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BackgroundLow resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats.ObjectiveTo study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort.MethodsIn the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance.ResultsThere were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001).ConclusionLow mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Atrial fibrillation (AF) is defined as an irregular supraventricular tachycardia (SVT) without p waves, with duration30 seconds. Whether AF characteristics during short SVT episodes predict AF and stroke is not known.The purpose of this study was to determine whether irregularity and lack of p waves, alone or in combination, during short SVT episodes increase the risk of incident AF and ischemic stroke.The population-based Malmö Diet and Cancer study includes 24-hour ECG screening of 377 AF-free individuals (mean age 64.5 years; 43% men) who were prospectively followed for13 years. There were 65 AF events and 25 ischemic stroke events during follow-up. Subjects with an SVT episode ≥5 beats were identified, and the longest SVT episode was assessed for irregularity and lack of p waves. The association between SVT classification and AF and stroke was assessed using multivariable adjusted Cox regression.The incidence of AF increased with increasing abnormality of the SVTs. The risk-factor adjusted hazard ratio for AF was 4.95 (95% confidence interval 2.06-11.9; P.0001) for those with short irregular SVTs (70 beats) without p waves. The incidence of ischemic stroke was highest in the group with regular SVT episodes without p waves (hazard ratio 14.2; 95% confidence interval 3.76-57.6; P.0001, adjusted for age and sex).Characteristics of short SVT episodes detected at 24-hour ECG screening are associated with incident AF and ischemic stroke. Short irregular SVTs without p waves likely represent early stages of AF or atrial myopathy. Twenty-four-hour ECG could identify subjects suitable for primary prevention efforts.

Aims: ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmo Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development.Methods and results: There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women.Conclusion: ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk. (Less)

Aims Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs. Methods and results In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen, or warfarin. We used the updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI = 0, 1, 2, 3, and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories. There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI = 0 (P 0.10 for each). Conclusion Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs. warfarin were independent of the degree of comorbidity present.

Atrial fibrillation (AF) is a common clinically significant cardiac arrhythmia. This phase 3 randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to sinus rhythm in patients with recent-onset (>3 hours to ≤7 days) symptomatic AF from the Asia–Pacific region. Patients received an infusion of vernakalant (3 mg/kg) or placebo for 10 minutes. If AF had not been terminated 15 minutes later, a second infusion of vernakalant (2 mg/kg) or placebo for 15 minutes was administered. The primary efficacy end point was conversion of AF to sinus rhythm for >1 minute within 90 minutes. The study was terminated early for administrative reasons; 123 patients from Korea, Taiwan, and India were randomized to receive vernakalant (n = 55) or placebo (n = 56). A greater proportion of patients who received vernakalant (52.7%) than placebo (12.5%) met the primary end point (P < 0.001), and cardioversion was faster in the vernakalant group than in the placebo group (P < 0.001). Vernakalant was generally well tolerated; the incidence of treatment-emergent adverse events was similar between the groups. We conclude that vernakalant is efficacious in the rapid cardioversion of recent-onset AF in patients from the Asia–Pacific region.

Background Atrial fibrillation (AF) episodes are thought to be started by an electrical trigger reaching susceptible atria. Such a trigger could be present long before the occurrence of sustained symptomatic arrhythmia. Objective We sought to determine whether supraventricular extrasystoles (SVESs) and supraventricular tachycardias (SVTs) measured at 24-hour Holter electrocardiogram were associated with an increased incidence of AF. Methods In 1998–2000, 389 individuals (44% men; mean age 65 years) were examined using 24-hour Holter electrocardiogram. Six individuals with known prevalent AF were excluded. After a mean follow-up of 10.3 years, there were 45 cases of incident AF. Hazard ratios (HRs) were computed using multivariable Cox regression adjusting for age, sex, systolic blood pressure, height, weight, smoking, and homeostatic model assessment of insulin resistance. Results Frequency of SVESs as well as SVT episodes per hour were independent predictors of incident AF (HR per log unit 1.38; 95% confidence interval 1.14–1.68; P = .001 and HR 1.95; 95% confidence interval 1.21–3.13; P = .006, respectively). Further adjustment for education level, alcohol use, use of medication, and physical activity did not substantially alter the results, nor did analysis using competing risks regression accounting for a competing risk of death. The maximum duration of SVT or the heart rate at SVT was not significantly associated with the incidence of AF. Conclusion SVESs and SVTs independently predict AF. The prognostic significance was similar for SVESs, SVTs, and a combination of the two. Repeated efforts to detect AF could be of merit in individuals with frequent supraventricular activity.

The aim of the study was to investigate the resting levels of novel cardiovascular biomarkers in common types of noncardiac syncope.An observational study was conducted including 255 patients (mean age 60 years, range 15-93; 45% men) with unexplained syncopal attacks. Subjects underwent an expanded head-up tilt test including carotid sinus massage, and nitroglycerin provocation if indicated. Using logistic regression, we explored the associations between specific diagnoses of syncope and resting levels of circulating biomarkers: C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional fragments of pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM).A total of 142 (56%) patients were diagnosed with vasovagal syncope (VVS), 85 (33%) with orthostatic hypotension (OH) and 47 (18%) with carotid sinus hypersensitivity (CSH); in addition, 74 (29%) patients had more than one diagnosis. Thirty-five patients (14%) demonstrated a cardioinhibitory reflex. The probability of VVS was highest in the first quartile of MR-proANP [Q1 vs. Q4: odds ratio (OR) 5.57, 95% confidence interval (CI) 1.86-16.74; P0.001] and CT-proET-1 (OR 7.17, 95% CI 2.43-21.13; P0.001). By contrast, the probability of OH was highest in the fourth quartile of CT-proET-1 (Q4 vs. Q1: OR 8.66, 95% CI 2.49-30.17; P0.001). Furthermore, CSH was most frequently observed in the first quartile of MR-proANP (Q1 vs. Q4: OR 6.57, 95% CI 1.62-26.62; P = 0.008) among those over 60 years of age, whereas the cardioinhibitory reflex was strongly associated with low CT-proET-1 levels (Q1 vs. Q4: OR 69.7, 95% CI 6.97-696.6; P0.001). Moreover, in patients with VVS, a high concentration of CT-proET-1 was predictive of OH (OR per 1 SD 2.4, 95% CI 1.15-5.02; P = 0.02), whereas low CT-proET-1 suggested involvement of the cardioinhibitory reflex (OR per 1SD 0.42, 95% CI 0.25-0.70; P = 0.001).The levels of MR-proANP and CT-proET-1 are markedly changed in common forms of syncope, suggesting the involvement of novel neurohormonal mechanisms in syncopal attacks.

Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of vernakalant in converting atrial flutter (AFL) to sinus rhythm. This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg vernakalant (n 39) or placebo (n 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving vernakalant (1 of 39, 3) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving vernakalant (mean change from baseline 8.2 b.p.m.) vs. patients receiving placebo (0.2 b.p.m.) (P 0.037). A post-hoc analysis revealed that vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated. (Less)

Objective: Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity and premature death but the underlying mechanisms are incompletely understood. The aim of this study was to investigate if adrenergic dysfunction may be a contributing factor. Patients and methods: Forty-nine patients with mild PHPT (serum calcium 2.7 ± 0.1 mmol/L) and 48 control subjects, matched for age and sex, were examined; patients within 1 month before parathyroidectomy (PTX) and 6 months postoperatively; control subjects at inclusion. Heart rate variability (HRV) was analyzed in 24-hour electrocardiograms, and plasma concentrations of epinephrine and norepinephrine were measured at rest and immediately after standardized physical tests. Results: At baseline, the patients showed, compared to the controls, reduced stress-related increase of circulating epinephrine (P < 0.05) and norepinephrine (P < 0.05). No significant change was observed 6 months after PTX. At baseline, there were no significant differences between patients and controls in HRV or heart rate but 6 months after curative PTX, the patients showed significantly reduced HRV in both frequency and time domain, and their maximum and average heart rate had decreased (P = 0.011 and P = 0.018, respectively). The patients with the highest preoperative levels of circulating parathyroid hormone showed the greatest changes in heart rate and HRV postoperatively. Conclusions: This study demonstrates a previously unknown impairment of catecholamine response to physical stress in PHPT along with changes of HRV, also indicating adrenergic dysfunction. These factors should be considered in the ongoing controversy regarding the management of patients with mild "asymptomatic" PHPT. (Less)

The objective of the present study was to assess the safety and effectiveness of vernakalant hydrochloride injection (RSD1235), a novel antiarrhythmic drug, for the conversion of atrial fibrillation (AF) or atrial flutter to sinus rhythm (SR). Patients with either AF or atrial flutter were randomized in a 1:1 ratio to receive vernakalant (n = 138) or placebo (n = 138) and were stratified by an arrhythmia duration of >3 hours to ≤7 days (short duration) and 8 to ≤45 days (long duration). The first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if the arrhythmia had not terminated. A total of 265 patients were randomized and received treatment. The primary end point was conversion of AF to SR for ≥1 minute within 90 minutes of the start of the drug infusion in the short-duration AF group. Of the 86 patients receiving vernakalant in the short-duration AF group, 44 (51.2%) demonstrated conversion to SR compared to 3 (3.6%) of the 84 in the placebo group (p

Aims To investigate whether a systematic approach to unexplained syncopal attacks based on the European Society of Cardiology guidelines would improve the diagnostic and therapeutic outcomes. Methods and results Patients presenting with transient loss of consciousness to the Emergency Department of Skane University Hospital in Malmo were registered by triage staff. Those with established cardiac, neurological, or other definite aetiology and those with advanced dementia were excluded. The remaining patients were offered evaluation based on an expanded head-up tilt test protocol, which included carotid sinus massage, and nitroglycerine challenge if needed. Out of 201 patients registered over a period of 6 months, 129 (64.2%) were found to be eligible; of these, 101 (38.6% men, mean age 66.3 +/- 18.4 years) decided to participate in the study. Head-up tilt test allowed diagnoses in 91 cases (90.1%). Vasovagal syncope (VVS) was detected in 45, carotid sinus hypersensitivity (CSH) in 27, and orthostatic hypotension (OH) in 51 patients. Twelve patients with VVS and 15 with CSH also had OH, whereas 25 were diagnosed with OH only. In a multivariate logistic regression, OH was independently associated with age [OR (per year): 1.05, 95% CI 1.02-1.08, P = 0.001], history of hypertension (2.73, 1.05-7.09, P = 0.039), lowered estimated glomerular filtration rate (per 10 mL/min/1.73 m(2): 1.17, 1.01-1.33, P = 0.032), use of loop diuretics (10.44, 1.22-89.08, P = 0.032), and calcium-channel blockers (5.29, 1.03-27.14, P = 0.046), while CSH with age [(per year) 1.12, 1.05-1.19, P < 0.001), use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (4.46, 1.22-16.24, P = 0.023), and nitrates (27.88, 1.99-389.81, P = 0.013). Conclusion A systematic approach to patients presenting with unexplained syncopal attacks considerably increased diagnostic efficacy and accuracy. Potential syncope diagnoses have a tendency to overlap and show diversity in demographic, anamnestic, and pharmacological determinants. (Less)

Background— The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and Results— Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90 minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and received treatment (short duration, n=220; long duration, n=116). Of the 145 vernakalant patients, 75 (51.7%) in the short-duration AF group converted to sinus rhythm (median time, 11 minutes) compared with 3 of the 75 placebo patients (4.0%; P P Conclusion— Vernakalant demonstrated rapid conversion of short-duration AF and was well tolerated.

Background and Purpose— Patients with atrial fibrillation have a varied risk of stroke, depending on age and comorbid conditions. The objective of this study was to assess the predictive value of stroke risk classification schemes and to identify patients with atrial fibrillation who are at substantial risk of stroke despite optimal anticoagulant therapy. Methods— Seven recognized classification schemes—the American College of Chest Physicians 2001, American College of Chest Physicians 2004, Stroke Prevention in Atrial Fibrillation (SPAF), Atrial Fibrillation Investigators, Framingham, van Walraven, and CHADS 2 —were compared for their ability to predict ischemic stroke in patients receiving anticoagulant therapy. Data came from the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials, which compared the efficacy of adjusted-dose warfarin and the direct thrombin inhibitor ximelagatran (36 mg twice daily) in preventing thromboembolic events in 7329 patients with chronic or paroxysmal nonvalvular atrial fibrillation who were at moderate or high risk of ischemic stroke. The main outcome measure was ischemic stroke, as determined by a central event adjudication committee. Results— During 11 245 patient-years of follow-up, 159 patients had an ischemic stroke (1.4%/year). As indicated by c statistics and hazard ratios, 3 of the classification schemes predicted stroke significantly better than chance: Framingham ( c =0.64), CHADS 2 ( c =0.65), and SPAF ( c =0.61). Conclusions— In a large cohort of atrial fibrillation patients at moderate or high risk of ischemic stroke treated with warfarin or ximelagatran, the CHADS 2 , SPAF, and Framingham schemes had greater predictive accuracy than chance. This predictive ability may allow clinicians to target high-risk patients for more aggressive intervention.

Background Ambulatory electrocardiogram monitoring (Holter) with ST-analysis as a measure of myocardial ichemia has in populations with coronary heart disease been shown to predict major coronary events: death, myocardial infarction or coronary revascularization. There has, however, been conflicting evidence regarding the usefulness of this technique in identification of healthy subjects with increased risk for coronary heart disease. The aim of this study was to assess if Holter monitoring with ST-analysis could be used to predict future major coronary events in asymptomatic middle-aged men with a defined aggregation of traditional risk factors for coronary heart disease. Methods One hundred and fifty-five asymptomatic participants from the city of Malmö, Sweden, with known levels of conventional cardiovascular risk factors underwent Holter monitoring for analysis of transient ST-segment depression at the age of 55 years. Fifteen years after the Holter monitoring, hospital records, diagnosis and death registries were revisited for major coronary events. Results An ST-segment depression of 1 mm or greater (0.1 mV) was considered significant for myocardial ischemia and was found in 54 of the 155 men. There were no significant differences in risk factors in the two groups at baseline. The 15-year incidence of a first major coronary event was significantly higher in men with ST-segment depression (39%) than in men without ST-segment depression (20%) ( P < 0.015). A Holter electrocardiogram could predict future major coronary events with a positive and negative predictive value of 35 and 80%, respectively. Conclusions Holter monitoring can be used as a complement to conventional risk factor evaluation in deciding whether or not to treat risk factors for CHD in asymptomatic subjects.

Objectives. To assess the optimal stroke prevention treatment for patients with atrial fibrillation (AF) and a low-medium risk ( Design. A total of 668 patients with persistent or permanent AF, without an indication for full dose and with adequate rate control on sotalol, were randomized to warfarin 1.25 mg + aspirin 75 mg daily (W/A, 334 patients) or no anticoagulation (C, 334 patients). The mean follow-up period was 33 months. The protocol intended to verify a 37% relative risk reduction provided a 4% stroke incidence in the C group. Results. The stroke incidence was less in the W/A group, although the reduction was not statistically significant (W/A 9.6% versus C 12.3%). Four haemorrhagic strokes were identified, two in each group. Secondary end-points were transient ischaemic attacks (TIA) (W/A 3.3% versus C 4.5%), all cause mortality (W/A 9.3% versus C 10.8%), cardiovascular morbidity (W/A 17.7% versus C 22.2%) and the combination of stroke + TIA (W/A 11.7% versus C 16.5%). Bleedings were documented in 19 versus four patients (W/A 5.7% versus C 1.2%) (P = 0.003), although none fatal. Sinus rhythm (SR) was recorded occasionally in 68 patients (W/A 9.6% versus C 10.8%). The stroke incidence tended to be higher in those with SR than without, 16.2% versus 10.4%. Conclusions. Our results were inconclusive, but consistent with a small beneficial effect of W/A for reduction of stroke and major vascular events in AF patients at moderate risk. The low-dose regiment produced, however, a significantly increased risk of bleedings. Documented SR occasionally recorded may represent a subpopulation that warrants full dose warfarin.

Background —Reduced lung function has been associated with increased rates of myocardial infarction. Whether the occurrence and prognostic significance of ventricular arrhythmia is related to lung function is largely unknown. Methods and Results —We performed a population-based study of 68-year-old men without a history of stroke or myocardial infarction; 402 men participated. Mortality and coronary events (fatal or nonfatal) were studied in relation to ventricular arrhythmia during 24 hours, percentage of the predicted forced expiratory volume (FEV1 %pred ), vital capacity (VC %pred ), and the FEV/VC ratio. During 14 years of follow-up, 181 men died and 87 experienced a coronary event. Occurrence of frequent or complex ventricular arrhythmia (Lown class 2 to 5) was significantly and inversely associated with FEV1 %pred . Men with Lown class 2 to 5 and a low FEV1 %pred (below median) had significantly higher mortality (71.5 versus 26.8 per 1000 person-years; P P =0.02) than men with Lown class 2 to 5 and a high FEV1 %pred . These associations remained significant after adjustments for potential confounders (mortality: relative risk [RR], 2.91; 95% CI,1.68 to 5.04; coronary events: RR, 2.16; 95% CI, 1.07 to 4.37). In men without frequent or complex arrhythmia (Lown 0 to 1), a low FEV1 %pred was not significantly associated with mortality (RR, 1.37; 95% CI, 0.92 to 2.05) or coronary events (RR, 1.24; 95% CI, 0.67 to 2.27) after adjustments for confounders. The FEV/VC ratio showed similar associations with arrhythmia, mortality, and coronary events. Conclusions —Lung function is inversely associated with the occurrence of ventricular arrhythmia. The increased incidence of myocardial infarction and death associated with arrhythmia was mainly limited to men with a low FEV1 %pred or FEV/VC. We suggest that lung function should be considered when assessing the prognostic significance of ventricular arrhythmia.

Background and Purpose —With the exception of atrial fibrillation (AF), little scientific attention has been given the associations between cardiac arrhythmias and incidence of stroke. We sought to study whether atrial and ventricular arrhythmias assessed during a 24-hour ambulatory ECG registration are associated with incidence of stroke. Methods —The population-based cohort “Men Born in 1914” was examined with 24-hour ambulatory ECG registrations at 68 years of age. Four hundred two men without previous myocardial infarction or stroke were included, and 236 of them had hypertension (≥160/95 mm Hg or treatment). Fourteen-year rates of stroke (fatal and nonfatal) and all-cause mortality were updated from national and regional registers. Frequent or complex ventricular arrhythmias was defined as Lown class 2 to 5. A high frequency of atrial ectopic beats (AEB) was defined as the fifth quintile (ie, ≥218 AEB per 24 hours). Results —Fifty-eight men suffered a first stroke during the follow-up. Stroke rates (per 1000 person-years) among men with AF (n=14), with frequent AEB (n=77), and without AF or frequent AEB (n=311) were 34.5, 19.5, and 11.6, respectively. The corresponding values among men with hypertension were 40.7, 32.3, and 14.7, respectively. Frequent AEB (compared with absence of AF and frequent AEB) was significantly associated with stroke among all men (relative risk=1.9; 95% CI, 1.02 to 3.4; P =0.04) and among hypertensive men (relative risk=2.5; 95% CI, 1.3 to 4.8; P =0.009) after adjustments for potential confounders. The increased stroke rates among men with Lown class 2 to 5 did not reach statistical significance. Conclusions —A high frequency of AEB is associated with an increased incidence of stroke.

To assess the effects of 6 months intervention with +ramipril on resting and post exercise left ventricular function in patients with stable ischaemic heart disease and preserved left ventricular systolic function.Patients (n=98, age 65+/-9 years, 37% women) were randomized to double-blind treatment with ramipril 5 mg. day(-1)(n=32), ramipril 1.25 mg. day(-1)(n=34), or placebo (n=32). Resting and post maximum exercise echocardiography/Doppler examinations were performed at baseline and after 6 months. Changes over 6 months in resting transmitral E-wave deceleration time (Edt) and Edt adjusted for heart rate (Edt/RR) differed between the ramipril 5 mg, ramipril 1.25 mg, and placebo groups: Edt 24+/-82, -1+/-69, and -29+/-64 ms, respectively, P=0. 012; Edt/RR 30+/-105, 2+/-61, and -28+/-69 ms, respectively, P=0.015. Changes in the difference between resting and post exercise Edt/RR also varied between groups: -53+/-137, -28+/-118, and 35+/-101 ms, respectively, P=0.029. No differences in E/A indices were noted. Resting atrioventricular plane displacement improved in the combined ramipril groups vs the placebo group: 0.2+/-0.8 vs -0.2+/-1.3 mm, P0.05.Conclusion Six months ramipril treatment in patients with stable ischaemic heart disease and preserved left ventricular systolic function improved resting left ventricular function and reduced the exercise induced diastolic filling abnormalities usually seen in these patients.

Engstrom G, Hedblad B, Janzon L, Juul-Moller S (Malmo University Hospital, Malmo, Sweden). Ventricular arrhythmias during 24-h ambulatory ECG recording: incidence, risk factors and prognosis in men with and without a history of cardiovascular disease. J Intern Med 1999; 246: 363–372. Objective. To study incidence, prognosis and risk factors of ventricular arrhythmias in men with and without asymptomatic non-invasively detected cardiovascular disease (CVD). Design. Prospective cohort study with 11 years’ follow-up. The subjects went through 24-h ambulatory electrocardiographic (ECG) registrations and non-invasive examinations of leg and carotid arteries at the baseline examination. Setting. Malmo, Sweden. Subjects. Four hundred and forty-three randomly selected 68-year-old men. Main outcome measures. Mortality and cardiac event rates during an 11-year period. Results. Frequent or complex arrhythmias (Lown class 2–5) were common in men both with and without CVD. However, the associated prognoses were different. In men with CVD, frequent or complex arrhythmias were associated with increased cardiac event rates (P = 0.001) and increased mortality (P = 0.054). This pattern was also found in men with asymptomatic leg and carotid artery disease, although the frequency of arrhythmia in Lown class 2–5 was similar to that in men without CVD. Men with angina pectoris or previous myocardial infarction in combination with leg or carotid artery disease had the most arrhythmias and the worst prognosis. No relationship between frequent or complex arrhythmias and mortality or cardiac events was found in men without CVD. In a logistic regression, smoking and diabetes mellitus were significant and independent determinants of frequent or complex arrhythmias in men with CVD. High alcohol consumption was associated with arrhythmias in men without CVD. Conclusion. Ambulatory ECG recording is a feasible method to improve risk assessment in men with CVD. In this group, frequent or complex arrhythmias are associated with smoking and diabetes mellitus.

Aim To assess to what extent do frequent or complex ventricular arrhythmias, detected during 24 h ambulatory electrocardiographic recording (ECG), influence prognosis with regard to survival and incidence of ischaemic heart disease. Methods and results The study subjects were the 456 randomly selected men born in 1914, the population-based cohort study of 1982–83, in Malmo, Sweden. The main outcome measures were total mortality and incidence of cardiac event (myocardial infarction and death from ischaemic heart disease). Frequent or complex ventricular arrhythmias (Lown classes 2–5) were detected in 49% of the men with (n=77), and in 35% of those without, a history of myocardial infarction or angina pectoris at baseline, P =0·019. Independent of clinically evident coronary artery disease at baseline, and after adjustment for traditional atherosclerotic risk factors and use of digitalis or betablocker therapy, frequent or complex ventricular arrhythmias were associated with an increased mortality from ischaemic heart disease (relative risk (RR), 2·1; 95% confidence interval (CI), 1·2–3·9) and an increased cardiac event rate (RR, 1·6; 95% CI, 1·0–2·5)). Men free from both ischaemic-type ST depression and frequent or complex ventricular arrhythmias (used as the control group) had the lowest ischaemic heart disease death rate, 5·9 per 1000 person-years. The combination of ST depression and frequent or complex ventricular arrhythmias was associated with an ischaemic heart disease death rate of 20·9 per 1000 person-years. The cardiac event rate in these two groups was 15·6 and 76·1 per 1000 person-years, respectively (adjusted RR, 2·3; CI, 1·1–4·6). Conclusion In elderly men without a history of myocardial infarction and angina pectoris, frequent or complex ventricular arrhythmias during ambulatory ECG recording is associated with an increased incidence of myocardial infarction and mortality. Men who, during ambulatory ECG recording, also demonstrate ST-segment depression have an even less favourable prognosis.

Objective: In order to assess the diagnostic accuracy of ST depression in the diagnosis of coronary artery disease (CAD) in patients with suspected myocardial ischemia we compared ST depression in 3-lead ambulatory ECG (AECG) with that of exercise tolerance testing (ETT). Methods: Significant coronary artery stenosis in coronary angiography was used as a standard reference. ST analysis could be performed in 106 of the investigated 113 patients, all with suspected CAD. One person with left bundle branch block was excluded from the ST analysis, and six persons could not perform ETT. Results: Seventy-eight of the 106 patients had at least one significant stenosis (> 70% narrowing) and 28 had no stenosis according to coronary angiography. The sensitivity for AECG was 62% and for ETT it was 63%, the specificity for AECG was 79% and for ETT the specificity was 57%. The accuracy for AECG was 66%, and for ETT it was 61%. We also evaluated late potentials (LPs) from the AECG tapes in order to correlate LP to left ventricular function (LVF), myocardial infarction (Ml), and/or CAD. We found that LP correlates better to advanced CAD than to Ml or LVF. Conclusion: The accuracy of ST diagnosis of CAD in patients with suspected myocardial ischemia using AECG was equal to that of a maximal ETT. LP finding from an AECG tape may support the argument for CAD in patients with ST depressions at AECG.

Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity and premature death, but the underlying mechanisms are incompletely understood. The aim of this study was to investigate whether adrenergic dysfunction may be a contributing factor.Forty-nine patients with mild PHPT (serum calcium 2·7 ± 0·1 mM) and 48 control subjects, matched for age and sex, were examined; patients within 1 month before parathyroidectomy (PTX) and 6 months postoperatively; control subjects at inclusion. Heart rate variability (HRV) was analysed in 24-h electrocardiograms, and plasma concentrations of epinephrine and norepinephrine were measured at rest and immediately after standardized physical tests.At baseline, the patients showed, compared to the controls, reduced stress-related increase of circulating epinephrine (P0·05) and norepinephrine (P0·05). No significant change was observed 6 months after PTX. At baseline, there were no significant differences between patients and controls in HRV or heart rate, but 6 months after curative PTX, the patients showed significantly reduced HRV in both frequency and time domain, and their maximum and average heart rate had decreased (P = 0·011 and P = 0·018, respectively). The patients with the highest preoperative levels of circulating parathyroid hormone showed the greatest changes in heart rate and HRV postoperatively.This study demonstrates a previously unknown impairment of catecholamine response to physical stress in PHPT along with changes of HRV, also indicating adrenergic dysfunction. These factors should be considered in the ongoing controversy regarding the management of patients with mild 'asymptomatic' PHPT.

The objective of this long-term ECG (LTER) study in 394 68-year-old men, selected at random from the general population of Malmö, Sweden, was to determine the prevalence and occurrence of cardiac arrhythmias and their impact on morbidity and mortality from IHD. According to Lown classification, 29.4% (116 men) had ventricular arrhythmia (VA) group 4-5. Serious ventricular arrhythmia (Lown group 4-5) was more common in men with asymptomatic ischaemic type ST-segment depression (STD) than in those without it (37.8% vs. 26.7%: P less than 0.05). During the mean follow-up period of 53.1 months there were seven IHD deaths (6%) among the 116 patients with VA, Lown 4-5, and nine IHD deaths (3.2%) among the 278 patients without serious VA, Lown 0-3, (P = 0.26). Six and three of these deaths, respectively, were considered to be sudden (P = 0.022). The increased cardiac event rate (fatal or non-fatal MI or deaths due to chronic IHD) associated with a serious ventricular arrhythmia disappeared when history of IHD at baseline and occurrence of STD during LTER were taken into account. The study did not provide any evidence to suggest that ventricular arrhythmia was triggered by myocardial ischaemia. Five of 9 (56%) deaths due to IHD in men with STD occurred among the 38% (37/98) of patients who belonged to Lown class 4-5. It is concluded that the prognostic information derived from LTER can be improved by combined monitoring of STD and ventricular arrhythmias.

This open, parallel-group study compares quinidine and sotalol treatment for maintenance of sinus rhythm after direct current conversion of patients with chronic atrial fibrillation. The patients from 15 centers in Sweden were randomized to sotalol (98 patients) or quinidine (85 patients) after 2 hours of sinus rhythm after direct current conversion. According to primary efficacy assessment, 52% of the patients in the sotalol group and 48% of the patients in the quinidine group remained in sinus rhythm during the following 6-month treatment period (NS). Furthermore, 34% of the patients treated with sotalol and 22% of the patients treated with quinidine relapsed into atrial fibrillation (NS). Heart rate after relapsing into atrial fibrillation was higher in the patients treated with quinidine (109 beats/min) than in the patients treated with sotalol (78 beats/min, p less than 0.001). Patients treated with sotalol were found to be less symptomatic at the time of relapse compared with relapsing patients in the quinidine group. In terms of safety, more patients were withdrawn from quinidine than from sotalol treatment (26% vs. 11%, p less than 0.05), and sotalol was generally better tolerated than quinidine. Twenty-eight percent of the patients treated with sotalol and 50% of the patients treated with quinidine reported side effects (p less than 0.01). The difference was primarily a result of early (within the first month of treatment) gastrointestinal and skin side effects in the group of patients treated with quinidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Keywords: nordsync, syncope, syncope-ethiology, syncope-mechanism.A patient presenting with a transient loss of con-sciousness (TLOC) can be a real challenge for theclinician with short- and long-term outcomes rang-ing from an isolated and benign event to a poten-tially lethal arrhythmia and sudden cardiacdeath.[1] The problem is not uncommon: between1% and 2% of all admissions at the EmergencyDepartments are related to TLOC, and one of threepatients will finally be hospitalized [2–4]. In theprimary care, we may expect two TLOC incidencesper 1000 person-years[5] but this number is prob-ably underestimated as other sources report 4–5times higher occurrence[6, 7]. Syncope, a tempo-rary impairment of circulation leading to suddenbrain hypoperfusion, is the absolutely dominantcause of TLOC.[8, 9] The main etiology of syncopeconsists of neurocardiogenic reflexes, autonomicdisorders (such as orthostatic hypotension), pri-mary cardiovascular disease (arrhythmic and/orstructural heart disease), or combination of these[1]. Accordingly, syncope excludes by definitionneurological diseases such as epilepsy, and syn-cope mimics such as psychogenic pseudo syncopalattacks. Today, handling of patients with syncopalattacks often results in long term rotation withinthe health care system between various specialists,general practitioners, cardiologists, neurologists,internists, geriatricians, otolaryngologists, paedia-tricians, and even psychiatrists without receivingthe proper diagnosis and treatment. A solutionproposed by various consensus groups would be tofollow specially designed diagnostic algorithms, orto create dedicated ‘syncope units’.[1, 10, 11]However, patients with syncope constitute not onlya clinical problem but an economical one as well. InSouthern Sweden, in Region Skane, 3 312 patients(2 760 per million inhabitants) were diagnosedwith syncope (ICD-10 code R55.9) during the year2009 according to the official statistic reports. Thetotal annual costs for the health care system werelarge: 1,9 million € directly at the ED; 8,3 million €in patients with fractures; 10,7 million € in patientswith arrhythmias; and 17,0 million € in patientswith valve disease. Consequently, there is adistinct need to improve the management of syn-cope, when we consider both clinical and economicaspects.As mentioned above, syncope can be regarded asan aggregation of different etiological factors undera common umbrella of the cardinal symptom, atime-limited circulatory disorder resulting in a lossof consciousness and a spontaneous recovery. In aseries of review articles published in this issue ofJournal of Internal Medicine, three main syncopaltriggers, neurocardiogenic reflexes, syndromes oforthostatic intolerance, and a primary cardiacdisease are discussed. All authors participated inthe First Nordic Symposium on Syncope ‘Nord-Sync2011’, which was held 20–21st of October,2011 in Malm€o, Sweden. First, Wieling and col-leagues revisit carotid sinus hypersensitivity (CSH)as an example of classical reflex syncope.[12] Theysuggest that CSH should be thought of as being acontinuum on a spectrum between cardioinhibi-tion and vasodilation. Based on new experimentaland epidemiological data, they also propose amodified and stricter set of criteria for diagnosinga symptomatic CSH, traditionally named as carotidsinus syndrome. Further, Fedorowski and Meland-er explore the history, pathophysiology, epidemiol-ogy and clinical consequences of orthostaticintolerance syndromes, a heterogonous groupcharacterised by impaired hemodynamic responseon standing. [13] They focus on orthostatic intol-erance as a ‘hidden danger’, which leads to synco-pal attacks per se or, alternatively, evokes a reflexsyncope, increases the mortality and cardiovascu-lar disease risk, and complicates treatment ofconcomitant diseases such as hypertension andheart failure. Finally, a review by Arnar [14] takesus on a brief and concise trip across the structuralchanges in the heart and primary arrhythmias, allof which can result in a syncopal attack. Thisauthor underlines a well-known fact, that thepresence of structural heart disease and/or afamily history of sudden unexplained death areassociated with a worse prognosis and warrant amore comprehensive cardiac investigation includ-ing genetic testing if indicated.

Objective To assess the effects of a 6-month angiotensin-converting enzyme (ACE) inhibitor intervention on myocardial ischaemia. Method We randomized 389 patients with stable coronary artery disease to double-blind treatment with ramipril 5 mg/day (n = 133), ramipril 1.25 mg/day (n = 133), or placebo (n = 123). Forty-eight-hour ambulatory electrocardiography was performed at baseline, and after 1 and 6 months. Results Relevant baseline variables were similar in all groups. Changes over 6 months in duration of ≥ 1 mm ST-segment depression (STD), total ischaemic burden and maximum STD did not differ significantly between the treatment groups. There was no difference in the frequency of adverse events between the groups. Conclusion ACE inhibitor treatment has little impact on incidence and severity of myocardial ischaemia in patients with stable ischaemic heart disease.

Aims To evaluate the feasibility and follow-up results of atrial lead implantation and a change to dual chamber pacing following long-term treatment with single chamber ventricular stimulation. Methods and Results During a 30-month period, 70 consecutive patients with ventricular pacemakers were referred for pulse generator exchange or lead reoperation. Using defined criteria, an upgrade procedure was considered indicated in 34 of the cases (49%); these patients had a mean age of 74·8±8·8 years, and had been treated with VVI or VVIR pacing for a mean time of 7·8±3·8 years (range 1·8–17). An atrial lead was successfully implanted via ipsilateral subclavian venipuncture through the existing pectoral pacemaker pocket in 33 of the 34 cases (97% of the attempts). Postoperatively, one atrial lead dislodgement was seen, and another patient required atrial lead adjustment due to P wave undersensing. The mean follow-up period was 14±10 months. During this time, four patients developed permanent atrial fibrillation (annual incidence 11%). In 82% of the patients in whom an upgrade procedure was attempted, dual chamber pacing was maintained at the end of follow-up. Conclusion Restoration of AV synchrony is possible in a substantial proportion of patients treated with long-term ventricular stimulation. Atrial lead placement through ipsilateral subclavian venipuncture is generally feasible, and the vast majority of cases remain in dual chamber pacing with normal function during intermediate term follow-up.

The ECG method is an accepted method for diagnosing myocardial ischemia. However, the diagnostic accuracy is highly dependent of the pre-test prevalence of coronary artery disease (CAD) in the individual patient.

Patients with insulin-dependent diabetes mellitus (IDDM) may develop autonomic neuropathy (AN) and cardiac complications. The association between AN and cardiac dysfunction was assessed in 34 IDDM patients (age 40 years, diabetes duration 21 years, 15 women) by echocardiography/Doppler and autonomic nerve function tests. The expiration/inspiration ratio (E/I) was used to assess parasympathetic damage, and the acceleration and brake indices for assessment of sympathetic impairment. AN was present in 21 patients. Patients with abnormal E/I (n = 11) had lower E/A ratios than patients without AN; early to atrial peak filling ratio (E/Amax) was median 1.1 (inter-quartile range 0.2) vs 1.4 (0.7), p = 0.022; early to atrial integral filling ratio (E/Aintegral) was 1.7 (0.3) vs 2.3 (1.2), p = 0.006. Patients with AN and normal E/I (sympathetic neuropathy, n = 10) and patients without AN had similar E/A ratios. E/Aintegral was also lower in patients with abnormal E/I compared with patients with AN and normal E/I; 1.7 (0.3) vs 2.2 (0.7), p = 0.008. Systolic function and cardiac dimensions were generally unaffected and similar in the three groups. In conclusion, diastolic dysfunction and parasympathetic neuropathy are related in IDDM patients.

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/l ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/l ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean (interquartile range)]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol l-1 vs 50 [15] pmol l-1; p < 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (rs = 0.65; p < 0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.

This open, parallel-group, multicenter study was conducted to compare the efficacy and safety of sotalol with that of quinidine for the prevention of atrial fibrillation relapse following DC conversion 183. DC-converted 183 patients with a 1- to 12-month history of atrial fibrillation were randomized to sotalol or quinidine after 2 hours of sinus rhythm following the conversion and followed on treatment for 6 months. The efficacy of sotalol and quinidine for the prevention of atrial fibrillation relapse during a 6-month period following DC conversion was similar. However, sotalol was better tolerated than quinidine.

Adrenaline infusions (AI) (0.5 micrograms adrenaline per 10 kg body weight per minute over 120 minutes) were given weekly for three weeks to 20 healthy male volunteers aged twenty-one to thirty-eight years. The AI was given after three days' treatment with diltiazem (D), verapamil (V), or placebo (PI) in a single-blind fashion. After pretreatment with Pl, serum potassium (s-K) decreased from 3.93 +/- 0.30 mmol/L (M +/- SD) to 3.33 +/- 0.31 (P less than 0.001) with the greatest change 69.75 +/- 46.24 minutes after the start of the AI. Corresponding values for s-Mg were 0.84 +/- 0.06 to 0.78 +/- 0.05 (P less than 0.01) and 106.50 +/- 36.71 minutes, for s-Ca 2.40 +/- 0.07 to 2.30 +/- 0.08 (P less than 0.01) and 103.50 +/- 36.06 minutes, for s-P 1.05 +/- 0.17 to 0.91 +/- 0.17 (P less than 0.02) and 80.25 +/- 47.25 minutes, and for s-urate 344.79 +/- 50.55 to 329.26 +/- 47.80 (P greater than 0.05) and 63.95 +/- 46.05 minutes. After pretreatment with D, AI produced similar electrolyte changes as after Pl, but the rise in blood glucose was slightly more pronounced and the drop in s-urate less pronounced. The heart rate (HR) before AI after pretreatment with D was lower than after Pl, but the increase during the AI was of the same magnitude. The AI-induced changes in systolic (SBP) and diastolic (DBP) blood pressure after D did not differ significantly from those seen after Pl, and neither did QT and QTc, whereas the PR duration was prolonged (0.18 +/- 0.03 second) when compared with Pl (0.16 +/- 0.02) (P less than 0.05). Although the magnitude of the change in DBP was not influenced, V prolonged the time till the lowest DBP (48.95 +/- 26.38 minutes) when compared with Pl (31.50 +/- 29.16 minutes) (P greater than 0.05). The other variables followed the same pattern as for D. In conclusion AI in healthy volunteers produced a drop in s-K but in addition a drop in s-Mg and s-Ca, the latter appearing later than the drop in s-K. Pretreatment with diltiazem and verapamil did not influence the magnitude of these changes but reduced the drop in s-urate.

One hundred and one representative post-myocardial infarction (MI) patients were investigated with radionuclide angiocardiography (RNA) and exercise test within 1 month of the MI and after 6 and 12 months. From the RNA were calculated the left ventricular ejection fraction (LVEF) and a quantified phase image, the phase standard deviation (phase-SD), representing the timing of the left ventricular contraction. The mean phase-SD was significantly higher among these patients (18 degrees, 19 degrees and 18 degrees, respectively, at the three investigations) compared to phase-SD in normals (6 degrees), indicating an impaired timing of the left ventricular (LV) contraction. At all three investigations a significant correlation was found between the phase-SD and the LVEF (r = -0.58, r = -0.74 and r = -0.75, respectively) and the corrected QT interval (r = 0.27, r = 0.44 and r = 0.39, respectively). Maximal serum ASAT in patients with their first MI correlated significantly to phase-SD. Low exercise capacity or unfavourable NYHA classification was associated with high phase-SD. Phase-SD higher than mean was also associated with significantly increased mortality during the follow-up year (p = 0.0057). In conclusion, phase-SD, reflecting the timing of the LV contraction wave, is easily accessible and clinically relevant. It merits further investigation as a prognostic factor after an MI.