Tommaso Sanna

Cryptogenic stroke and underlying atrial fibrillation

BACKGROUND Current guidelines recommend at least 24 hours of electrocardiographic (ECG) monitoring after an ischemic stroke to rule out atrial fibrillation. However, the most effective duration and type of monitoring have not been established, and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20 to 40% of cases (cryptogenic stroke). Detection of atrial fibrillation after cryptogenic stroke has therapeutic implications. METHODS We conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Patients 40 years of age or older with no evidence of atrial fibrillation during at least 24 hours of ECG monitoring underwent randomization within 90 days after the index event. The primary end point was the time to first detection of atrial fibrillation (lasting >30 seconds) within 6 months. Among the secondary end points was the time to first detection of atrial fibrillation within 12 months. Data were analyzed according to the intention-to-treat principle. RESULTS By 6 months, atrial fibrillation had been detected in 8.9% of patients in the ICM group (19 patients) versus 1.4% of patients in the control group (3 patients) (hazard ratio, 6.4; 95% confidence interval [CI], 1.9 to 21.7; P<0.001). By 12 months, atrial fibrillation had been detected in 12.4% of patients in the ICM group (29 patients) versus 2.0% of patients in the control group (4 patients) (hazard ratio, 7.3; 95% CI, 2.6 to 20.8; P<0.001). CONCLUSIONS ECG monitoring with an ICM was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke. (Funded by Medtronic; CRYSTAL AF ClinicalTrials.gov number, NCT00924638.).

Major Racial Differences in Coronary Constrictor Response Between Japanese and Caucasians With Recent Myocardial Infarction

BACKGROUND Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial. METHODS AND RESULTS The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non-infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183+/-59 versus 247+/-53 mg/dL, P<0.006) but showed a lower incidence of vasodilation (2% versus 9% of coronary segments) and a greater incidence of spasm after acetylcholine (47% versus 15% of arteries, P<0.00001). Incidence of spasm was higher in IRAs than in NIRAs in both populations (67% versus 39% and 23% versus 11%, respectively). Multivessel spasm was more common (64% versus 17%, P<0.02) and vasoconstriction of nonspastic segments was greater in Japanese patients (-23.4+/-14.9% versus -20.1+/-15.7%, P<0.02) in the presence of similar average basal coronary tone with respect to post-nitroglycerin dilation and of nonsignificant differences of coronary atherosclerotic score. CONCLUSIONS Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.

Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome.

Background— The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in Brugada syndrome is still debated. Methods and Results— We studied 18 consecutive patients (15 males, 3 females; mean age 42.0±12.4 years) with clinical phenotype of Brugada syndrome and normal cardiac structure and function on noninvasive examinations. Clinical presentation was ventricular fibrillation in 7 patients, sustained polymorphic ventricular tachycardia in 7, and syncope in 4. All patients underwent cardiac catheterization, coronary and ventricular angiography, biventricular endomyocardial biopsy, and DNA screening of the SCN5A gene. Biopsy samples were processed for histology, electron microscopy, and molecular screening for viral genomes. Microaneurysms were detected in the right ventricle in 7 patients and also in the left ventricle in 4 of them. Histology showed a prevalent or localized right ventricular myocarditis in 14 patients, with detectable viral genomes in 4; right ventricular cardiomyopathy in 1 patient; and cardiomyopathic changes in 3. Genetic studies identified 4 carriers of SCN5A gene mutations that cause in vitro abnormal function of mutant proteins. In these patients, myocyte cytoplasm degeneration was present at histology, whereas terminal dUTP nick end-labeling assay showed a significant increase of apoptotic myocytes in right and left ventricle versus normal controls (P=0.014 and P=0.013, respectively). Conclusions— Despite an apparently normal heart at noninvasive evaluation, endomyocardial biopsy detected structural alterations in all 18 patients with Brugada syndrome. Mutations in the SCN5A gene, identified in 4 of the 18 patients, may have induced concealed structural abnormalities of myocardiocytes that accounted for paroxysmal arrhythmic manifestations.

Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: A systematic review and meta-analysis. Part 2: Patients treated with therapeutic hypothermia

AIMS AND METHODS To systematically review the accuracy of early (≤7 days) predictors of poor outcome, defined as death or vegetative state (Cerebral Performance Categories [CPC] 4-5) or death, vegetative state or severe disability (CPC 3-5), in comatose adult survivors from cardiac arrest (CA) treated using therapeutic hypothermia (TH). Electronic databases were searched for eligible studies. Sensitivity, specificity, and false positive rates (FPR) for each predictor were calculated. Quality of evidence (QOE) was evaluated according to the GRADE guidelines. RESULTS 37 studies (2403 patients) were included. A bilaterally absent N20 SSEP wave during TH (4 studies; QOE: Moderate) or after rewarming (5 studies; QOE: Low), a nonreactive EEG background (3 studies; QOE: Low) after rewarming, a combination of absent pupillary light and corneal reflexes plus a motor response no better than extension (M≤2) (1 study; QOE: Very low) after rewarming predicted CPC 3-5 with 0% FPR and narrow (<10%) 95% confidence intervals. No consistent threshold for 0% FPR could be identified for blood levels of biomarkers. In 6/8 studies on SSEP, in 1/3 studies on EEG reactivity and in the single study on clinical examination the investigated predictor was used for decisions to withdraw treatment, causing the risk of a self-fulfilling prophecy. CONCLUSIONS in the first 7 days after CA, a bilaterally absent N20 SSEP wave anytime, a nonreactive EEG after rewarming or a combination of absent ocular reflexes and M≤2 after rewarming predicted CPC 3-5 with 0% FPR and narrow 95% CIs, but with a high risk of bias.

Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL AF): design and rationale.

BACKGROUND Patients with atrial fibrillation (AF) are at increased risk for ischemic stroke. In patients who have suffered a stroke, screening for AF is routinely performed only for a short period after the stroke as part of the evaluation for possible causes. If AF is detected after an ischemic stroke, oral anticoagulation therapy is recommended for secondary stroke prevention. In 25% to 30% of stroke patients, the stroke mechanism cannot be determined (cryptogenic stroke). The incidence of paroxysmal AF undetected by short-term monitoring in patients with cryptogenic stroke is unknown, but has important therapeutic implications on patient care. The optimum monitoring duration and method of AF detection after stroke are unknown. The purpose of this study is to evaluate the incidence of AF and time to AF detection in patients with cryptogenic stroke using an insertable cardiac monitor. STUDY DESIGN The CRYSTAL AF trial is a randomized prospective study to evaluate a novel approach to long-term monitoring for AF detection in patients with cryptogenic stroke. Four hundred fifty cryptogenic stroke patients (by definition, without a history of AF) will be enrolled at approximately 50 sites in Europe, Canada, and the United States. Patients will be randomized in a 1:1 fashion to standard arrhythmia monitoring (control arm) or implantation of the subcutaneous cardiac monitor (Reveal XT; Medtronic, Inc, Minneapolis, MN) (continuous monitoring arm). OUTCOMES The primary end point is time to detection of AF within 6 months after stroke. The clinical follow-up period will be at least 12 months. Study completion is expected at the end of 2012.

Uncovering Atrial Fibrillation Beyond Short-Term Monitoring in Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke and Underlying Atrial Fibrillation Trial.

Background—Atrial fibrillation (AF) can be a cause of previously diagnosed cryptogenic stroke. However, AF can be paroxysmal and asymptomatic, thereby making detection with routine ECG methods difficult. Oral anticoagulation is highly effective in reducing recurrent stroke in patients with AF, but its initiation is dependent on the detection of AF. Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) is the first randomized study to report the detection of AF in cryptogenic stroke patients using continuous long-term monitoring via insertable cardiac monitors (ICM). Methods and Results—Patients with prior cryptogenic stroke were randomized to control (n=220) or ICM (n=221) and followed for ⩽36 months. Cumulative AF detection rates in the ICM arm increased progressively during this period (3.7%, 8.9%, 12.4%, and 30.0% at 1, 6, 12, and 36 months, respectively), but remained low in the control arm (3.0% at 36 months). This resulted in oral anticoagulation prescription in 94.7% of ICM patients with AF detected at 6 months, 96.6% at 12 months, and 90.5% at 36 months. Among ICM patients with AF detected, the median time to AF detection was 8.4 months, 81.0% of first AF episodes were asymptomatic, and 94.9% had at least 1 day with >6 minutes of AF. Conclusions—Three-year monitoring by ICM in cryptogenic stroke patients demonstrated a significantly higher AF detection rate compared with routine care. Given the frequency of asymptomatic first episodes and the long median time to detection, these findings highlight the limitations of using traditional AF detection methods. The majority of patients with AF were prescribed oral anticoagulation therapy. Clinical Trial Registration—Clinicaltrials.gov; Unique identifier: NCT00924638.

Predictors for atrial fibrillation detection after cryptogenic stroke Results from CRYSTAL AF

Objective: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). Methods: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. Results: Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4–2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3–2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2–1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3–12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0–5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3–2.8], p = 0.0009) and PR interval (HR 1.3 [1.2–1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70–0.85). The same predictors were found at 36 months. Conclusion: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Risk of arrhythmias in myotonic dystrophy: trial design of the RAMYD study.

Objective Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. DM1 is a multisystem disorder also affecting the heart with an increased incidence of sudden death, which has been explained with the common impairment of the conduction system often requiring pacemaker implantation; however, the occurrence of sudden death despite pacemaker implantation and the observation of major ventricular arrhythmias generated the hypothesis that ventricular arrhythmias may play a causal role as well. The aim of the study was to assess the 2-year cumulative incidence and the value of noninvasive and invasive findings as predictive factors for sudden death, resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia and severe sinus dysfunction or high-degree atrioventricular block. Methods/design More than 500 DM1 patients will be evaluated at baseline with a clinical interview, 12-lead ECG, 24-h ECG and echocardiogram. Conventional and nonconventional indications to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implantation have been developed. In the case of an indication to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implant at baseline or at follow-up, the patient will be referred for the procedure. At the end of 2-year follow-up, all candidate prognostic factors will be tested for their association with the endpoints. Trial registration: ClinicalTrials.gov ID NCT00127582. Conclusion The available evidence supports the hypothesis that both bradyarrhythmias and tachyarrhythmias may cause sudden death in DM1, but the course of cardiac disease in DM1 is still unclear. We expect that this large, prospective, multicenter study will provide evidence to improve diagnostic and therapeutic strategies in DM1.

Infarct Topography and Detection of Atrial Fibrillation in Cryptogenic Stroke: Results from CRYSTAL AF.

Background: Insertable cardiac monitors (ICM) have been shown to detect atrial fibrillation (AF) at a higher rate than routine monitoring methods in patients with cryptogenic stroke (CS). However, it is unknown whether there are topographic patterns of brain infarction in patients with CS that are particularly associated with underlying AF. If such patterns exist, these could be used to help decide whether or not CS patients would benefit from long-term monitoring with an ICM. Methods: In this retrospective analysis, a neuro-radiologist blinded to clinical details reviewed brain images from 212 patients with CS who were enrolled in the ICM arm of the CRYptogenic STroke And underLying AF (CRYSTAL AF) trial. Kaplan-Meier estimates were used to describe rates of AF detection at 12 months in patients with and without pre-specified imaging characteristics. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values were calculated using Cox regression. Results: We did not find any pattern of acute brain infarction that was significantly associated with AF detection after CS. However, the presence of chronic brain infarctions (15.8 vs. 7.0%, HR 2.84, 95% CI 1.13-7.15, p = 0.02) or leukoaraiosis (18.2 vs. 7.9%, HR 2.94, 95% CI 1.28-6.71, p < 0.01) was associated with AF detection. There was a borderline significant association of AF detection with the presence of chronic territorial (defined as within the territory of a first or second degree branch of the circle of Willis) infarcts (20.9 vs. 10.0%, HR 2.37, 95% CI 0.98-5.72, p = 0.05). Conclusions: We found no evidence for an association between brain infarction pattern and AF detection using an ICM in patients with CS, although patients with coexisting chronic, as well as acute, brain infarcts had a higher rate of AF detection. Acute brain infarction topography does not reliably predict or exclude detection of underlying AF in patients with CS and should not be used to select patients for ICM after cryptogenic stroke.

Chronic autoimmune autonomic neuropathy responsive to immunosuppressive therapy

Autoimmune autonomic neuropathy refers to a group of autoimmune disorders characterized by the failure of both sympathetic and parasympathetic systems,1 related to the presence of autoantibodies against neuronal ganglionic acetylcholine (AChR) receptors.2 These antibodies are detectable in the serum of about 30% of patients with paraneoplastic-acquired autoimmune autonomic neuropathy and in 50% of patients with idiopathic subacute autoimmune autonomic neuropathy.3 We describe a 59-year-old woman who presented 6 months after the gradual development of severe dysautonomia, characterized by recurrent orthostatic syncope, dry mouth, early satiety, constipation, and urinary retention. Family history was negative and she denied any viral illness preceding the onset of the above symptoms. The results of physical examination showed her blood pressure to be 115/70 mm Hg in a supine position, but fell to 80/50 mm Hg in a sitting position; the patient was unable to stand upright for more than a few seconds because of a fainting sensation. Pupillary responses to light were torpid; however, the remaining neurologic examination was normal. Routine blood tests, including glucose determination, were normal. X-ray gastrointestinal transit evaluation after barium ingestion documented markedly delayed gut motility …