pressure-volume relation is employed to evaluate left ventricular contractility. In clinical studies, pharmacologic vasoconstriction is used to increase left ventricular systolic pressure to assess pressure-volume relations. However, the effect of vasoconstrictors on the ventricular contractile state is not well characterized. The effects of methoxamine and phenylephrine on systemic arterial pressure and left ventricular contractility in rabbits were studied with three protocols. In protocol 1, anesthetized rabbits (n = 10) were injected with incremental doses of methoxamine and phenylephrine intravenously. Methoxamine (4 mg) increased the mean arterial pressure by 50 +/- 12% (mean +/- SE) (n = 5, p = 0.001). Phenylephrine (0.2 mg) increased mean arterial pressure by 82 +/- 14% (n = 5, p = 0.004). In protocol 2, isolated blood-perfused hearts were injected with incremental doses of these drugs in the ascending aorta in amounts approximately equal to the concentrations injected in the intact rabbits. Methoxamine (2 mg) reduced isovolumic peak systolic left ventricular pressure by 43 +/- 9% (n = 7, p = 0.003), whereas phenylephrine (0.1 mg) increased the isovolumic pressure by 24 +/- 9% (n = 7, p less than 0.05). These responses indicated an enhanced contractile state with phenylephrine and a reduced contractile state with methoxamine. Pretreatment with propranolol blunted the effect of phenylephrine on isovolumic pressure (n = 6, p less than 0.02). In protocol 3, cross-circulation experiments allowed study of the effect of these drugs on isovolumic left ventricular pressure in the isolated heart and simultaneously on the systemic arterial pressure in the intact anesthetized rabbit (support rabbit).(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic estimation of critical left ventricular size in infants with isolated aortic valve stenosis.

With the current trend to performing surgical valvotomy for infantile aortic stenosis without cardiac catheterization, there is a need to develop echocardiographic criteria for adequacy of left ventricular size. The echocardiograms and catheterization data of all 25 infants less than 3 months of age undergoing aortic valvotomy for isolated aortic valve stenosis from September 1980 through July 1990 were reviewed. Significant differences (p less than 0.05) between the survivors and nonsurvivors were noted for age at operation (30 +/- 28 vs. 3 +/- 1.5 days), mitral valve diameter (10.1 +/- 1.7 vs. 7.7 +/- 1.5 mm), left ventricular end-diastolic dimension (18.4 +/- 6.4 vs. 11.4 +/- 3 mm), left atrial dimensions (15.3 +/- 3.8 vs. 10 +/- 2.4 mm), left ventricular cross-sectional area on the parasternal long-axis echocardiogram (4 +/- 1.9 vs. 2 +/- 1.9 cm2) and angiographically determined left ventricular end-diastolic volume (43 +/- 23 vs. 11 +/- 5 ml/m2). There was no difference with respect to patient weight, body surface area, aortic root dimension or left ventricular ejection fraction. Left ventricular cross-sectional area less than 2 cm2 as measured on the parasternal long-axis echocardiogram was found in 5 of 7 nonsurvivors and 0 of 12 survivors, making this a risk factor for perioperative death (p less than 0.05). Left ventricular end-diastolic dimension less than 13 mm was found in 5 of 6 nonsurvivors and 2 of 17 survivors, making this another risk factor for early mortality (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of left ventricular volume loading in infants with coarctation of the aorta and a large ventricular septal defect.

Clinical characteristics and angiographic ventricular volume data were obtained in 25 infants aged 1 to 66 days who presented with coarctation of the aorta, ventricular septal defect and congestive heart failure to determine if left ventricular volume loading was present and if there were hemodynamic or volumetric variables that were predictive of operative mortality in this group. Pulmonary to systemic flow ratio averaged 2.8 +/- 0.8 and right ventricular/left ventricular peak pressure ratio was 0.96 +/- 0.12. Left ventricular end-diastolic volume averaged 116 +/- 49% of normal and was less than the investigators' lower limit of normal in 5 (20%) of 25 patients. In contrast, right ventricular end-diastolic volume, measured in eight patients, averaged 173 +/- 47% of normal and was greater than the investigators' upper limit of normal in seven (88%) of eight. Left ventricular ejection fraction averaged 0.47 +/- 0.17 and was below normal (less than 0.55) in 14 (58%) of 24 patients. Preoperative volume and ejection fraction data did not differ in infants with coarctation plus ventricular septal defect and a similar group of 19 infants with isolated coarctation. Abnormal left ventricular operative volume distensibility was inferred by normal or decreased left ventricular end-diastolic volume and increased left ventricular end-diastolic pressure (greater than 12 mm Hg) in 12 (55%) of 24 patients. Early plus late mortality was related to left ventricular size: 3 of 5 patients with a small left ventricular end-diastolic volume died, compared with only 4 of 20 with a normal or increased volume (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: a multicenter study.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) commonly undergo cardiac transplantation as primary management. METHODS: We examined outcomes of primary transplantation for unpalliated HLHS. We analyzed data from the 20 institutions of the Pediatric Heart Transplant Study Group, from January 1, 1993, through December 31, 1998, using actuarial and parametric survival analysis and competing outcomes analysis. RESULTS: During the 6 years studied, 1,234 patients were listed for cardiac transplantation; 262 patients (21.2%) had unpalliated HLHS. The number (and percentage) of patients with HLHS decreased from 58 (27% of patients listed) in 1993 to 30 (14%) in 1998. Overall, 25% of infants with HLHS died while waiting; primary cause of death was cardiac failure (50%). Of the remaining patients awaiting transplantation, 23 (9%) underwent Norwood/Fontan-type surgeries as interim palliation: 52% died. Ultimately, 175 patients underwent cardiac transplantation (67%); 50% received organs by 2 months after listing. Post-transplant actuarial survival was 72% at 5 years, with 76% of deaths (35/46) occurring within 3 months; early mortality was caused primarily by graft failure within the first 30 days after transplantation (in 54%). Among 1-month survivors, survival at 1 and at 5 years was 92% and 85%, respectively. Of the 262 patients listed with unpalliated HLHS, overall survival, taking into account mortality after listing and after transplantation, was 68% at 3 months and 54% at 5 years. CONCLUSIONS: Cardiac transplantation offers good intermediate survival for infants with unpalliated HLHS.

The B-aminopropionitrile-fed turkey: a model for detecting potential drug action on arterial tissue.

Broad-breasted white male turkeys develop hypertension, tachycardia and aortic arteriosclerosis spontaneously by approximately 5 weeks of age. When fed B-aminopropionitrile (BAPN), aortic tensile strengths are lowered, and a high percentage of the turkeys die from aortic dissecting aneurysms. There are essentially no deaths from aneurysms when either dl-propranolol or reserpine is fed in concert with BAPN; practolol and soltalol partially protect the BAPN-fed turkey from lethal aneurysms while hydralazine and phenelzine sulphate potentiate mortality from aneurysms. Dl-propranolol decreases and reserpine increases dP/dtmax and both drugs lower arterial pressure and heart rate when fed with BAPN. Such diets also decrease the ultrastructural disarray of collagenous and elastic fibres in the media of the abdominal aorta that occurs from the feeding of BAPN and thereby raise aortic tensile strength. Sotalol and practolol when fed to BAPN-fed turkeys lower blood pressure and dP/dtmax, but neither drug affects aortic tensile strength and both counteract the deleterious effect of BAPN on the ultrastructure of collagenous and elastic fibres to a minor degree. Phenelzine sulphate does not affect arterial pressure while hydralazine reduces arterial pressure; both drugs decrease aortic tensile strength and increase the ultrastructural disruption of aortic elastin and collagen in the BAPN turkey. The results suggest that dl-propranolol, reserpine, phenelzine sulphate, and hydralazine have an action on aortic tissue and indicate the usefulness of the BAPN-fed turkey as a model for identifying potential drug effects on aortic elastin and collagen.

Anatomical arrangement of muscle tissue in the anterior mitral leaflet in man.

Muscle tissue in atrioventricular (A-V) cardiac valve leaflets was studied in 35 human hearts and was found to be more prominent in the anterior leaflet of the mitral (MAL) than in the other valve leaflets. From serial sectioning and wax model reconstruction, the anatomic arrangement of the muscle in the MAL indicates bundles passing from the two commissural regions towards the mid-zone of the valve. Age did not appear to reduce the mass of muscle tissue in the MAL. The possibility of muscle contraction in the MAL increasing leaflet tension and accelerating post-artial movements received support by comparisons of the anterior and posterior leaflets of the mitral valve in their movements towards closure.

Operative repair of coarctation of the aorta in infancy: results with and without ventricular septal defect.

Coarctation of the aorta (CA) presenting in infancy is a life-threatening condition, especially if associated with intracardiac left-to-right shunts. Between 1971 and 1980, 51 infants with symptomatic CA have been diagnosed and treated. Ventricular septal defect (VSD) was present in 18 patients and patent ductus arteriosus in 24. End-to-end repair was performed in 20 patients, 17 (85%) of whom were long-term survivors. Subclavian flap angioplasty repair was used in 28 patients, of whom 25 (89%) were long-term survivors. During long-term follow-up 6 patients (35%) who underwent end-to-end repair had recurrent CA, whereas only 3 patients (12%) who underwent subclavian flap angioplasty had recurrent CA (p less than 0.05). The mortality rate in patients with associated VSD was higher (4 of 18, 22%). Pulmonary trunk banding with subsequent VSD repair was associated with a better survival (13 of 14 patients, 90%) than when banding was not performed (2 of 5 patients) (p less than 0.05). These results suggest subclavian flap angioplasty is the preferred treatment for symptomatic CA occurring in infancy. Concomitant pulmonary trunk banding in patients with VSD can be performed with the expectation of a lower mortality at subsequent VSD repair.

Altered early left ventricular diastolic cardiac function in the premature infant.

Developmental changes in diastolic ventricular function were assessed in 31 premature infants and in 10 normal-term infants. They were studied during the first 72 hours of life using instantaneous rates of change of left ventricular (LV) cavity dimension, derived from M-mode echocardiography. Maximal velocity of lengthening of the LV cavity was significantly lower in premature infants (38 +/- 7 mm/s) than in term infants (88 +/- 15 mm/s). This variable increased with increasing maturity over the 4 gestational age groups evaluated (r = 0.87). This index normalized for instantaneous LV dimension was lower in the most immature infants (4.5 +/- 1 s-1) than in term infants (6.8 +/- 2 s-1). Eight of the premature infants were studied serially at 1, 3 and 7 days of age. Maximal velocity of lengthening divided by stroke dimension improved from 12.9 +/- 2 s-1 at 1 day of age to 16.5 +/- 3 s-1 at 7 days. These results suggest depressed early diastolic function in premature infants.

Left ventricular function in cyanotic congenital heart disease.

Left ventricular function was studied with quantitative biplane cineangiocardiography in 39 preoperative and 23 postoperative patients with cyanotic congenital heart disease. Diagnoses included pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (group 1), tricuspid atresia (group 2) and pulmonary atresia with ventricular septal defect (group 3). Preoperative patients ranged in age from 1 day to 7 years and postoperative patients from 7 weeks to 23 years. Left ventricular end-diastolic volume was increased in preoperative patients in groups 1 and 2 (132 and 136 percent of normal, respectively) but was normal in patients in group 3. Left ventricular ejection fraction was decreased to a similar extent in preoperative groups 1 to 3: 0.54, 0.55 and 0.56, respectively. After a shunt procedure left ventricular end-diastolic volume increased to 228 and 266 percent of normal in groups 1 and 2, respectively, but remained within normal limits in group 3. Left ventricular ejection fraction was normal in postoperative group 1 patients, whose ages averaged 1.8 years, but remained decreased in group 2 and 3 patients, whose ages averaged 8.1 and 5.6 years, respectively. Duration of cyanosis and degree of left ventricular dilatation appear to be important variables in regard to pump function in patients with cyanotic congenital heart disease.

Myocardial injury in infants with congenital heart disease: evaluation by creatine kinase MB isoenzyme analysis.

Total creatine kinase (CK) and the myocardial isoenzyme CK MB activity were prospectively determined in 282 children hospitalized for cardiac catheterization and evaluation for suspected congenital cardiac abnormalities and compared with a hospitalized control group of children without such abnormalities. The percent CK MB and CK MB activity were abnormally elevated in symptomatic children with a large left to right shunt due either to a large ventricular septal defect (n = 22; p less than 0.001) or to complete atrioventricular canal (n = 10; p less than 0.001). Serum CK MB activity and percent CK MB were significantly related to the size of the shunt and the age of presentation with clinical symptoms of congestive heart failure in infants with a ventricular septal defect. CK MB activity was abnormally elevated in infants with symptomatic coarctation of the aorta, either with or without a ventricular septal defect (n = 15; p less than 0.001), and in infants with symptomatic aortic stenosis (n = 4; p less than 0.02). In contrast, CK MB activity was normal in asymptomatic children with coarctation of the aorta (n = 14) or aortic stenosis (n = 8) despite comparable systolic pressure gradients. CK MB activity and percent CK MB were abnormally elevated in those children with the cyanotic congenital cardiac abnormalities of either transposition of the great arteries (n = 32; p less than 0.001) or right ventricular outflow tract obstruction (n = 31; p less than 0.001). These results suggest that children with congenital cardiac abnormalities may have significant myocardial cell injury and release of CK MB that may be detected by the determination of serum CK MB activity. Cell injury may be secondary to arterial desaturation or acute pressure-volume overload, or both, as manifested by clinical symptoms of heart failure and measured hemodynamic variables.

Radionuclide stroke count ratios for assessment of right and left ventricular volume overload in children.

The ratio of left ventricular to right ventricular stroke counts measured by radionuclide angiography has been used in adults to estimate the severity of left-sided valvular regurgitation. The validation of this technique in children for assessment of right and left ventricular volume overload is reported herein. Radionuclide stroke count ratios in 60 children aged 0.5 to 19 years (mean 11) were determined. Based on their diagnoses, the patients were divided into 3 groups: (1) normal--40 patients with no shunts or valvular regurgitation, (2) left ventricular volume overload--13 patients with mitral or aortic regurgitation, or both, and (3) right ventricular volume overload--7 patients, 2 with severe tricuspid regurgitation, 3 with atrial septal defects, and 2 with total anomalous pulmonary venous drainage. The radionuclide stroke count ratio clearly differentiated these groups (p less than 0.05): normal patients had a stroke count ratio of 1.04 +/- 0.17 (mean +/- 1 standard deviation), the left ventricular volume overload group had a stroke count ratio of 2.43 +/- 0.86, and the right ventricular volume overload group had a stroke count ratio of 0.44 +/- 0.17. In 22 of our 60 patients, radionuclide stroke count ratios were compared with cineangiographic stroke volume ratios, resulting in a correlation coefficient of 0.88. It is concluded that radionuclide ventriculography is an excellent tool for qualitative and quantitative assessment of valvular regurgitation in children.

Assessment of ventricular size and function in congenitally corrected transposition of the great arteries.

Twenty-four quantitative cineangiographic studies were performed in 19 patients with congenitally corrected transposition of the great arteries to assess right and left ventricular size and function. Ages ranged from 7 days to 44 years and associated lesions included ventricular septal defect (13 of 19), pulmonary stenosis (9 of 19), and systemic (tricuspid) valvular insufficiency (7 of 19). Systemic (anatomically right) ventricular end-diastolic volume was within normal limits in most patients and averaged 119% of predicted normal. Pulmonary (anatomically left) ventricular end-diastolic volume also was normal in most patients, averaged 112% of predicted, and was not different from systemic (right) ventricular end-diastolic volume. Systemic ventricular ejection fraction (RVEF) averaged 0.61 +/- 0.02 and was not different from pulmonary ventricular ejection fraction (LVEF) (0.65 +/- 0.02), but important differences were apparent when age was considered. With exclusion of 2 patients with hypoplastic systemic ventricles and 2 studies performed less than 6 months after open heart surgery, all 12 patients aged less than 10 years had a normal RVEF, whereas 2 of 5 patients aged greater than 17 years had a definitely low RVEF and 1 of 5 had a value at the lower limit of normal. In children, systemic and pulmonary ventricular pump function is usually normal in congenitally corrected transposition of the great arteries and any deviation from normal should suggest ventricular hypoplasia or an increase in afterload. After childhood, systemic ventricular dysfunction is more common and may reflect the inability of the anatomic right ventricle to function as the systemic pumping chamber over a normal lifetime in most patients with congenitally corrected transposition of the great arteries.

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1. The present study evaluated the time-dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determining changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C-13 hydroxy metabolite, doxorubicinol. 2. Following addition of doxorubicin (175 microM) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3. Doxorubicin (175 microM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 microM), however, failed to produce time-related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4. During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5. To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration-response experiments with doxorubicinol (0.9-7.2 microM) were conducted. 6. Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin-treated than in doxorubicinol-treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function.7. Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 microM doxorubicinol promoted a 15 fold greater release rate than 3 microM doxorubicin.8. Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time-dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Modulation by propranolol of the lysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey.

dl-Propranolol (propranolol) fed to immature and mature aneurysm-prone turkeys (Broad-Breasted White, BBW) for 6 weeks significantly raised the tensile strength of tissue rings from the abdominal aorta. The drug-mediated increase in tensile strength values was dose-related and independent of its heart rate- and arterial pressure-lowering effects. Propranolol acts, in part, by (a) stimulating lysyl oxidase to produce greater amounts of reactive aldehydes for intermolecular cross-links, (b) enhancing the progression of chemically unstable to stable forms of intermolecular elastin cross-links (lysinonorleucine and the desmosines), and (c) reducing the density of the age-related intermolecular cross-linking of collagen (pyridinoline). These propranolol effects on the lysyl cross-links were demonstrated in both the immature and mature animals and suggest a heretofore unrecognized potential for this widely used cardiovascular drug.

Intramural left anterior descending coronary artery: significance of the depth of the muscular tunnel.

To establish whether an intramural left anterior descending coronary artery (LADA) is a simple anatomic or a singularly pathologic variant we studied 39 hearts, each with an intramural course of the LADA and no coronary artery disease, valvular derangement, cardiomyopathy, or congenital anomaly. Seventeen of the 39 hearts had no myocardial lesions, while 22 had gross and/or microscopic alterations in the myocardial territory supplied by the intramural LADA. The myocardial lesions consisted of one or more of the following: interstitial fibrosis, replacement fibrosis, contraction band necrosis, and/or increased vascular density in areas of focal fibrosis. The coronary anatomy of the 22 hearts with myocardial lesions (group 1) was compared with that of the 17 hearts without myocardial changes (group 2). Each of the group 1 hearts had an intramural LADA deeply placed within the ventricular wall and attenuation of potential collateral blood flow because of a co-existing intramural course of the posterior descending artery, other epicardial coronary arteries, and/or a diminutive right coronary artery. The myocardial changes in group 1 hearts and their absence in group 2 hearts suggest that the deep, intramural LADA of the group 1 hearts is abnormal rather than a simple anatomic variant of normal. Furthermore, the deep intramural LADA may be associated with sudden death since 13 of the 22 group 1 hearts were from sudden death victims. Six of these 13 persons died suddenly during vigorous exercise.

Myxoid heart disease: an assessment of extravalvular cardiac pathology in severe mitral valve prolapse.

Because of the microscopic features of the affected leaflets in mitral valve prolapse (MVP), myxoid degeneration of the valve is a common pathologic designation applied to this condition. We undertook this study as a means of gaining an insight into the occurrence and prevalence of extravalvular cardiac alterations in hearts with severe MVP. Tissues of 24 hearts with severe myxomatous transformation of the mitral valve as the sole cardiac abnormality were examined. Eighteen of the 24 subjects with severe MVP died suddenly. Only two of these had pathologic evidence of severe mitral insufficiency. Twenty-four normal hearts served as controls. The two groups of hearts came from victims of homicide, suicide, accident, or natural death. Sections of the mitral valve, working myocardium, conduction system, and cardiac nerves and ganglia were studied by routine and special connective tissue and proteoglycan stains. Similar to the findings in severely affected mitral valves, prominent deposits of proteoglycans in neural and conduction tissue readily distinguished hearts with myxomatous valve changes from the control hearts. We conclude that the commonly recognized local derangement of valvular tissue in MVP is but one specific reflection of a more general myxomatous alteration in cardiac connective tissue.

Response of the hypertrophied left ventricle to global ischemia. Comparison of hyperkalemic cardioplegic solution with and without verapamil.

The hypertrophied left ventricle is at considerably greater risk for injury when subjected to global ischemia than is an otherwise normal heart. We evaluated the efficacy of verapamil, a calcium-channel blocking agent, as an adjunct to standard crystalloid cardioplegic solution in animals with left ventricular hypertrophy subjected to myocardial ischemia during cardiopulmonary bypass. Infracoronary aortic stenosis was produced in 15 mongrel puppies by plication of the noncoronary cusp of the aortic valve. Studies were conducted 3 to 4 months later. Left ventricular catheter-tip pressure transducers and major and minor axis ultrasonic dimension crystals were inserted, and the animals were then supported by cardiopulmonary bypass with 30 minutes of normothermic ischemia. Animals were randomized to receive either standard hyperkalemic crystalloid cardioplegic solution (n = 8) or the same solution with verapamil, 0.1 mg/kg (n = 7). After the 30 minutes of ischemia, the animals were supported on cardiopulmonary bypass for an additional 30 minutes and then separated from bypass. They were then studied for another 2 hours by measurement of myocardial adenosine triphosphate content, myocardial blood flow, systolic function with use of the end-systolic pressure/volume ratio, and compliance with use of the natural strain coefficient of the minor axis at 15 mm Hg end-diastolic pressure. There was a better recovery of systolic function in the animals treated with verapamil (89.2% versus 63.3%). The compliance as measured with use of the minor axis natural strain coefficient returned essentially to baseline in the group of animals treated with verapamil (0.236 +/- 0.038 before ischemia and 0.254 +/- 0.043 2 hours after ischemia), but it fell markedly in the control animals (0.219 +/- 0.027 before ischemia and 0.153 +/- 0.016 2 hours after ischemia). Myocardial adenosine triphosphate levels were not significantly different at any time during the study. Likewise, myocardial blood flow was not significantly different between groups. We conclude that the addition of verapamil to hyperkalemic cardioplegic solution improves recovery of both systolic and diastolic function after global ischemia in dogs with left ventricular hypertrophy resulting from aortic stenosis. The precise mechanism for this is unknown.