Whole Blood Gene Expression Differentiates between Atrial Fibrillation and Sinus Rhythm after Cardioversion.

BACKGROUND: Treatment to restore sinus rhythm among patients with atrial fibrillation (AF) has limited long-term success rates. Gene expression profiling may provide new insights into AF pathophysiology. OBJECTIVE: To identify biomarkers and improve our understanding of AF pathophysiology by comparing whole blood gene expression before and after electrical cardioversion (ECV). METHODS: In 46 patients with persistent AF that underwent ECV, whole blood samples were collected 1-2 hours before and 4 to 6 weeks after successful cardioversion. The paired samples were sent for microarray and plasma biomarker comparison. RESULTS: Of 13,942 genes tested, expression of SLC25A20 and PDK4 had the strongest associations with AF. Post-cardioversion, SLC25A20 and PDK4 expression decreased by 0.8 (CI 0.7-0.8, p = 2.0x10-6) and 0.7 (CI 0.6-0.8, p = 3.0x10-5) fold respectively. Median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations decreased from 127.7 pg/mL to 44.9 pg/mL (p = 2.3x10-13) after cardioversion. AF discrimination models combining NT-proBNP and gene expression (NT-proBNP + SLC25A20 area under the curve = 0.88, NT-proBNP + PDK4 AUC = 0.86) had greater discriminative capacity as compared with NT-proBNP alone (AUC = 0.82). Moreover, a model including NT-proBNP, SLC25A20 and PDK4 significantly improved AF discrimination as compared with other models (AUC = 0.87, Net Reclassification Index >0.56, p<5.8x10-3). We validated the association between SLC25A20 and PDK4 with AF in an independent sample of 17 patients. CONCLUSION: This study demonstrates that SLC25A20, PDK4, and NT-proBNP have incremental utility as biomarkers discriminating AF from sinus rhythm. Elevated SLC25A20 and PDK4 expression during AF indicates an important role for energy metabolism in AF.

Mean platelet volume is related with ischemic stroke in patients with sinus rhythm.

Stroke is the leading cause of disability worldwide. It is known that atrial fibrillation and left atrial enlargement contribute ischemic stroke, and mean platelet volume (MPV) increases in patients with ischemic stroke and atrial fibrillation. We aimed to determine whether higher MPV is associated with ischemic stroke in patients with sinus rhythm. We evaluated 74 patients in sinus rhythm and with ischemic stroke (Group 1) and 90 age-matched and sex-matched healthy individuals as control group (Group 2). After physical and echocardiographic examination, 24-48 h Holter monitoring and complete blood counts were studied. There were no statistically significant differences in age, sex rates, and comorbidities between groups. Left atrial diameter was higher in Group 1 than Group 2 (P = 0.001), but both were in normal range. MPV was significantly higher in Group 1 (P < 0.001) and was an independent determinant [odds ratio (OR): 1.840; P < 0.001; 95% confidence interval (CI) 1.330-2.545] of ischemic stroke with left atrial (OR: 1.138; P = 0.006; 95% CI 1.037-1.248). In conclusion, higher MPV is associated with acute ischemic stroke in patients with sinus rhythm and without heart failure or left atrial enlargement. MPV and left atrial diameter are independent predictors of ischemic stroke in this patient population.

ECG Case of the Month: Unexpected Atrioventricular Conduction in High-Grade Atrioventricular Block. Sinus rhythm; high-grade second degree atrioventricular block with a junctional escape rhythm and three capture complexes, each with right bundle branch block aberration; possible septal myocardial infarct of indeterminate age; ST-T and U wave changes suggesting hypokalemia.

A 90-year-old man with a history of high blood pressure, a cerebrovascular accident without focal residua, dementia, and stage 3 chronic kidney disease went to the emergency department because of dizziness and near syncope. His medications were aspirin 81 mg qd, clopidogrel 75 mg qod, escitalopram oxalate 10 mg qd, Seroquel 25 mg qd, and memantine hydrochloride 10 mg qd. He had orthostatic hypotension with supine blood pressure of 173/77 mm Hg falling to 116/68 on standing, while pulse increased from 66 to 84 beats/ min. He received IV fluid and returned home. Two days later he saw his primary care physician because of episodes of dizziness and confusion. The figure shows an electrocardiogram recorded during that visit.

Cost of acute stroke care for patients with atrial fibrillation compared with those in sinus rhythm.

BACKGROUND: Atrial fibrillation (AF) is a major risk factor for stroke. Cost-effectiveness studies of anticoagulants for stroke prevention in AF rarely utilise AF-stroke-specific cost data in their analyses, as data are limited. Data that exist do not account for AF found on prolonged cardiac monitoring after stroke, further underestimating the clinical and economic burden of AF-stroke. OBJECTIVE: Our objective was to investigate differences in direct medical costs of acute stroke care among patients with and without AF. METHODS: Data were prospectively collected from 213 consecutive patients with confirmed stroke (196 ischaemic [IS], 17 intracranial haemorrhage [ICH]), admitted to a UK district general hospital between November 2011 and October 2012. Sociodemographic, clinical and cardiac monitoring characteristics were recorded, and resource use was calculated using a 'bottom-up' approach. Univariate and multivariate stepwise regressions were performed to identify predictors of direct cost. RESULTS: Among patients with IS, 73 had AF (37%). These patients were older, experienced greater stroke severity, lengths of hospitalisation, inpatient mortality and discharge to institutionalised care than those without AF. Mean acute care costs for the year 2012 were £6,978 (standard deviation [SD] 6,769, range 510-36,952). Mean (SD) costs were significantly higher for patients with AF than for those without (£9,083 [7,381] vs. £5,729 [6,071], p = <0.001). AF independently predicted acute care cost along with history of heart failure and stroke severity. The adjusted independent effect of having AF on costs was an additional £2,173 (95% confidence interval 91-4,254; p = 0.041). Costs for patients with an ICH did not differ according to cardiac rhythm. CONCLUSION: Direct medical costs of acute stroke care for patients with AF may be 50% greater than for patients without. Economic studies should take this into account to ensure the benefits of anticoagulants are not underestimated.

A decrease in serum aldosterone level is associated with maintenance of sinus rhythm after successful cardioversion of atrial fibrillation.

BACKGROUND: The activation of the renin-angiotensin-aldosterone system has been implicated in the progression of atrial structural remodeling during atrial fibrillation (AF). However, consequences of the changes of aldosterone in AF have not been evaluated. OBJECTIVES: This study's aim was to evaluate changes of serum aldosterone concentration after successful cardioversion of persistent AF and to determine the prognostic value of these changes. METHODS: The prospective, single center study included 45 consecutive patients with nonvalvular persistent AF and preserved left ventricular systolic function, referred for cardioversion. None of the patients were taking aldosterone antagonists. Blood samples for aldosterone measurement were collected twice: 24 hours before and 24 hours after cardioversion. RESULTS: Forty-three patients were successfully converted to sinus rhythm. On the 30th day following cardioversion, 24 patients maintained sinus rhythm (group A), 19 patients relapsed to AF (group B). Serum aldosterone concentration before cardioversion did not differ significantly between both groups (175.6 +/- 112.82 pg/mL vs 125.8 +/- 51.2 pg/mL; P = 0.25). However, in group A serum aldosterone level decreased significantly within 24 hours after cardioversion, from 175.6 +/- 112.8 pg/mL to 101.4 +/- 44.2 pg/mL (P = 0.0034). In group B, the aldosterone level before and after cardioversion did not differ significantly (125.8 +/- 51.2 pg/mL vs 118.2 +/- 59.6 pg/mL; P = 0.68). Logistic regression analysis revealed that a decrease in plasma aldosterone concentration after direct current cardioversion more than 13.2 pg/mL predicted sinus rhythm maintenance in a 30-day follow-up, with 87% sensitivity and 64% specificity. CONCLUSIONS: There is a positive correlation between the fall in aldosterone concentration 24 hours after cardioversion and maintenance of sinus rhythm during 30 days of observation.

Thoracic aortic plaque enhances hypercoagulability in patients with nonrheumatic atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) are at risk for thromboembolism, and coexistent cardiovascular diseases could affect their prothrombotic profiles. The relationship between plasma hemostatic markers and aortic atherosclerosis was determined in patients with AF or in sinus rhythm (SR). METHODS AND RESULTS: Sixty patients with nonrheumatic AF and 46 patients in SR who underwent transesophageal echocardiography and did not receive anticoagulant therapy constituted the study group. Markers for platelet activity (platelet factor 4 and beta-thromboglobulin), thrombotic status (thrombin-antithrombin III complex and prothrombin fragment 1+2 (F1+2)) and fibrinolytic status (plasmin-alpha2-plasmin inhibitor complex (PIC) and D-dimer) were determined. Levels of F1+2, PIC and D-dimer were higher in AF patients with severe atheroma than in those without severe atheroma (p<0.05). In patients in SR, hemostatic markers were not significantly increased even if they had severe aortic atherosclerosis. AF (Odds ratio (OR) 4.06, p=0.04) and age>or=75 years (OR 3.98, p=0.02) were independently predictive of elevated D-dimer levels and severe atheroma was predictive of elevated F1+2 levels (OR 5.52, p=0.04). CONCLUSIONS: Elderly patients with AF and severe aortic atherosclerosis might be in a prothrombotic state, and could benefit from intensive antithrombotic therapy.

CO2-dependent components of sinus arrhythmia from the start of breath holding in humans.

A substantial portion of sinus arrhythmia in conscious humans appears to be caused by the CO2-dependent central respiratory rhythm. Under some circumstances, therefore, sinus arrhythmia might indicate the presence of the central respiratory rhythm. Humans can voluntarily modify their central respiratory rhythm (e.g., by pacing breathing or by delaying or advancing breaths), but it is not clear what happens to it from the start of breath holding. In this study, we show that sinus arrhythmia persists from the start of breath holds prolonged by preoxygenation. We also show that some of the frequency components of sinus arrhythmia start within each subject's eupneic frequency range and change when end-tidal Pco2 is lowered or raised, as we would expect if the central respiratory rhythm continues from the start of breath holding. We discuss whether sinus arrhythmia can indicate if the central respiratory rhythm continues from the start of breath holding.

Acute moderate alcohol consumption affects cardiovascular responses in healthy males with different tolerance levels.

We investigated the effect of acute moderate alcohol consumption or placebo on respiratory sinus arrhythmia (RSA) in 48 healthy participants with different levels of alcohol tolerance but no abuse. In the electrocardiogram recording, auditory stimuli were presented at defined points in the respiratory cycle, which allows a non-invasive measure of CNS control over RSA. After alcohol consumption we found a decrease in RSA with auditory stimulation. Moreover, individuals with low tolerance showed only a slight change in the RSA after alcohol intake compared to baseline, whereas the placebo drink led to a reduced RSA. In subjects with high alcohol tolerance, alcohol consumption led to a reduction of RSA, with no change after placebo. These results suggest a centrally driven influence on RSA that is changed by alcohol ingestion depending upon subjects' levels of alcohol tolerance.

Direct effect of Pa(CO2) on respiratory sinus arrhythmia in conscious humans.

Respiratory sinus arrhythmia (RSA) may improve the efficiency of pulmonary gas exchange by matching the pulmonary blood flow to lung volume during each respiratory cycle. If so, an increased demand for pulmonary gas exchange may enhance RSA magnitude. We therefore tested the hypothesis that CO2 directly affects RSA in conscious humans even when changes in tidal volume (V(T)) and breathing frequency (F(B)), which indirectly affect RSA, are prevented. In seven healthy subjects, we adjusted end-tidal PCO2 (PET(CO2)) to 30, 40, or 50 mmHg in random order at constant V(T) and F(B). The mean amplitude of the high-frequency component of R-R interval variation was used as a quantitative assessment of RSA magnitude. RSA magnitude increased progressively with PET(CO2) (P < 0.001). Mean R-R interval did not differ at PET(CO2) of 40 and 50 mmHg but was less at 30 mmHg (P < 0.05). Because V(T) and F(B) were constant, these results support our hypothesis that increased CO2 directly increases RSA magnitude, probably via a direct effect on medullary mechanisms generating RSA.

Deficits of respiratory-cardiac coupling in heavy drinkers.

1. Physiological evidence of chronic alcohol abuse prior to the onset of clinical signs of alcohol dependence is difficult to obtain The purpose of this study was to search for possible non-invasive indicators for chronic alcohol consumption yielding information in addition to conventional biological markers. 2. The authors investigated the relationship between respiratory-cardiac coupling and blood alcohol concentration (BAC) in male subjects who lost their driver's license from drunk driving. 3. We found that subjects who had a high BAC level (0.16-0.31% at the time of offense) show altered respiratory sinus arrhythmia (RSA) and, in particular, an altered heart-rate response to auditory stimulation and compared them to a control group of social drinkers. Normal subjects showed a pronounced acoustic heart-rate response, i.e., particularly during expiration there was a difference between the interbeat-interval (IBI) traces with and without auditory stimulation. Subjects who had lost their driver's license from drunk driving had an overall severely reduced heart-rate response, that was even absent particularly in the subgroup having high BAC values (0.21-0.31%). The authors also found some evidence that in the latter subgroup IBI, RSA, and acoustic heart-rate responses partially recover after a six-month period of abstinence. 4. Specific parameters of the acoustic heart-rate response are changed in our group of alcohol abusers presumably, due to impairment of vagal function. These parameters may therefore be useful to serve as a non-invasive measure of alcohol abuse.

Therapeutic effects of imipramine are counteracted by its metabolite, desipramine, in patients with generalized anxiety disorder.

Imipramine has been shown to reduce anxiety in patients with generalized anxiety disorder (GAD). However, some properties of imipramine may diminish or counteract its anxiolytic effects. The authors previously found that the greater the reduction in cardiac vagal control after 6 weeks of imipramine treatment, the smaller the improvement in anxiety-related symptoms. The purpose of this study was to determine whether the authors' previous findings were replicable and to gather information on the plasma levels of imipramine, desipramine (the major metabolite of imipramine), and anticholinergic levels. Fourteen patients with GAD were administered imipramine for 6 weeks. Their scores from self-administered and investigator-administered rating scales were obtained before and after the treatment, and the changes in these scores were contrasted with the changes in cardiac vagal tone, along with the absolute plasma levels of imipramine, desipramine, and anticholinergic activity at the end of week 6. The authors observed a greater improvement in symptoms of anxiety in those who showed the smallest decreases in cardiac vagal tone and in those who showed the smallest increases in desipramine and anticholinergic plasma levels. Moreover, strong relationships were observed between desipramine and anticholinergic levels. These results demonstrate that imipramine not only has therapeutic effects, but it may also have properties that result in physiologic states that counteract its therapeutic effects. Future research should investigate the direct anticholinergic effects of desipramine and determine whether there is a parallel between the anticholinergic effects and the clinical outcome of other pharmacologic treatments, including antidepressants with predominantly norepinephrine or serotonin reuptake inhibitory properties.

[Use of digitalis in geriatrics: is it effective on the heart in sinus rhythm?]. / L'uso della digitale in geriatria: è utile nel cuore in ritmo sinusale?

The therapeutic activity of digitalis in cardiac failure is linked to its positive inotropic effect on the myocardium and its ability to control cardiac activity in atrial fibrillation. Chronic stimulation with digoxin in aged subjects with sinus rhythm, however, is of debatable utility Reference is made to a series of 35 subjects (mean age 76.5 yr) in sinus rhythm, 30 of whom had been taking digoxin for over 3 yr. Clinical and instrumental parameters were assessed and heart function was classified according to the NYHA arrangement. Subjects were randomly placed in two groups matched for sex, age and cardiac condition. The first group received digoxin, the second a placebo. No significant differences between the two groups were noted over a 3-month period. In keeping with the recent literature, it is felt that digitalis is not necessary for the dynamic cardiac control of aged subjects in sinus rhythm. In addition, it is suggested that hydrosaline retention in such subjects can be controlled by restriction of salt intake, rest and diuretics.