Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

BACKGROUND: The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy. METHODS AND RESULTS: Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family. CONCLUSIONS: Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.

Genetic Counseling and Screening Issues in Familial Dilated Cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDC), a treatable condition characterized by left ventricular dilatation and systolic dysfunction of unknown cause, has only recently been recognized to have genetic etiologies. Although familial dilated cardiomyopathy (FDC) was thought to be infrequent, it is now believed that 30-50% of cases of IDC may be familial. Echocardiographic and electrocardiographic (ECG) screening of first-degree relatives of individuals with IDC and FDC is indicated because detection and treatment are possible prior to the onset of advanced, symptomatic disease. However, such screening often creates uncertainty and anxiety surrounding the significance of the results. Furthermore, FDC demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making genetic counseling complex. The provision of genetic counseling for IDC and FDC will require collaboration between cardiologists and genetics professionals, and may also improve the recognition of FDC, the availability of support services, and overall outcomes for patients and families.

Prevention of pulmonary insufficiency through prophylactic use of PEEP and rapid respiratory rates.

This study evaluated the effectiveness of prophylactic positive end-expiratory pressure (PEEP) rapid respiratory rates (RRR), and high tidal volume (HTV) in prevention of congestive atelectasis. Measurements of pulmonary hemodynamics, mechanics, gas exchange, functional residual capacity (FRC), pathology, and cinemicroscopy were performed in 45 anesthetized dogs subjected to hemorrhagic hypotension. Randomly, the animals received control ventilation, HTV (20 ml. per kilogram), RRR (32 breaths per minute), or PEEP (5 cm. of water). Carbon dioxide was added as needed to maintain normocapnia. Control and HTV animals showed characteristic changes of congestive atelectasis (capillary congestion, stasis, interstitial edema, periarterial hemorrhage, alveolar edema, and hemorrhage). These microscopic and cinemicroscopic changes were prevented by PEEP and RRR and correlated with decreased physiological shunting (PEEP 10 percent, RRR 13 percent, HTV 22 percent; p less than 0.01) in the postshock phase. PEEP increased FRC by 40 percent (p less than 0.02) and reduced the pulmonary artery--small pulmonary vein gradient (PA-SPV), suggesting a direct effect on the capillary bed. RRR did not affect FRC but minimized the SPV-LA gradient. This effect on the pulmonary venules theoretically could be mediated by stimulating lymphatic flow, thereby decreasing interstitial edema. Thus PEEP and RRR are beneficial when used prophylactically but may work by widely differing mechanisms.

Artifacts in the measurement of pulmonary artery wedge pressure.

Pulmonary artery wedge pressure (PAWP) will only reflect left atrial pressure (LAP) if continuity of fluid exists from the catheter tip to the left atrium. Either increased airway pressure or decreased hydrostatic pressure may lead to discontinuity of the fluid column and midinterpretation of PAWP. Simultaneous measurements of PAWP and LAP were made in 19 anesthetized dogs. Placement of the pulmonary artery wedge catheter above the left atrium (West Zone I) in combination with the incremental addition of 5 cm H2O of PEEP caused a 5 mm Hg gradient between PAWP and LAP in the normovolemic animal. Augmenting PEEP further or hypovolemia (i.e., decrease in LAP) increased the gradient. Hypervolemia (increase in LAP) diminished the gradient. Fluid continuity between the PAW catheter and LA is a prerequisite for monitoring LAP with the Swan-Ganz catheter. Increases in PEEP, placement of the catheter above the left atrium and hypovolemia may occlude the fluid column and cause artifacts in the PAWP obtained.

The role of carbon dioxide in the development of pulmonary insufficiency.

The effects of carbon dioxide (PCO2 = 40 versus PCO2 = 20) on pulmonary function changes during 2 hours of hemorrhagic hypotension followed by resuscitation are evaluated in 21 dogs. Pulmonary hemodynamics, mechanics, gas exchange, functional residual capacity, and morphology are studied. In the preshock period, hypocapnia is associated with a decreased cardiac output, increased dead space, and increased alveolar-arterial (A-a) gradiant (room air). During the period of hypotension, all parameters in both groups changed similarly. After resuscitation, the A-a gradients in the two groups further widened. Following the return to control levels of normocapnia in all animals, the group which had been hypocapnic during the hypotensive episode continued to show increased shunting (20 versus 13 percent, p less than 0.05). These results correlated well with cinemicroscopic findings, which showed the normocapnic group to have less interstitial edema and better capillary flow.

Bypass graft for coronary arterial stenosis following radiation therapy.

A 48-year-old man developed symptoms of progressive angina pectoris leading to myocardial infarction 12 years after two large doses of radiation for treatment of superior vena caval syndrome. Angiographic studies showed an isolated critical stenosis in the left anterior descending coronary artery, for which a successful surgical procedure for saphenous vein bypass graft was was performed. Coronary arterial stenosis following radiation therapy has been reported rarely, but this case supports the thesis that such lesion can be treated surgically.

Comparison of patients with coronary artery or valve disease: intraoperative differences in blood volume and observations of vasomotor response.

A review of 296 patients undergoing cardiac operations has shown that those with coronary artery disease have a blood volume deficit. The 148 patients with valve disease had a normal blood volume of 78 ml/kg (normal range, 68--88 ml/kg), while the 148 coronary artery disease had a blood volume of 69 ml/kg (p less than 0.001). Infusion of plasma prior to cardiopulmonary bypass as well as the total transfusion required afterward to maintain blood pressure indicated an important clinical difference in these two groups. Another finding was that the requirement for a drug to control blood pressure prior to use of cardiopulmonary bypass was greater in the coronary patients (p less than 0.01). Comparison of the requirement for a hypotensive agent before and after bypass showed a greater predictability in the valve group. This experience leads us to conclude that patients with coronary artery disease and angina not only have a low blood volume, but they also have a marked vasoactive lability which shows up in their hemodynamic response to the conduct of an operation and to anesthesia.

Preliminary report: Evaluation of tissue ingrowth into experimental Replamineform vascular prostheses.

A new experimental arterial prosthesis has been developed by replacing the minimal surface microporous calcite structure of sea urchine spines. Prostheses having a 4 mm. inside diameter and a homogenous 15 to 20 mu porous network have been prepared in bioelectric polyurethane and segmented polyurethane. Ten prostheses were placed in the femoral and carotid arteries of dogs weighing 27 to 35 kilograms and were harvested at a time interval of 3 to 14 days to characterize the tissue ingrowth. Eight of the ten prostheses were widely patent at time of harvest, with tissue ingrowth evident as early as the third day and with complete fibroblastic and capillary penetration of the 1 mm. thick walls developed by the end of one week. By 2 weeks there was uniform formation of 50 to 100 mu well organized neointimal surfaces.

Palliative esophageal intubation for carcinoma. A combined push-pull method.

The use of prosthetic tubes for palliation of esophageal carcinoma can be carried out with safety using a combined push-pull method. The advantages of simultaneous endoscopy and laparotomy are illustrated in two cases. For safe durable palliation, emphasis must be placed upon seating the tube under direct vision as well as upon the firm fixation of the tube of the abdominal wall to prevent its subsequent migration.

Management of acute aortic dissection.

The therapy for acute dissecting aneurysm of the aorta remains a difficult problem for thoracic surgeons. Because of an excessive operative mortality in patients with acute dissection who were operated on within 24 hours of hospital admission, we have utilized intensive medical management to delay surgical intervention. Even patients with acute aortic insufficiency can be supported medically, allowing their operations to be delayed at least 3 weeks or longer. Since this policy has been implemented, there has been no operative mortality in our last 13 patients with acute dissection. Medical therapy as the definitive treatment is now reserved solely for Type III dissections or for patients who cannot be operated on for other reasons. This report outlines our rationale for therapy and our current method of managing acute dissection.

Retrograde aortic perfusion by partial cardiopulmonary bypass: effect of mixing on measured arterial oxygen tension.

Partial venoarterial bypass with return of oxygenated blood to the femoral artery can produce mixing in the aorta of the blood from the oxygenator and left ventricular sources at flow rates of less than 50% of the total body flow. This was observed in six anesthetized sheep with normal lungs maintained on controlled ventilation on partial cardiopulmonary (venoarterial) bypass. The evidence of mixing increases with the extracorporeal flow rate, reaching the aortic arch in a majority of cases at the higher rates. Management of bypass and the interpretation of its effects depend on definite knowledge of the presence or absence of mixing. Partial bypass will raise the arterial oxygen tension (Pao-2) of the blood continuing to flow through the lungs. This effect is independent of mixing (Pao-2) and may be related either to the addition of oxygen to the blood or to an enhanced pulmonary ventilation-perfusion relationship.