Ischemic stroke and the emerging role of left atrial function.

INTRODUCTION: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Emerging evidence suggests that left atrial (LA) dysfunction could play a role in the pathophysiology of ischemic stroke, as a possible contributor and as a predictive biomarker. AREAS COVERED: This narrative review details the intricate relationship between LA function, atrial fibrillation (AF), and ischemic stroke. We discuss imaging techniques used to assess LA function, the mechanisms by which impaired LA function may contribute to stroke, and its potential as a prognostic marker of stroke. EXPERT OPINION: There is a lack of evidence-based treatments of LA dysfunction in both primary and secondary stroke prevention. This is partly due to the lack of a practical clinical definition and unanswered questions concerning the clinical implications of LA dysfunction in patients without AF. Until such questions are resolved, addressing well-known cardiovascular risk factors, like hypertension and obesity, should be prioritized for preventing AF and ischemic stroke. These risk factors are closely tied to atrial remodeling, emphasizing the importance of targeting primary modifiable factors for preventing future morbidity and mortality.

Left atrial late gadolinium enhancement in patients with ischaemic stroke.

AIMS: To evaluate the extent of left atrial (LA) fibrosis in patients with a recent stroke without atrial fibrillation and controls without established cardiovascular disease. METHODS AND RESULTS: This prospectively designed study used cardiac magnetic resonance to detect LA late gadolinium enhancement as a proxy for LA fibrosis. Between 2019 and 2021, we consecutively included 100 patients free of atrial fibrillation with recent ischaemic stroke (<30 days) and 50 age- and sex-matched controls. LA fibrosis assessment was achieved in 78 patients and 45 controls. Blinded to the cardiac magnetic resonance results, strokes were adjudicated according to modified Trial of Org 10172 in Acute Stroke Treatment classification as undetermined aetiology (n = 42) or as attributable to large- or small-vessel disease (n = 36). Patients with stroke had a larger extent of LA fibrosis [6.9%, interquartile range (IQR) 3.6-15.4%] than matched controls (4.2%, IQR 2.3-7.5%; P = 0.007). No differences in LA fibrosis were observed between patients with stroke of undetermined aetiology and those with large- or small-vessel disease (6.6%, IQR 3.8-16.0% vs. 6.9%, IQR 3.4-14.6%; P = 0.73). CONCLUSION: LA fibrosis was more extensive in patients with stroke than in age- and sex-matched controls. A similar extent of LA fibrosis was observed in patients with stroke of undetermined aetiology and stroke classified as attributable to large- or small-vessel disease. Our findings suggest that LA structural abnormality is more frequent in patients with stroke than in controls independent of aetiological classification.

Parasympathetic tonus in type 2 diabetes and pre-diabetes and its clinical implications.

Autonomic imbalance reflected by higher resting heart rate and reduced parasympathetic tone may be driven by low-grade inflammation (LGI) and impaired glycemic control in type 2 diabetes mellitus (T2DM) and pre-diabetes. We examined the interaction of parasympathetic components of heart rate variability (HRV), variables of LGI, and glucose metabolism in people with T2DM, pre-diabetes, and normal glucose metabolism (NGM). We recorded HRV by Holter (48 h) in 633 community-dwelling people of whom T2DM n = 131, pre-diabetes n = 372, and NGM n = 130 and mean HbA1c of 7.2, 6.0 and 5.3%, respectively. Age was 55-75 years and all were without known cardiovascular disease except from hypertension. Fasting plasma glucose, fasting insulin, HOMA-IR, HbA1c and LGI (CRP, Interleukin-18 (IL-18), and white blood cells) were measured. Root-mean-square-of-normal-to-normal-beats (RMSSD), and proportion of normal-to-normal complexes differing by more than 50 ms (pNN50) are accepted measures of parasympathetic activity. In univariate analyses, RMSSD and pNN50 were significantly inversely correlated with level of HbA1c and CRP among people with T2DM and pre-diabetes, but not among NGM. RMSSD and pNN50 remained significantly inversely associated with level of HbA1c after adjusting for age, sex, smoking, and BMI among people with T2DM (ß = - 0.22) and pre-diabetes (ß = - 0.11); adjustment for LGI, HOMA-IR, and FPG did not attenuate these associations. In backward elimination models, age and level of HbA1c remained associated with RMSSD and pNN50. In people with well controlled diabetes and pre-diabetes, a lower parasympathetic activity was more related to age and HbA1c than to markers of LGI. Thus, this study shows that the driver of parasympathetic tonus may be more the level of glycemic control than inflammation in people with prediabetes and well controlled diabetes.

Left Atrial Volumes and Function, and Long-Term Incidence of Ischemic Stroke in the General Population.

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long-term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community-based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow-up of 16.5 years (interquartile range: 11.4-16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause-specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02-1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01-1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow-up (HR, 1.12 per 10% decrease [95% CI, 1.00-1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all-cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993172.

Atrial cardiomyopathy in patients with ischaemic stroke: a cross-sectional and prospective cohort study-the COAST study.

INTRODUCTION: Despite workup for the aetiology of ischaemic stroke, about 25% of cases remain unexplained. Paroxysmal atrial fibrillation is typically suspected but often not detected. Even if atrial fibrillation (AF) is detected, the quantitative threshold of clinically relevant AF remains unclear. Emerging evidence suggests that left atrial (LA) functional and structural abnormalities may convey a risk of ischaemic stroke in which AF is only one of several features. These abnormalities have been termed 'atrial cardiomyopathy'. This study uses cardiac magnetic resonance (CMR) to evaluate atrial cardiomyopathy among patients with stroke of undetermined aetiology compared with those with an attributable mechanism and controls without established cardiovascular disease. METHODS AND ANALYSIS: This cross-sectional and prospective cohort study included 100 patients with recent ischaemic stroke and 50 controls with no established cardiovascular disease. The study will assess LA structural and functional abnormalities with CMR. Inclusion began in March 2019, and follow-up is planned to be complete in January 2023. There are two scheduled follow-ups: (1) 18 months after individual inclusion, counting from the index diagnostic MRI of the brain, (2) end of study follow-up at 18 months after inclusion of the last patient, assessing the incidence of recurrent ischaemic stroke, AF and cardiovascular death. The primary endpoint is the extent of CMR-assessed atrial fibrosis in the LA at baseline. The study is powered to detect a difference of 6% fibrosis between stroke of undetermined aetiology and stroke of known mechanism with a SD of 9%, a significance level of 0.05, and power of 80%. ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics (H-18055313). All participants in the study signed informed consent. Results from the study will be published in peer-reviewed journals regardless of the outcome. TRIAL REGISTRATION NUMBER: NCT03830983.

Are Prolonged Ventricular Pauses in Atrial Fibrillation a Marker of Poor Prognosis?

BACKGROUND: In patients with atrial fibrillation (AF), the long-term prognosis of long electrocardiographic pauses in the ventricular action is not well studied. METHODS: Consecutive Holter recordings in patients with AF (n = 200) between 2009 and 2011 were evaluated, focusing on pauses of at least 2.5 s. Outcomes of interest were all-cause mortality and pacemaker implantation. RESULTS: Forty-three patients (21.5%) had pauses with a mean of 3.2 s and an SD of 0.9 s. After a median follow-up of 99 months (ranging 89-111), 47% (20/43) of the patients with and 45% (70/157) without pauses were deceased. Pauses of ≥2.5 s did not constitute a risk of increased mortality: HR = 0.75 (95% CI: 0.34-1.66); p = 0.48, neither did pauses of ≥3.0 s: HR = 0.43 (95% CI: 0.06-3.20); p = 0.41. Sixteen percent of patients with pauses underwent pacemaker implantation during follow-up. Only pauses in patients referred to Holter due to syncope and/or dizzy spells were associated with an increased risk of pacemaker treatment: HR = 4.7 (95% CI: 1.4-15.9), p = 0.014, adjusted for age, sex, and rate-limiting medication. CONCLUSION: In patients with AF, prolonged electrocardiographic pauses of ≥2.5 s or ≥3.0 s are not a marker for increased mortality in this real-life clinical study.

Excessive supraventricular ectopic activity and risk of incident atrial fibrillation in a consecutive population referred to ambulatory cardiac monitoring.

BACKGROUND: Excessive supraventricular ectopic activity (ESVEA), defined as ≥720 premature atrial contractions (PAC) per day or any runs of ≥20 PACs, has been proposed as a surrogate marker for paroxysmal atrial fibrillation (PAF). OBJECTIVE: We aimed to estimate the prognostic impact of ESVEA on the future development of PAF in consecutive patients referred to ambulatory cardiac monitoring. METHODS: The cohort consists of a population with comorbidities referred to 48-hour ambulatory electrocardiogram aged 30-98 (n = 1316) between 2009 and 2011. After exclusion of known or current atrial fibrillation (AF) (n = 527) and patients with pacemakers (n = 7), 782 patients were included, with a median follow-up of 8.1 years. Events of incident AF and death were retrieved from patient records. RESULTS: Mean age was 58.6 ± 15.5 years and 56.5% were women. A total of 101 patients had ESVEA at baseline (12.9%). During follow-up, 69 (8.9%) developed incidental AF. Twenty-three patients with ESVEA developed AF (23%). Incidence rate of AF in patients with and without ESVEA was 37.1/1000 person-years and 9.1 per 1000 person-years, respectively (P < .001). ESVEA was associated with incident AF after adjustment for potential confounders in Cox regression analysis (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.40-4.09) and in competing risk analysis with death as competing risk (subdistribution HR: 2.35; 95% CI: 1.30-4.17). CONCLUSION: ESVEA increases the risk of incident AF substantially in a population referred to ambulatory cardiac monitoring.

P-wave indices as predictors of atrial fibrillation.

BACKGROUND: P-wave duration (PDURATION ) and P-wave area (PAREA ) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P-wave area/P-wave duration (PAREA/DURATION ) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P-wave morphology. OBJECTIVE: To assess the prognostic value of P-wave area/P-wave duration index (PAREA/DURATION index) in lead II together with other P-wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study. METHODS: The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12-lead Electrocardiography (ECGs) were analyzed manually. RESULTS: The median follow-up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U-shaped association between PAREA/DURATION and rate of AF. The lowest quintile of PAREA/DURATION index in lead II was associated with increased rate of AF, HR 2.80 (1.64-4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The PAREA in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25-3.75), but did not improve the Framingham model. PDURATION and P-wave terminal force (PTF) were not significantly associated with AF. CONCLUSION: A flat P wave as expressed by a small PAREA/DURATION index in lead II is associated with increased rate of incident AF beyond known AF risk factors.

Common source of miscalculation and misclassification of P-wave negativity and P-wave terminal force in lead V1.

BACKGROUND: P-wave terminal force (PTF) > 4000 ms·µV and deep terminal negativity (DTN) are ECG markers of left atrial abnormality associated with both atrial fibrillation and stroke. When the precordial lead V1 is placed higher than the correct position in the fourth intercostal space, it may cause increased PTF and DTN. Several studies have documented that electrode misplacement, especially high placement, is common. The influence of electrode misplacement on these novel ECG markers has not previously been quantified. OBJECTIVE: The objective was to assess the influence of electrode misplacement on PTF and DTN. METHOD: 12-Lead ECGs were recorded in 29 healthy volunteers from the Department of Cardiology at the Copenhagen University Hospital of Bispebjerg. The precordial electrode V1 was placed in the fourth, third and second intercostal space, giving a total of 3 ECGs per subject. Continuous variables were compared using Dunnett's post-hoc test and categorical variables were compared using Fischer's exact test. RESULTS: High placement of V1 electrodes resulted in a more than three-fold increase of PTF (IC4 = 2267 ms·µV, IC2 = 7996 ms·µV, p-value < 0.001). There was a similar increase of DTN (IC4 = 0%, IC2 = 28%, p-value < 0.001). P-wave area and amplitude of the negative deflection increased, and P-wave area and amplitude of the positive deflection decreased. The P-wave shape changed from being predominantly positive or biphasic in IC4 to 90% negative in IC2. The PR-duration and P-wave duration were not altered by electrode placement. CONCLUSION: High electrode placement results in significant alteration of PTF and DTN in lead V1.

Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects.

BACKGROUND AND PURPOSE: Stroke is independently associated with the common conditions of hypokalemia and supraventricular ectopy, and we hypothesize that the combination of excessive supraventricular ectopic activity and hypokalemia has a synergistic impact on the prognosis in terms of stroke in the general population. METHODS: Subjects (55-75 years old) from the Copenhagen Holter Study cohort (N=671) with no history of atrial fibrillation or stroke were studied-including baseline values of potassium and ambulatory 48-hour Holter monitoring. Excessive supraventricular ectopic activity is defined as ≥30 premature atrial complexes per hour or any episodes of runs of ≥20. Hypokalemia was defined as plasma-potassium ≤3.6 mmol/L. The primary end point was ischemic stroke. Cox models were used. RESULTS: Hypokalemia was mild (mean, 3.4 mmol/L; range, 2.7-3.6). Hypokalemic subjects were older (67.0±6.94 versus 64.0±6.66 years; P<0.0001) and more hypertensive (165.1±26.1 versus 154.6±23.5 mm Hg; P<0.0001). Median follow-up time was 14.4 years (Q1-Q3, 9.4-14.7 years). The incidence of stroke was significantly higher in the hypokalemic group (hazard ratio, 1.84; 95% confidence interval, 1.04-3.28) after covariate adjustments, as well as in a competing risk analysis with death (hazard ratio, 1.51; 95% confidence interval, 1.12-2.04). Excessive supraventricular ectopic activity was also associated with stroke (hazard ratio, 2.23; 95% confidence interval, 1.33-3.76). The combination of hypokalemia and excessive supraventricular ectopic activity increased the risk of events synergistically. Stroke rate was 93 per 1000 patient-year (P<0.0001) in this group (n=17) compared with 6.9 (n=480); 11 (n=81), and 13 (n=93) per 1000 patient-year in the groups without the combination. CONCLUSIONS: The combination of hypokalemia and excessive supraventricular ectopy carries a poor prognosis in terms of stroke.

The circadian variation of premature atrial contractions.

AIMS: The aim of the study was to assess a possible circadian variation of premature atrial contractions (PACs) in a community-based population and to determine if the daily variation could be used to assess a more vulnerable period of PACs in predicting later incidence of atrial fibrillation (AF). METHODS AND RESULTS: We studied 638 subjects between the ages of 55 and 75 years from the Copenhagen Holter Study who underwent up to 48 h electrocardiogram recording. Follow-up on cardiovascular endpoints was performed in 2013 with a median follow-up time of 14.4 years. According to previous studies, two subgroups were studied based on a cut-off point of ≥720 PACs/day termed frequent PACs (n = 66) and not frequent PACs with <720 PACs/day (n = 572). Based on median values, a circadian rhythm could not be demonstrated in the population as a whole and the group without frequent PACs. However, a circadian variation was observed in the group with frequent PACs, who had the fewest PACs/h during the night with a nadir at 6 am and then reaching a peak value in the afternoon at 3 pm. Runs of PACs in all subjects showed a similar circadian variation. Both PACs/h and runs of PACs seemed to follow the daily variation in heart rate. After adjusting for relevant risk factors, the risk of AF was equal in all time intervals throughout the day. CONCLUSION: Premature atrial contractions showed a circadian variation in subjects with frequent PACs. No specific time interval of the day was more predictive of AF than others.

Excessive Atrial Ectopy and Short Atrial Runs Increase the Risk of Stroke Beyond Incident Atrial Fibrillation.

BACKGROUND: Approximately 30% of ischemic strokes have an unknown cause. Increased atrial ectopy (AE) increases the risk of atrial fibrillation (AF), but the risk of stroke in patients with increased AE is unknown. OBJECTIVES: This study aimed to examine whether increased AE and short atrial runs increase the risk of stroke beyond incident AF. METHODS: Data were collected during a 15-year follow-up of the Copenhagen Holter Study cohort with 678 men and women between 55 and 75 years of age, with no earlier history of cardiovascular disease, stroke, or AF. Study subjects underwent 48-h ambulatory electrocardiography, fasting blood tests, and clinical examination. Excessive supraventricular ectopic activity (ESVEA) was defined as the presence of either ≥30 premature atrial contractions (PACs)/hour daily or any runs of ≥20 PACs. RESULTS: Ninety-nine subjects (15%) demonstrated ESVEA. After adjusting for baseline risk factors, ESVEA was associated with ischemic stroke when censoring subjects at time of AF (hazard ratio [HR]: 1.96; 95% confidence interval [CI]: 1.10 to 3.49) or when modeling AF as a time-varying exposure (HR: 2.00; 95% CI: 1.16 to 3.45). Among subjects with ESVEA who developed a stroke, 14.3% had diagnosed AF before their stroke. The incidence of stroke in subjects with ESVEA and a CHA2DS2-VASc (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female) score of ≥2 was 2.4% per year, comparable to the risk observed in AF. In day-to-day analysis, ESVEA was a consistent finding. CONCLUSIONS: ESVEA was associated with an increased risk of ischemic stroke beyond manifest AF in this middle-aged and older population. Stroke was more often the first clinical presentation, rather than AF, in these study subjects.