Thomas A. Traill

Hypertensive Hypertrophic Cardiomyopathy of the Elderly

Using echocardiography, we identified 21 patients with a syndrome that included severe concentric cardiac hypertrophy, a small left ventricular cavity, and supernormal indexes of systolic function without concurrent medical illness or ischemic heart disease. Thirteen of the patients presented with dyspnea or chest pain. All patients studied had a history of hypertension and were compared with normotensive controls matched for age and sex. The patients were elderly (mean age, 73.3 years), predominantly female (16 patients), and mostly black (15 patients). Their cardiac function was characterized by excessive left ventricular emptying (ejection fraction on two-dimensional echocardiography [patients vs. controls], 79 +/- 4 vs. 59 +/- 5 per cent, P less than 0.001) and abnormal diastolic function as manifested by a prolonged early diastolic filling period (279 +/- 25 vs. 160 +/- 45 msec, P less than 0.001) and reduced peak diastolic dimension increase (11 +/- 4 vs. 16 +/- 5 cm per second, P less than 0.05). In spite of the clinical presentation of heart failure, all of 9 patients receiving either beta-receptor antagonists or calcium-channel blocking agents obtained symptomatic relief, whereas 6 of 12 patients receiving vasodilator medications had severe hypotensive reactions, including one death. We conclude that this unique subset of hypertensive patients has a clinical syndrome that warrants recognition and tailored management.

The Clinical and Genetic Spectrum of the Holt-Oram Syndrome (Heart-Hand Syndrome)

BACKGROUND The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies. METHODS Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members. RESULTS A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2). CONCLUSIONS Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

Preclinical Diagnosis of Familial Hypertrophic Cardiomyopathy by Genetic Analysis of Blood Lymphocytes

BACKGROUND The clinical diagnosis of familial hypertrophic cardiomyopathy is usually made on the basis of the physical examination, electrocardiogram, and echocardiogram. Making an accurate diagnosis can be particularly difficult in children, who may not have cardiac hypertrophy until adulthood. Recently, we demonstrated that mutations in the cardiac myosin heavy-chain genes cause familial hypertrophic cardiomyopathy in some families. We report a diagnostic test for familial hypertrophic cardiomyopathy that relies on the detection of mutations in the beta myosin heavy-chain gene in circulating lymphocytes that we used to evaluate three generations of a family, including the children. METHODS AND RESULTS Using the polymerase chain reaction, we found that normal and mutant beta cardiac myosin heavy-chain genes are transcribed in circulating lymphocytes. This allowed us to examine beta cardiac myosin heavy-chain messenger RNA from blood lymphocytes, even though ordinary expression of the gene is virtually restricted to the heart. Base sequences amplified from this messenger RNA were analyzed with a ribonuclease protection assay to identify small deletions, abnormal splicing, or missense mutations. Using this technique we identified a novel missense mutation in a patient with familial hypertrophic cardiomyopathy. We evaluated 15 of the patients adult relatives and found perfect agreement with the clinical diagnosis (8 affected and 7 not affected). Clinical analysis of 14 of the children (age, 1 to 20 years) of these affected family members revealed 1 child with echocardiographic findings diagnostic of familial hypertrophic cardiomyopathy. However, genetic analyses showed that six other children had also inherited the missense mutation and might later manifest the disease. CONCLUSIONS Transcripts of beta cardiac myosin heavy-chain gene can be detected in blood lymphocytes and used to screen for mutations that cause familial hypertrophic cardiomyopathy. This approach makes practical the identification of mutations responsible for this disorder and may be applicable to other diseases in which direct analysis is difficult because the mutated gene is expressed only in certain tissues. Preclinical or prenatal screening in an affected family will make it possible to study the disease longitudinally and to develop preventive interventions.

Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial.

The value of the addition of beta-blockers to coronary vasodilator therapy in the treatment of patients with unstable angina at rest is controversial. We conducted a double-blind, randomized, placebo-controlled 4 week trial of propranolol in 81 patients with unstable angina, 39 of whom were assigned to placebo and 42 of whom received propranolol in a dose of at least 160 mg daily. All patients were also treated with coronary vasodilators, including 80 mg nifedipine daily and long-acting nitrates. The incidences of cardiac death, myocardial infarction, and requirement for bypass surgery or coronary angioplasty did not differ between the two groups (propranolol = 16; placebo = 18). The propranolol group had a lower cumulative probability of experiencing recurrent resting angina than the placebo group (p = .013), and over the first 4 days of the trial the mean number of clinical episodes of angina (propranolol 0.9 +/- 0.2, placebo 1.8 +/- 0.3, p = .036), duration of angina (propranolol 15.1 +/- 4.3 min, placebo 38.1 +/- 8.4, p = .014), and nitroglycerin requirement (propranolol 1.1 +/- 0.3 tablets, placebo 3.5 +/- 0.8, p = .003) were also fewer. Continuous electrocardiographic recording for ischemic ST segment changes revealed fewer daily ischemic episodes in the propranolol group (2.0 +/- 0.5) than in the placebo group (3.8 +/- 0.7, p = .03), and a shorter duration of ischemia (propranolol 43 +/- 10 min, placebo 104 +/- 28 min, p = .039). Thus propranolol, in patients with unstable angina, in the presence of nitrates and nifedipine is not detrimental and reduces the frequency and duration of symptomatic and silent ischemic episodes.

Histologic predictors of acute cardiac rejection in human endomyocardial biopsies: A multivariate analysis

To identify specific histologic abnormalities that could predict early cardiac rejection before the development of myocyte necrosis, 167 consecutive endomyocardial biopsy samples from 18 cardiac transplant recipients were retrospectively analyzed and 17 histologic variables were semiquantitatively graded from 0 to 3. Forty-five biopsy samples contained foci of myocyte necrosis and were labeled Rejectors. The two samples immediately preceding Rejector biopsies were labeled Predictors (n = 44). All remaining samples were labeled Others (n = 78). Endocardial and interstitial infiltrates, interstitial mononuclear cells, pyroninophilic mononuclear cells, polymorphonuclear leukocytes and other cells (eosinophils and plasma cells) were significantly increased in graded severity in Rejector biopsy samples as compared with Predictors or Others (p less than 0.001, ANOVA testing). These variables cannot distinguish Predictor biopsy specimens from Others. On the other hand, interstitial edema, perivascular karyorrhexis and perivascular infiltrate with intermyocyte extension are histologic abnormalities that can distinguish Predictor biopsy samples from Others (p less than 0.001, ANOVA testing). Multiple logistic regression analysis indicates that the relative risk of developing myocyte necrosis when a biopsy sample contains interstitial edema is 8.1. With perivascular infiltrate with intermyocyte extension in addition, the relative risk is 41.4. In summary, three histologic abnormalities have been identified that help predict the future development of myocyte necrosis within the next two endomyocardial biopsies. Biopsy specimens with these abnormalities probably represent early cardiac rejection before the development of myocyte necrosis.

Acute Nifedipine Withdrawal: Consequences of Preoperative and Late Cessation of Therapy in Patients With Prior Unstable Angina

Reports of acute ischemic events after withdrawal of calcium antagonist therapy in outpatients and during bypass surgery in patients with prior angina at rest prompted the examination of the effect of nifedipine withdrawal in 81 patients who had completed a prospective, double-blind randomized trial of nifedipine versus placebo for rest angina. Thirty-nine patients underwent bypass surgery for uncontrolled angina or left main coronary artery disease. No significant difference between patients withdrawn from nifedipine or placebo was seen in the incidence of perioperative myocardial infarction, hypotension requiring intraaortic balloon counterpulsation, vasopressor or vasodilator requirements or incidence of significant arrhythmias. An additional 42 patients had completed 2 years on a protocol consisting of nitrates and propranolol in addition to nifedipine or placebo. During a mean of 66 hours of continuous monitoring after withdrawal of nifedipine or placebo, heart rate and blood pressure were unchanged. A worsening of previously present angina at rest occurred in five patients who had continued to experience rest angina before drug withdrawal, four of whom were withdrawn from nifedipine. No patient with class I to III angina experienced new onset of rest angina during drug withdrawal. No patient experienced myocardial infarction. There was no significant difference between patients withdrawn from nifedipine or placebo in the duration or frequency of ischemic ST changes on continuous electrocardiographic monitoring, or in duration or positive results of serial exercise treadmill testing. Thus, no early adverse effects of acute nifedipine withdrawal were found in patients with prior rest angina at the time of bypass surgery or in stable patients receiving long-term medical therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulus-evoked sinus arrest in severe Guillain-Barre syndrome A case report

Guillain-Barre syndrome, or acute inflammatory demyelinating polyradiculoneuropathy, is frequently accompanied by cardiac and autonomic dysfunction. We report a patient in whom minor autonomic stimulation by upgaze, tongue protrusion, opening the mouth against resistance, eyeball pressure, and carotid sinus massage produced asystole. The frequency of potentially lethal dysrhythmias in Guillain-Barre syndrome, coupled with the relative ease of cardiac pacing, makes recognition of these phenomena of utmost importance in affected patients. NEUROLOGY 1996;47: 1239-1242

Severe Aortic Regurgitation Secondary to Antisynthetase Syndrome

A 47-year-old woman with hypertension and a history of antisynthetase syndrome (ASS) diagnosed in 2002 (positive anti-PL-7 antibodies) and on long-term immunosuppressive therapy was admitted to the hospital in 2008 for worsening chest pain, shortness of breath, hypoxemia, and diffuse muscle weakness. Plain chest radiograph showed bilateral lower-lobe infiltrates and computed tomography confirmed bilateral patchy infiltrates consistent with interstitial lung disease. After being treated aggressively with high-dose immunosuppressive therapy, the patient improved and was discharged home. She was subsequently readmitted a few days later with progressive dyspnea. A transthoracic echocardiogram (TTE) showed moderate to severe aortic regurgitation (Figure 1A; online-only Data Supplement Movie IA and IB) that was not present in a prior TTE performed 4 months before admission (requested to screen for left ventricular hypertrophy; patient was asymptomatic at that time; Figure 1B and online-only Data Supplement Movie IIA and IIB). During the next 4 weeks, …

Surgical treatment of postinfarction ventricular septal defect with aortic stenosis

A 69-year-old man with an acute postinfarction ventricular septal defect was also found to have aortic stenosis. Successful management required closure of the postinfarction ventricular septal defect and replacement of the stenotic aortic valve. The contribution of aortic stenosis to the cause of the infarction and the postinfarction ventricular septal defect, as well as the implications for surgical management, are discussed.