Outcomes after "unroofing" of a myocardial bridge of the left anterior descending coronary artery in children with hypertrophic cardiomyopathy.

The importance of myocardial bridging of a coronary artery in the setting of hypertrophic cardiomyopathy is controversial, although we have previously reported an association with myocardial ischemia and sudden death in children. We report five symptomatic children in whom symptoms or evidence of myocardial ischemia resolved or improved after supraarterial myotomy alone.

Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.

OBJECTIVES: To assess patients with different types of mutations of the beta myosin heavy chain (beta MHC) gene causing hypertrophic cardiomyopathy (HCM) and to determine the prognosis of patients according to the affected functional domain of beta MHC. DESIGN AND SETTING: Cohort study of subjects referred to an HCM clinic at an academic hospital. PATIENTS: 70 probands from the HCM clinic were screened for mutations of the beta MHC gene and 148 family members of the genotype positive probands were further assessed. The control group for the genetic studies consisted of 106 healthy subjects. MAIN OUTCOME MEASURES: Direct DNA sequencing was used to screen 70 probands for mutations of the beta MHC gene. Family members underwent genotypic and detailed clinical, ECG, and echocardiographic assessments. The survival of genotype positive subjects was evaluated according to the type of functional domain affected by the missense mutation and according to phenotypic characteristics. RESULTS: A mutation of the beta MHC gene was detected in 15 of 70 probands (21%). Of 148 family members studied in these 15 families, 74 were identified with a beta MHC defect. Eleven mutations were detected, including four novel mutations: Ala196Thr, Pro211Leu, Val404Leu, and Arg870Cys. Median survival was 66 years (95% confidence interval (CI) 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain (p = 0.02). Significant independent predictors of decreased survival were the non-conservative (that is, associated with a change in the amino acid charge) missense mutations that affected the actin binding site (hazard ratio 4.4, 95% CI 1.6 to 11.8; p = 0.003) and those that affected the rod portion of beta MHC (hazard ratio 4.8, 95% CI 1.2 to 19.4; p = 0.03). No phenotypic characteristics were associated with decreased survival or cardiovascular morbidity. CONCLUSIONS: The type of beta MHC functional domain affected by the missense mutation is predictive of overall prognosis in HCM.

Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstruction and relief with myectomy.

OBJECTIVES: This study examined: 1) the impact of myectomy on postoperative mitral regurgitation (MR) and 2) the association between the severity of MR and the left ventricular outflow tract (LVOT) gradient. BACKGROUND: For patients with hypertrophic obstructive cardiomyopathy (HOCM) and MR, controversy exists as to whether myectomy alone is sufficient in eliminating MR. Furthermore, the relationship between the degree of MR and the LVOT peak gradient has not been well defined. METHODS: We performed pre- and postoperative transthoracic as well as intraoperative transesophageal studies in 104 consecutive patients with HOCM undergoing septal myectomy. Left ventricular outflow tract gradient and the nature of MR were assessed. RESULTS: In the 93 patients without independent mitral valve disease, a relationship was observed between MR severity and the LVOT gradient. Left ventricular outflow tract gradient (mean +/- standard deviation) for trivial, mild, moderate and severe MR were: 23.2+/-19.1, 43.8+/-25.4, 70.1+/-21.0 and 104+/-21.0 mm Hg (p < 0.001). Early postoperative, MR was absent or trivial in 80%, mild in 19% and moderate in 1%. None of these patients required additional mitral valve surgery. For patients with independent mitral valve disease (n = 11), five required mitral valve surgery as well as myectomy. The remainder had significant reductions in the degree of MR with myectomy alone. CONCLUSIONS: For patients with HOCM and MR not due to independent mitral valve disease, myectomy significantly reduced the degree of MR, without requirement for additional mitral valve surgery. In these patients the severity of MR was directly related to the magnitude of the LVOT gradient.

Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.

BACKGROUND: The molecular basis of idiopathic dilated cardiomyopathy, a primary myocardial disorder that results in reduced contractile function, is largely unknown. Some cases of familial dilated cardiomyopathy are caused by mutations in cardiac cytoskeletal proteins; this finding implicates defects in contractile-force transmission as one mechanism underlying this disorder. To elucidate this important cause of heart failure, we investigated other genetic causes of dilated cardiomyopathy. METHODS: Clinical evaluations were performed in 21 kindreds with familial dilated cardiomyopathy. A genome-wide linkage study prompted a search of the genes encoding beta-myosin heavy chain, troponin T, troponin I, and alpha-tropomyosin for disease-causing mutations. RESULTS: A genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-13 (maximal lod score, 5.11; theta=0), where the gene for cardiac beta-myosin heavy chain is encoded. Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds. Cardiac beta-myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponin T (deltaLys210) caused early-onset ventricular dilatation (average age at diagnosis, 24 years) and diminished contractile function and frequently resulted in heart failure. Affected persons had neither antecedent cardiac hypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor histopathological findings characteristic of hypertrophy. CONCLUSION: Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction. Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins on muscle mechanics must trigger two different series of events that remodel the heart.

Morbidity outcome in patients with hypertrophic obstructive cardiomyopathy undergoing cardiac septal myectomy: early-extubation anesthesia versus high-dose opioid anesthesia technique.

OBJECTIVE: Anesthetic management of patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing septal myectomy is challenging. The morbidity outcome of early-extubation anesthesia (EEA), or fast tracking, versus high-dose opioid (HDO) anesthesia was studied. DESIGN: Retrospective study. SETTING: University teaching hospital. PARTICIPANTS: One hundred seventy-five cardiac septal myectomy patients (EEA, n = 53; HDO, n = 122). INTERVENTIONS: EEA technique consisted of low-dose fentanyl, 10 to 15 microg/kg; propofol infusion; midazolam; and inhalation agent. HDO technique consisted of fentanyl, 50 to 100 microg/kg, and benzodiazepines, with or without an inhalation agent. Demographic data, preoperative symptoms, and data on anesthesia management and postoperative complications were recorded. MEASUREMENTS AND MAIN RESULTS: There were no differences between the groups (EEA v HDO, respectively) regarding age, sex, preoperative symptoms (dyspnea, 89% v 79%; palpitations, 28% v 26%; angina, 47% v 61%; syncope, 47% v 41%), redo surgery, or combined surgery. Mean +/- standard deviation time to tracheal extubation was 7.2 +/- 5.3 hours in EEA versus 19.4 +/- 10.5 hours in HDO patients (p < 0.0001). Intensive care unit (ICU) stay was significantly shorter in EEA versus HDO patients (2.2 v 3.0 days; p < 0.005), with the trend toward earlier hospital discharge (9.7 v 11.3 days; p = 0.09). There was a high requirement for temporary pacing in both groups immediately postoperatively (EEA, 60% v HDO, 48%; p > 0.08). Permanent pacemaker insertion postoperatively was required in 7 of 53 patients (13%) in the EEA group and 11 of 122 patients (9%) in the HDO group (p > 0.25). Atrial arrhythmias occurred postoperatively in 25% of EEA patients versus 34% of HDO patients (p > 0.08). CONCLUSION: EEA facilitates earlier tracheal extubation by 12 hours in patients with HOCM undergoing septal myectomy, significantly shortening ICU stay by 1 day without increasing perioperative cardiac morbidity or mortality.

Hypertrophic cardiomyopathy. Clinical spectrum and treatment.

HCM is a heterogeneous disease genotypically, phenotypically, pathophysiologically, clinically, and therapeutically. In decisions on the management of these patients, it is important to recognize this heterogeneity and to direct therapy at the predominant abnormalities.

Reductions in muscle sympathetic nerve activity after long-term metoprolol for dilated cardiomyopathy: preliminary observations.

OBJECTIVE: To determine whether efferent muscle sympathetic nerve activity diminishes in subjects with dilated cardiomyopathy who improve after long term treatment with metoprolol. METHODS: Microneurographic, echocardiographic, plethysmographic, and neurohumoral data were obtained immediately before and 20 months after the addition of beta blockade in seven subjects with idiopathic dilated cardiomyopathy with clinical deterioration despite conventional treatment. RESULTS: Six subjects (three men, three women, aged 24-62 years) were restudied after a mean (SEM) of 20 (2.4) months treatment with metoprolol (45.8 (2.6) mg/d). Long term treatment was associated with decreases in left ventricular end diastolic and end systolic diameter (P < 0.005), left ventricular mass index (P < 0.05), and atrial natriuretic factor (P < 0.05), and increases in fractional shortening (P < 0.05) and mean blood pressure (P < 0.05). There was a 50% reduction in peroneal muscle sympathetic nerve activity (from 49.2 (10.1) to 24.5 (4.7) bursts/min; (P < 0.005) and a 62% decrease in calf vascular resistance (from 56.2 (4.4) to 21.2 (5.7) units; P < 0.005). This reduction in pulse synchronous nerve activity was not simply a function of bradycardia (heart rate fell from 94.2 (4.6) to 62.8 (5.7) beats/min; P < 0.005) since muscle sympathetic burst incidence also decreased (from 51 (8.7) to 37.5 (5.2) bursts/100 heart beats; P < 0.05). Similar haemodynamic improvement was observed in the seventh subject, who was switched to sotalol 200 mg/d and restudied after 20 months, but burst frequency was 50% higher and calf vascular resistance 93% higher. CONCLUSIONS: Muscle sympathetic nerve activity and calf vascular resistance decrease in patients with dilated cardiomyopathy who improve after long term treatment with metoprolol. Inhibition of central sympathetic outflow may be one mechanism by which metoprolol benefits such subjects.

Novel insights into the clinical manifestations and treatment of hypertrophic cardiomyopathy.

Knowledge of the pathophysiology, clinical manifestations, and treatment of hypertrophic cardiomyopathy continues to evolve. In subaortic obstructive hypertrophic cardiomyopathy, the importance of elongated mitral leaflets in causing the outflow obstruction and concomitant mitral regurgitation has been further elucidated, and marked worsening of the obstruction during upright exercise has been clearly demonstrated. Treatment options now include dual chamber pacing as well as medical and surgical therapy. The syndrome of midventricular obstruction with apical infarction and aneurysm formation most commonly results from apical infarction in the presence of extensive apical hypertrophy, with the noninfarcted midventricular hypertrophic tissue responsible for the midventricular obstruction. Attention is drawn to the variable pathophysiology and frequency of subaortic obstruction in hypertrophic cardiomyopathy in the elderly, the etiology of which is probably multifactorial. Finally, the interrelationship of impaired ventricular relaxation, coronary flow dynamics, and myocardial ischemia is discussed.

Acute dose-response effects of intravenous disopyramide in hypertrophic obstructive cardiomyopathy.

To evaluate the acute hemodynamic effects of intravenous disopyramide in hypertrophic obstructive cardiomyopathy (HOCM), 25 patients (12 men, 13 women) with an average age of 40 years (range 18 to 70 years) were evaluated while undergoing cardiac catheterization-angiography. Biplane left ventricular angiography was performed with standard intracardiac-systemic hemodynamics, including resting and provoked (after ventricular premature beat) left ventricular outflow tract gradients, by using simultaneous LV and aortic pressures as disopyramide was being administered (total dose 100 mg, bolus 10 mg every 3 minutes). Average baseline thermodilution cardiac output equalled 4.5 +/- 1.2 L/min, with all 25 subjects demonstrating systolic anterior motion of the mitral apparatus (mild, 3 [12%]; moderate, 8 [32%]; severe, 14 [64%]). Although heart rate originally slowed during disopyramide administration, average heart rate increased during the final stages (before, 78 +/- 15 vs after, 82 +/- 13 beats/min; p < 0.05). Systemic aortic pressures increased during intravenous disopyramide (before, 107 +/- 21/71 +/- 19 mm Hg vs after, 120 +/- 28/81 +/- 13 mm Hg; p < 0.05), with a decline in LV end-diastolic pressure (before, 19 +/- 7 vs after, 16 +/- 6 mm Hg; p < 0.01). Maximum LV systolic pressures decreased (before, 193 +/- 32 vs after, 146 +/- 29 mm Hg; p < 0.01), with a substantial reduction in resting LV outflow tract gradients (before, 86 +/- 34 vs after, 27 +/- 20 mm Hg; p < 0.001) in conjunction with less inducible obstruction (before, 124 +/- 33 vs after, 64 +/- 33 mm Hg; p < 0.001). Only minor electrocardiographic changes were seen during disopyramide infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: clarification of pathophysiology and importance in intraoperative decision making.

To better understand the pathophysiology of obstruction of left ventricular outflow in hypertrophic cardiomyopathy and to determine the value of intraoperative transesophageal Doppler echocardiography in decision making, 32 consecutive patients undergoing ventriculomyectomy were assessed. The mean preoperative left ventricular outflow gradient was 83 +/- 39 mm Hg and the mean basal septal width was 24 +/- 6 mm. Compared with transesophageal findings in 10 normal control subjects, the mitral leaflets were longer and the coaptation point was abnormal in the patients with obstructive hypertrophic cardiomyopathy (anterior and posterior leaflet lengths in the patients were 31 +/- 4 vs. 22 +/- 3 mm in the control group [p less than 0.00001] and 20 +/- 2 vs. 15 +/- 3 mm in the control group [p less than 0.00001]). The coaptation point in the patient group was in the body of the leaflets at a mean of 9 +/- 2 mm from the anterior leaflet tip, whereas it was at or within 3 mm of the leaflet tip in the normal group. During early systole, the distal third to half of the anterior mitral leaflet angled sharply anteriorly and superiorly (systolic anterior motion), resulting in leaflet-septal contact and incomplete mitral leaflet coaptation in mid-systole. This caused the formation of a funnel, composed of the distal parts of both leaflets, that allowed a jet of posteriorly directed mitral regurgitation to occur in mid- and late systole. The sequence of events in systole was eject/obstruct/leak. Transesophageal echocardiography was also helpful in planning the extent of the resection, assessing the immediate result and excluding important complications. In successful cases, the post-myectomy study showed 1) a dramatic thinning of the septum, with widening of the left ventricular outflow tract to a width similar to that in the normal subjects, 2) resolution of systolic anterior motion and the left ventricular outflow tract color mosaic, and marked reduction or abolition of mitral regurgitation despite persistence of abnormal mitral leaflet length and an abnormal mitral leaflet coaptation point. The routine use of transesophageal echocardiography in patients undergoing surgical myectomy for the treatment of obstructive hypertrophic cardiomyopathy is recommended.

Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy.

To evaluate scar-type and matrix connective tissue and to assess their role in the diastolic dysfunction of hypertrophic cardiomyopathy, surgically resected subaortic myectomy specimens and several autopsy hearts from patients with hypertrophic cardiomyopathy were studied. Eighteen specimens were differentially stained by a newly developed method that precisely determines relative collagen content; these tissues were compared with postmortem hypertrophied and normal control subaortic specimens. Quantitation revealed a 72% higher level (36.5 vs. 22.1 micrograms collagen/mg protein) of stainable collagen in the hearts with hypertrophic cardiomyopathy than in hypertrophied control hearts. The endocardial plaque was quantitated morphometrically, and it constituted only 4.6 +/- 1.7% of the total increased collagen content in the cardiomyopathy specimens. For the matrix studies, the cardiomyopathy specimens were stained by a silver impregnation technique that identifies connective tissue elements not normally visible with routine histologic methods. There was a marked increase in content of all matrix components, both in areas of pathologic scarring and in "normal" zones. Whorls of matrix connective tissue were noted in regions of myocyte whorls, as well as independent of them. Thus, these studies revealed a striking increase of both scar-type and matrix connective tissue in hypertrophic cardiomyopathy. The extensive scarring and the pronounced interstitial and intercellular matrix connective tissue may contribute to the increased ventricular chamber stiffness and impaired relaxation in this disease.

Echocardiographic and Doppler studies in hypertrophic cardiomyopathy.

This article discusses the central role of cardiac ultrasonography-- two dimensional echocardiography, Doppler echocardiography, continuous-wave Doppler, pulsed-wave Doppler--in the clinical assessment and management of patients with hypertrophic cardiomyopathy.

Comparison of proximal left anterior descending and circumflex coronary artery dimensions in aortic valve stenosis and hypertrophic cardiomyopathy.

To examine the "adequacy" of basal coronary flow in ventricular hypertrophy, the relation between proximal coronary artery dimensions and regional ventricular mass in aortic valve stenosis (AS) and hypertrophic cardiomyopathy (HC) was evaluated. Coronary artery size was determined by quantitative coronary arteriography while global/regional ventricular mass was calculated using computer-processed biplane 2-dimensional echocardiography. In comparison to 18 "normal" subjects, left anterior descending coronary dimensions were significantly larger in those with hypertrophy (normal 3.32 +/- 0.54, AS 3.82 +/- 0.71, HC 4.72 +/- 0.81 mm, p less than 0.05), with progressive increases in left anterior descending/circumflex coronary diameter ratios (normal 1.04 +/- 0.14, AS 1.18 +/- 0.19, HC 1.25 +/- 0.31, p less than 0.01). Compared to the AS group, indexed anteroseptal mass was greater in the HC subjects (AS 40.9 +/- 8.9 vs HC 72.1 +/- 21 g/m2, p less than 0.001). Both septal width/left anterior descending coronary diameter ratios (AS 3.61 +/- 1.06 vs HC 4.85 +/- 1.17 mm/mm, p less than 0.05) and indexed anteroseptal mass/left anterior descending coronary diameter ratios (AS 11.2 +/- 3.0 vs HC 15.6 +/- 3.4 g/m2/mm, p less than 0.01) were greater in HC subjects. Increased coronary dimensions were observed in both AS and HC, with the greatest changes noted within the left anterior descending distribution in HC, but when analyzed with respect to regional ventricular mass, these subjects demonstrated relative "inadequate" enlargement in coronary artery diameters. Underdeveloped epicardial coronary arteries may contribute to anteroseptal myocardial ischemia, with resultant angina pectoris, increased ventricular ectopic activity and sudden death in HC.

Apical hypertrophic cardiomyopathy: clinical follow-up and diagnostic correlates.

To determine the clinical course of apical hypertrophic cardiomyopathy, 26 patients (mean age 45 years) with asymmetric apical hypertrophy diagnosed by echocardiography or angiography were followed up for an average of 7.3 years (range 1 to 22). Presenting symptoms included atypical chest pain (n = 10), typical angina (n = 6), dyspnea (n = 5) and palpitation (n = 8). Ten patients were asymptomatic. At follow-up all patients had inverted precordial T waves, and 14 had the syndrome of "giant T wave negativity" (greater than or equal to 10 mm). In six patients with electrocardiographic follow-up of greater than 10 years (mean 13.4), precordial T wave inversion had progressed from -0.8 +/- 3.9 to -11.2 +/- 8.0 mm in lead V4 in association with increased QRS amplitude. Episodic atrial fibrillation occurred in 4 of 10 patients with echocardiographic left atrial enlargement. Although left ventricular systolic function was normal, diastolic relaxation was impaired in comparison with values in 10 healthy control subjects: in all 18 patients studied peak filling rate was decreased (4.44 +/- 0.44 versus 6.13 +/- 1.54 stroke volumes/s); time to peak filling was increased (174 +/- 40 versus 147 +/- 32 ms); and atrial systolic contribution to ventricular end-diastolic volume was increased (21.5 +/- 6.8 versus 11.5 +/- 4.6 stroke volume %). During follow-up, 21 of the 26 patients remained in stable condition or were asymptomatic. One patient with normal coronary arteries had an apical myocardial infarction with development of a discrete apical aneurysm and loss of "giant T wave negativity." This patient was the only one to have documented life-threatening ventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Causal relation between the pressure gradient and left ventricular ejection time in hypertrophic cardiomyopathy.

This study was designed to evaluate the relation between severity of obstruction to left ventricular outflow and left ventricular ejection time in hypertrophic obstructive cardiomyopathy. With dual catheters across the left ventricular outflow tract, the pressure gradient and corresponding left ventricular ejection time were measured in 10 patients as the pressure gradient was pharmacologically provoked or abolished, or both. The patients were studied during constant atrial pacing to avoid the potential errors introduced with heart rate correction equations. The pressure gradient was pharmacologically provoked or reduced over a range of greater than or equal to 62 mm Hg per patient. In each patient the left ventricular ejection time varied directly with the pressure gradient (mean r = 0.97, range 0.92 to 1.00). The change in magnitude of the pressure gradient varied directly with the corresponding change in the measured ejection time (mean r = 0.98, range 0.97 to 1.00). When the data from all 10 patients were pooled with use of Weissler's heart rate correction equation, the relation between the corrected left ventricular ejection time and the pressure gradient was still significant and linear (r = 0.86), but less so than in individual patients. This difference was the result of marked interpatient variability in the slope of this linear relation reflecting interpatient differences in other important factors, such as underlying myocardial contractility and stroke volume, that influence left ventricular ejection time. This study demonstrates a clear, direct and highly significant relation between the magnitude of the pressure gradient and the left ventricular ejection time in hypertrophic obstructive cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)