Stephen L. Kopecky

The natural history of lone atrial fibrillation. A population-based study over three decades

From 1950 to 1980, 3623 patients from Olmsted County, Minnesota, were found to have atrial fibrillation. Ninety-seven of these patients (2.7 percent), who were 60 years old or younger at diagnosis, had lone atrial fibrillation (atrial fibrillation in the absence of overt cardiovascular disease or precipitating illness), and their data were reviewed to determine the incidence of thromboemboli. Twenty of these patients (21 percent) had an isolated episode of atrial fibrillation, 56 (58 percent) had recurrent atrial fibrillation, and 21 (22 percent) had chronic atrial fibrillation. The total follow-up period was 1440 person-years, with a mean of 14.8 years per patient. The mean age at diagnosis was 44 years. Nineteen cardiovascular events occurred in 17 patients; 4 patients had strokes thought to be due to emboli from atrial fibrillation, and 4 had myocardial infarctions without overt evidence of previous coronary artery disease. The probability of survival at 15 years was 94 percent among the patients with lone atrial fibrillation. At 15 years, 1.3 percent of the patients had had a stroke on a cumulative actuarial basis. On an actuarial basis, there was no difference in survival or in survival free of stroke among the patients with the three types of lone atrial fibrillation (i.e., isolated, recurrent, and chronic). We conclude that lone atrial fibrillation in patients under the age of 60 at diagnosis is associated with a very low risk of stroke. This suggests that routine anticoagulation may not be warranted.

A CLINICAL TRIAL OF A CHEST-PAIN OBSERVATION UNIT FOR PATIENTS WITH UNSTABLE ANGINA

BACKGROUND Nearly half of patients hospitalized with unstable angina eventually receive a non-cardiac-related diagnosis, yet 5 percent of patients with myocardial infarction are inappropriately discharged from the emergency department. We evaluated the safety, efficacy, and cost of admission to a chest-pain observation unit (CPU) located in the emergency department for such patients. METHODS We performed a community-based, prospective, randomized trial of the safety, efficacy, and cost of admission to a CPU as compared with those of regular hospital admission for patients with unstable angina who were considered to be at intermediate risk for cardiovascular events in the short term. A total of 424 eligible patients were randomly assigned to routine hospital admission (a monitored bed under the care of the cardiology service) or admission to the CPU (where patients were cared for according to a strict protocol including aspirin, heparin, continuous ST-segment monitoring, determination of creatine kinase isoenzyme levels, six hours of observation, and a study of cardiac function). The CPU was managed by the emergency department staff. Patients whose test results were negative were discharged, and the others were hospitalized. Primary outcomes (nonfatal myocardial infarction, death, acute congestive heart failure, stroke, or out-of-hospital cardiac arrest) and use of resources were compared between the two groups. RESULTS The 212 patients in the hospital-admission group had 15 primary events (13 myocardial infarctions and 2 cases of congestive heart failure), and the 212 patients in the CPU group had 7 events (5 myocardial infarctions, 1 death from cardiovascular causes, and 1 case of congestive heart failure). There was no significant difference in the rate of cardiac events between the two groups (odds ratio for the CPU group as compared with the hospital-admission group, 0.50; 95 percent confidence interval, 0.20 to 1.24). No primary events occurred among the 97 patients who were assigned to the CPU and discharged. Resource use during the first six months was greater among patients assigned to hospital admission than among those assigned to the CPU (P<0.01 by the rank-sum test). CONCLUSIONS A CPU located in the emergency department can be a safe, effective, and cost-saving means of ensuring that patients with unstable angina who are considered to be at intermediate risk of cardiovascular events receive appropriate care.

Idiopathic Short QT Interval:A New Clinical Syndrome?

In this first clinical report of an idiopathic familial persistently short QT interval (QTI), we describe three members of one family (a 17-year-old female, her 21-year-old brother, and their 51-year-old mother) demonstrating this ECG phenomenon, associated in the 17-year-old with several episodes of paroxysmal atrial fibrillation requiring electrical cardioversion. Similar ECG changes seen in an unrelated 37-year-old patient were associated with sudden cardiac death. Our report also describes other manifestations of abnormal shortening of the QTI and considers the possible arrhythmogenic potential of the short QTI.

Monoclonal T-Cell Proliferation and Plaque Instability in Acute Coronary Syndromes

BACKGROUND Unstable angina (UA) is associated with systemic inflammation and with expansion of interferon-gamma-producing T lymphocytes. The cause of T-cell activation and the precise role of activated T cells in plaque instability are not understood. METHODS AND RESULTS Peripheral blood T cells from 34 patients with stable angina and 34 patients with UA were compared for the distribution of functional T-cell subsets by flow cytometric analysis. Clonality within the T-cell compartment was identified by T-cell receptor spectrotyping and subsequent sequencing. Tissue-infiltrating T cells were examined in extracts from coronary arteries containing stable or unstable plaque. The subset of CD4(+)CD28(null) T cells was expanded in patients with UA and infrequent in patients with stable angina (median frequencies: 10.8% versus 1.5%, P<0.001). CD4(+)CD28(null) T cells included a large monoclonal population, with 59 clonotypes isolated from 20 UA patients. T-cell clonotypes from different UA patients used antigen receptors with similar sequences. T-cell receptor sequences derived from monoclonal T-cell populations were detected in the culprit but not in the nonculprit lesion of a patient with fatal myocardial infarction. CONCLUSIONS UA is associated with the emergence of monoclonal T-cell populations, analogous to monoclonal gammopathy of unknown significance. Shared T-cell receptor sequences in clonotypes of different patients implicate chronic stimulation by a common antigen, for example, persistent infection. The unstable plaque but not the stable plaque is invaded by clonally expanded T cells, suggesting a direct involvement of these lymphocytes in plaque disruption.

Perturbation of the T-Cell Repertoire in Patients With Unstable Angina

BACKGROUND Monocytes are constitutively activated in unstable angina (UA), resulting in the production of IL-6 and the upregulation of acute phase proteins. Underlying mechanisms are not understood. To explore whether the production of the potent monocyte activator IFN-gamma is altered in UA, we compared cytokine production by T lymphocytes in patients with UA (Braunwalds class IIIB) and with stable angina (SA). METHODS AND RESULTS Peripheral blood lymphocytes were collected at the time of hospitalization and after 2 and 12 weeks. Cytokine-producing CD4(+) and CD8(+) T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA was associated with an increased number of CD4(+) and CD8(+) T cells producing IFN-gamma, whereas patients with SA had higher frequencies of IL-2(+) and IL-4(+) CD4(+) T cells. Expansion of the IFN-gamma( +) T-cell population in UA persisted for at least 3 months. Increased production of IFN-gamma in UA could be attributed to the expansion of an unusual subset of T cells, CD4(+)CD28(null) T cells. CONCLUSIONS Patients with UA are characterized by a perturbation of the functional T-cell repertoire with a bias toward IFN-gamma production, suggesting that monocyte activation and acute phase responses are consequences of T-cell activation. IFN-gamma is produced by CD4(+)CD28(null) T cells, which are expanded in UA and distinctly low in SA and controls. The emergence of CD4(+)CD28(null) T cells may result from persistent antigenic stimulation.

Long-Term Progression and Outcomes With Aging in Patients With Lone Atrial Fibrillation: A 30-Year Follow-Up Study

Background— The long-term natural history of lone atrial fibrillation is unknown. Our objective was to determine the rate and predictors of progression from paroxysmal to permanent atrial fibrillation over 30 years and the long-term risk of heart failure, thromboembolism, and death compared with a control population. Methods and Results— A previously characterized Olmsted County, Minnesota, population with first episode of documented atrial fibrillation between 1950 and 1980 and no concomitant heart disease or hypertension was followed up long term. Of this unique cohort, 76 patients with paroxysmal (n=34), persistent (n=37), or permanent (n=5) lone atrial fibrillation at initial diagnosis met inclusion criteria (mean age at diagnosis, 44.2±11.7 years; male, 78%). Mean duration of follow-up was 25.2±9.5 years. Of 71 patients with paroxysmal or persistent atrial fibrillation, 22 had progression to permanent atrial fibrillation. Overall survival of the 76 patients with lone atrial fibrillation was 92% and 68% at 15 and 30 years, respectively, similar to 86% and 57% survival for the age- and sex-matched Minnesota population. Observed survival free of heart failure was slightly worse than expected (P=0.051). Risk for stroke or transient ischemic attack was similar to the expected population risk during the initial 25 years of follow-up but increased thereafter (P=0.004), although CIs were wide. All patients who had a cerebrovascular event had developed ≥1 risk factor for thromboembolism. Conclusions— Comorbidities significantly modulate progression and complications of atrial fibrillation. Age or development of hypertension increases thromboembolic risk.

Outcome of valve repair and the cox maze procedure for mitral regurgitation and associated atrial fibrillation

OBJECTIVE The objective was to determine whether the Cox maze procedure provides adjunctive benefit in patients with atrial fibrillation undergoing mitral valve repair. METHODS We compared the outcome of 39 patients who had the Cox maze procedure plus mitral valve repair between January 1993 and December 1996 (maze group) with that of 58 patients with preoperative atrial fibrillation who had mitral valve repair during the same interval by the same surgeons (control group). Patients in the 2 cohorts were similar for age, gender, preoperative New York Heart Association class III or IV, and duration of preoperative atrial fibrillation. The control group had a higher incidence of previous heart surgery and coronary artery disease. RESULTS No operative deaths occurred, and 1 patient in each group required pacemaker implantation after the operation. Duration of cardiopulmonary bypass (122 +/- 40 minutes vs 58 +/- 27 minutes, P <.0001) and hospitalization (12.6 +/- 6.4 vs 9.3 +/- 3.4 days, P <.0025) were prolonged in patients having the Cox maze procedure. Overall, 2-year survival was similar (92% +/- 5% for maze patients and 96% +/- 3% for controls). Freedom from atrial fibrillation in the maze group was 74% +/- 8% 2 years after the operation compared with 27% +/- 7% for the control group (P <.0001). Freedom from stroke or anticoagulant-associated bleeding in the maze group was 100% 2 years after the operation compared with 90% +/- 8% in the control group (P =.04). At most recent follow-up, 82% of maze patients were in normal sinus rhythm (53% in control group). CONCLUSION The addition of the Cox maze procedure to mitral valve repair is safe and effective for selected patients, and elimination of atrial fibrillation decreased late complications.

An assessment by the Statin Muscle Safety Task Force: 2014 update

The National Lipid Associations Muscle Safety Expert Panel was charged with the duty of examining the definitions for statin-associated muscle adverse events, development of a clinical index to assess myalgia, and the use of diagnostic neuromuscular studies to investigate muscle adverse events. We provide guidance as to when a patient should be considered for referral to neuromuscular specialists and indications for the performance of a skeletal muscle biopsy. Based on this review of evidence, we developed an algorithm for the evaluation and treatment of patients who may be intolerant to statins as the result of adverse muscle events. The panel was composed of clinical cardiologists, clinical lipidologists, an exercise physiologist, and a neuromuscular specialist.

Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial

BACKGROUND Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. METHODS ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. RESULTS Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). CONCLUSIONS Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.

Preoperative Aspirin Therapy Is Associated With Improved Postoperative Outcomes in Patients Undergoing Coronary Artery Bypass Grafting

Background—Aspirin is beneficial in the setting of atherosclerotic cardiovascular disease. There are limited data evaluating preoperative aspirin administration preceding coronary artery bypass grafting and associated postoperative outcomes. Methods and Results—Using prospectively collected data from 1636 consecutive patients undergoing first-time isolated coronary artery bypass surgery at our institution from January 2000 through December 2002, we evaluated the association between aspirin usage within the 5 days preceding coronary bypass surgery and risk of adverse in-hospital postoperative events. A logistic regression model, which included propensity scores, was used to adjust for remaining differences between groups. Overall, there were 36 deaths (2.2%) and 48 adverse cerebrovascular events (2.9%) in the postoperative hospitalization period. Patients receiving preoperative aspirin (n=1316) had significantly lower postoperative in-hospital mortality compared with those not receiving preoperative aspirin [1.7% versus 4.4%; adjusted odds ratio (OR), 0.34; 95% CI, 0.15 to 0.75; P=0.007]. Rates of postoperative cerebrovascular events were similar between groups (2.7% versus 3.8%; adjusted OR, 0.67; 95% CI, 0.32 to 1.50; P=0.31). Preoperative aspirin therapy was not associated with an increased risk of reoperation for bleeding (3.5% versus 3.4%; P=0.96) or requirement for postoperative blood product transfusion (adjusted OR, 1.17; 95% CI, 0.88 to 1.54; P=0.28). Conclusions—Aspirin usage within the 5 days preceding coronary artery bypass surgery is associated with a lower risk of postoperative in-hospital mortality and appears to be safe without an associated increased risk of reoperation for bleeding or need for blood product transfusion.