David I. Silverman

Life expectancy in the Marfan syndrome

Data reported in 1972 indicated that lifespan in patients with the Marfan syndrome is markedly shortened, and that most deaths are cardiovascular. This study was performed to determine whether survival in the Marfan syndrome has changed since 1972, and to discern whether treatment (medical or surgical) has altered prognosis. Survival curves were generated on 417 patients from 4 referral centers, with a definite diagnosis of the Marfan syndrome. Birth date, age at death, cardiovascular surgery, or treatment with beta blockers, or any combination of these, were included in the analysis. Forty-seven of 417 patients died. Mean age at death (41 +/- 18 years) was significantly increased compared with age in 1972 (32 +/- 16 years, p = 0.0023). Median (50%) cumulative probability of survival in 1993 was 72 years compared with 48 years in 1972. Of 112 surgically treated patients, 10-year probability of survival was 70%. Patients undergoing surgery after 1980 enjoyed significantly increased survival than patients who had undergone operation before 1980 (p = 0.008). In conclusion, life expectancy for patients with the Marfan syndrome has increased > 25% since 1972. Reasons for this dramatic increase may include (1) an overall improvement in population life expectancy, (2) benefits arising from cardiovascular surgery, and (3) greater proportion of milder cases due to increased frequency of diagnosis. Medical therapy (including beta blockers) was also associated with an increase in probable survival.

Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study.

OBJECTIVES We sought to validate the safety of transesophageal echocardiographically guided early cardioversion in conjunction with short-term anticoagulation as a strategy for guiding early cardioversion in hospitalized patients with atrial fibrillation. BACKGROUND Because atrial thrombi are poorly seen by conventional imaging techniques, several weeks of prophylactic anticoagulation is routinely prescribed before cardioversion. Transesophageal echocardiography is a superior test for identifying atrial thrombi; preliminary feasibility studies have supported its use to guide early cardioversion for patients in whom no thrombus is observed, but safety has not been validated in any large series. METHODS All patients admitted to hospital with atrial fibrillation during a 4.5-year period were screened. The inclusion criterion was a clinical duration of atrial fibrillation > 2 days or of unknown duration. Patients received anticoagulation with heparin/warfarin and underwent conventional transthoracic echocardiography followed by transesophageal study. Patients in whom transesophageal echocardiography revealed no atrial thrombus underwent pharmacologic or electrical cardioversion followed by warfarin therapy for 1 month. Cardioversion was deferred in patients with evidence of atrial thrombi, and they received prolonged warfarin treatment. RESULTS Two hundred thirty-three patients (86% of those eligible) agreed to participate, and 230 underwent transesophageal echocardiography. Transesophageal echocardiography identified 40 atrial thrombi (left atrium 34, right atrium 6) in 34 patients (15%). One hundred eighty-six (95%) of 196 patients without thrombi had successful cardioversion to sinus rhythm, all without prolonged anticoagulation, and none (0%, 95% confidence interval 0% to 1.6%) experienced a clinical thromboembolic event. Eighteen patients with atrial thrombi underwent uneventful cardioversion after prolonged anticoagulation. CONCLUSIONS Compared with smaller series that have shown only feasibility, this large prospective and consecutive study of patients undergoing transesophageal echocardiographically facilitated early cardioversion in conjunction with short-term anticoagulation validates the safety of this strategy. This treatment algorithm has a safety profile similar to conventional therapy and minimizes both the period of anticoagulation and the overall duration of atrial fibrillation.

Cardioversion from Atrial Fibrillation without Prolonged Anticoagulation with Use of Transesophageal Echocardiography to Exclude the Presence of Atrial Thrombi

BACKGROUND Because atrial thrombi are poorly detected by conventional noninvasive techniques such as transthoracic echocardiography, patients with prolonged atrial fibrillation usually receive several weeks of oral anticoagulation therapy before cardioversion is attempted. We wondered whether transesophageal echocardiography, an accurate method of detecting atrial thrombi, would allow early cardioversion to be performed safely if no thrombi were identified. METHODS A total of 669 consecutive patients admitted with the diagnosis of atrial fibrillation were screened. Patients were excluded if they were receiving long-term anticoagulation, if the duration of atrial fibrillation was two days or less, if they were not candidates for cardioversion, or if transesophageal echocardiography was contraindicated. Of 119 qualifying patients, 94 agreed to participate; the average duration of atrial fibrillation was 4.5 weeks. Participating patients underwent transthoracic echocardiography and transesophageal echocardiography followed by cardioversion if no thrombi were seen. Short-term anticoagulation with heparin was used in 80 patients before cardioversion, and 60 patients received warfarin for one month after cardioversion. RESULTS Fourteen atrial thrombi were identified in 12 patients (13 percent), and 12 of the 14 thrombi were visualized only on transesophageal echocardiography. Cardioversion was deferred in all 12 patients. Two of these 12 patients died suddenly; 4 of the 10 surviving patients underwent uneventful cardioversion after prolonged oral anticoagulation. Seventy-eight of the 82 patients without thrombi underwent successful cardioversion to sinus rhythm (47 by means of antiarrhythmic drugs and 31 by electrical cardioversion), all without long-term oral anticoagulation. None of these patients (95 percent confidence interval, 0 to 4.6 percent) had an embolic event. CONCLUSIONS In patients with atrial fibrillation of unknown or prolonged duration who are not receiving long-term anticoagulation, atrial thrombi are detected by transesophageal echocardiography in only a small minority (13 percent in our study). Our preliminary data suggest that if transesophageal echocardiography excludes the presence of thrombi, early cardioversion can be performed safely without the need for prolonged oral anticoagulation before the procedure.

Controlled trial of fish oil for regression of human coronary atherosclerosis

OBJECTIVES This randomized clinical trial tested whether fish oil supplements can improve human coronary atherosclerosis. BACKGROUND Epidemiologic studies of populations whose intake of oily fish is high, as well as laboratory studies of the effects of the polyunsaturated fatty acids in fish oil, support the hypothesis that fish oil is antiatherogenic. METHODS Patients with angiographically documented coronary heart disease and normal plasma lipid levels were randomized to receive either fish oil capsules (n = 31), containing 6 g of n-3 fatty acids, or olive oil capsules (n = 28) for an average duration of 28 months. Coronary atherosclerosis on angiography was quantified by computer-assisted image analysis. RESULTS Mean (+/- SD) baseline characteristics were age 62 +/- 7 years, plasma total cholesterol concentration 187 +/- 31 mg/dl (4.83 +/- 0.80 mmol/liter) and triglyceride levels 132 +/- 70 mg/dl (1.51 +/- 0.80 mmol/liter). Fish oil lowered triglyceride levels by 30% (p = 0.007) but had no significant effects on other plasma lipoprotein levels. At the end of the trial, eicosapentaenoic acid in adipose tissue samples was 0.91% in the fish oil group compared with 0.20% in the control group (p < 0.0001). At baseline, the minimal lumen diameter of coronary artery lesions (n = 305) was 1.64 +/- 0.76 mm, and percent narrowing was 48 +/- 14%. Mean minimal diameter of atherosclerotic coronary arteries decreased by 0.104 and 0.138 mm in the fish oil and control groups, respectively (p = 0.6 between groups), and percent stenosis increased by 2.4% and 2.6%, respectively (p = 0.8). Confidence intervals exclude improvement by fish oil treatment of > 0.17 mm, or > 2.6%. CONCLUSIONS Fish oil treatment for 2 years does not promote major favorable changes in the diameter of atherosclerotic coronary arteries.

TRPM7-Mediated Ca2+ Signals Confer Fibrogenesis in Human Atrial Fibrillation

Rationale: Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most commonly sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown. Objective: To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF. Methods and Results: We demonstrate that the transient receptor potential (TRP) melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA largely eliminates TRPM7 current and Ca2+ influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca2+ influx and are more prone to myofibroblast differentiation, presumably attributable to the enhanced expression of TRPM7. TRPM7 small hairpin RNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor (TGF)-&bgr;1, the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca2+ signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-&bgr;1–induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-&bgr;1. Conclusions: Our results establish that TRPM7 is the major Ca2+-permeable channel in human atrial fibroblasts and likely plays an essential role in TGF-&bgr;1–elicited fibrogenesis in human AF.

Atrial ejection force: a noninvasive assessment of atrial systolic function.

OBJECTIVES The purpose of this study was to define atrial ejection force and to develop a method for its noninvasive measurement from echocardiographic data. BACKGROUND Assessment of diastolic function through measurement of the components of ventricular filling has largely neglected the vigor of atrial systole, in part because this has been difficult to quantify. However, atrial ejection force, defined as that force exerted by the left atrium to accelerate blood into the left ventricle during atrial systole, can be assessed noninvasively by combined two-dimensional imaging and Doppler echocardiography. This index of atrial function, based on classic newtonian mechanics, provides a physiologic assessment of atrial systolic function. METHODS To evaluate the usefulness of atrial ejection force, we studied the return of left atrial ejection force in 29 patients after elective cardioversion for atrial fibrillation. Transmitral Doppler inflow patterns at rest were assessed immediately after cardioversion and at 24 h, 1 week, 1 month and > 3 months later. A healthy adult group (n = 10) served as control subjects. RESULTS After successful cardioversion, atrial ejection force was significantly depressed compared with that in the control group (5.2 +/- 6.8 vs. 16.3 +/- 4.7 kdynes; p < 0.0001). Over successive weeks, atrial ejection force improved in the subgroup of patients who remained in sinus rhythm (n = 18), whereas no improvement was seen during the period of maintained sinus rhythm in the patients with subsequent reversion to atrial fibrillation (n = 11). CONCLUSIONS Atrial ejection force provides a physiologic assessment of atrial systolic function and is a potentially useful index for assessing atrial contribution to diastolic performance. In patients who successfully underwent cardioversion from atrial fibrillation, atrial ejection force improved over several weeks only in the subgroup in which sinus rhythm was maintained.

Likelihood of Spontaneous Conversion of Atrial Fibrillation to Sinus Rhythm

OBJECTIVES We sought to determine the likelihood and predictors of spontaneous conversion to sinus rhythm of recent-onset atrial fibrillation (symptoms <72 h). BACKGROUND Although spontaneous conversion of recent-onset atrial fibrillation is common, the likelihood and clinical and echocardiographic predictors have not been fully defined. Such data would be important for management of patients in whom early cardioversion is desired: Cardioversion could be delayed in patients with a high likelihood of spontaneous conversion, and it could be expeditiously pursued if spontaneous conversion is unlikely. METHODS We screened 1,822 consecutive adults admitted to the hospital with atrial fibrillation and prospectively identified 356 patients (45% male, mean age +/- SD 68 +/- 16 years) with atrial fibrillation of <72-h duration. The occurrence of spontaneous conversion to sinus rhythm and clinical and echocardiographic data were identified through retrospective chart review. RESULTS Spontaneous conversion to sinus rhythm occurred in 68% of the study group (n = 242; 95% confidence interval [CI] 63% to 73%). Among patients with spontaneous conversion, the total duration of atrial fibrillation was <24 h in 159 (66%), 24 to 48 h in 42 (17%) and >48 h in 41 (17%) (p < 0.001). Logistic regression analysis of clinical data identified presentation <24 h from onset of symptoms as the only predictor of spontaneous conversion (odds ratio 1.8, 95% CI 1.4 to 2.4, p < 0.0001). Normal left ventricular systolic function was more common among patients with spontaneous conversion (p = 0.03), but it was not an independent predictor of conversion. Left atrial dimension was similar between groups. CONCLUSIONS Spontaneous conversion to sinus rhythm occurs in almost 70% of patients presenting with atrial fibrillation of <72-h duration. Presentation with symptoms of <24-h duration is the best predictor of spontaneous conversion.

Cardioversion of Nonrheumatic Atrial Fibrillation: Reduced Thromboembolic Complications With 4 Weeks of Precardioversion Anticoagulation Are Related to Atrial Thrombus Resolution

BACKGROUND The use of warfarin anticoagulation for several weeks before cardioversion results in a 90% reduction in the incidence of cardioversion-related thromboembolism. The mechanism of this benefit, however, is unknown; it has been widely attributed to organization and adherence of atrial thrombi, a finding observed among pathological studies of patients with rheumatic valvular disease. METHODS AND RESULTS Serial transesophageal echocardiography was performed in 14 patients with nonrheumatic atrial fibrillation after identification of atrial thrombi on initial transesophageal study. All patients received warfarin anticoagulation and were followed clinically for signs of thromboembolism. Eighteen atrial thrombi were identified on initial transesophageal study, including 14 thrombi confined to the left atrial appendage, 2 in the body of the left atrium, 1 in the right atrial appendage, and 1 in the body of the right atrium. Thrombus size varied from 5 to 20 mm, and 6 were considered mobile. After a median of 4 weeks of warfarin, 16 of 18 atrial thrombi (89%; 95% CI, 73% to 100%) had completely resolved on transesophageal echocardiographic study. In addition, no new thrombi were identified on follow-up study, and no patient had a clinical thromboembolic event between studies. CONCLUSIONS These data strongly support the hypothesis that among patients with nonrheumatic atrial fibrillation, the mechanism of clinical benefit with 3 to 4 weeks of warfarin before cardioversion is related to thrombus resolution and prevention of new thrombus formation rather than thrombus organization.

Temporal dependence of the return of atrial mechanical function on the mode of cardioversion of atrial fibrillation to sinus rhythm

Abstract In conclusion, among patients with a clinical duration of AF of ≤5 weeks, recovery of atrial mechanical function appears related to the mode of cardioversion: a more prompt return of atrial mechanical function was seen in patients undergoing successful pharmacologic cardioversion versus those undergoing successful electrical cardioversion after unsuccessful pharmacologic cardioversion.

Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival

OBJECTIVES We attempted to determine whether a family history of severe cardiovascular disease in patients with the Marfan syndrome is associated with increased aortic dilation or decreased survival, or both. BACKGROUND The prognostic importance of a family history of severe cardiovascular disease in patients with the Marfan syndrome has been incompletely examined. We hypothesized that such a family history would correlate with increased aortic dilation and would be associated with decreased survival. METHODS One hundred eight affected patients and 48 unaffected family members from 33 multigenerational families with the Marfan syndrome underwent echocardiographic measurement of the aortic root, arch and mid-abdominal aorta. Date of birth and age at death ascertained from family pedigrees were used to perform life table analysis and estimate survival. RESULTS Aortic root and arch diameters were significantly greater in patients with a family history of severe cardiovascular disease than in patients without such a family history. Of subjects in the highest quartile for aortic size, > 80% had such a family history in contrast to < 10% of those in the lowest quartile (chi-square 57.37, p < 0.00001). Mean age at death and cumulative probability of survival were significantly lower in patients with such a family history. CONCLUSIONS Among patients with the Marfan syndrome, aortic dilation is greater and life expectancy shorter in those with a family history of severe cardiovascular manifestations. These data suggest that such a family history is an important risk factor for cardiovascular events in patients with the Marfan syndrome.