Raoul Stahrenberg

Enhanced Detection of Paroxysmal Atrial Fibrillation by Early and Prolonged Continuous Holter Monitoring in Patients With Cerebral Ischemia Presenting in Sinus Rhythm

Background and Purpose Diagnosis of paroxysmal atrial fibrillation is difficult but highly relevant in patients presenting with cerebral ischemia yet free from atrial fibrillation on admission. Early initiation and prolongation of continuous Holter monitoring may improve diagnostic yield compared with the standard of care including a 24-hour Holter recording. Methods— In the observational Find-AF trial (ISRCTN 46104198), consecutive patients presenting with symptoms of cerebral ischemia were included. Patients free from atrial fibrillation at presentation received 7-day Holter monitoring. Results— Two hundred eighty-one patients were prospectively included. Forty-four (15.7%) had atrial fibrillation documented by routine electrocardiogram on admission. All remaining patients received Holter monitors at a median of 5.5 hours after presentation. In those 224 patients who received Holter monitors but had no previously known paroxysmal atrial fibrillation, the detection rate with early and prolonged (7 days) Holter monitoring (12.5%) was significantly higher than for any 24-hour (mean of 7 intervals: 4.8%, P=0.015) or any 48-hour monitoring interval (mean of 6 intervals: 6.4%, P=0.023). Of those 28 patients with new atrial fibrillation on Holter monitoring, 15 (6.7%) had been discharged without therapeutic anticoagulation after routine clinical care (ie, with data from 24-hour Holter monitoring only). Detection rates were 43.8% or 6.3% for short supraventricular runs of ≥10 beats or prolonged episodes (<5 hours) of atrial fibrillation, respectively. Diagnostic yield appeared to be only slightly and not significantly increased during the first 3 days after the index event. Conclusions— Prolongation of Holter monitoring in patients with symptoms of cerebral ischemic events increases the rate of detection of paroxysmal atrial fibrillation up to Day 7, leading to a relevant change in therapy in a substantial number of patients. Early initiation of monitoring does not appear to be crucial. Hence, prolonged Holter monitoring (≥7 days) should be considered for all patients with unexplained cerebral ischemia.

The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction

Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF‐15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF‐15 plasma levels in HFnEF.

Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction

AIMS Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results. METHODS AND RESULTS We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass (P= 0.001), LV mass index (P= 0.001), relative wall thickness (P= 0.011), and LV posterior wall thickness (P< 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31-2.68; P= 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling. CONCLUSION Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.

Transthoracic Echocardiography to Rule Out Paroxysmal Atrial Fibrillation as a Cause of Stroke or Transient Ischemic Attack

Background and Purpose— We assessed whether echocardiography can predict paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia presenting in sinus rhythm. Methods— Within the prospective Find-AF cohort, 193 consecutive patients with cerebral ischemia and sinus rhythm on presentation had evaluation of echocardiographic parameters of left atrial size and function. PAF was diagnosed by 7-day Holter monitoring. Results— In 26 patients with PAF, late diastolic Doppler (A) and tissue Doppler (a′) velocities were lower whereas left atrial diameter, left atrial volume index (LAVI), LAVI/A, and LAVI/a′ were larger (P<0.05 for all) than they were in 167 patients without PAF. In multivariate models A, a′, LAVI/A, and LAVI/a′ predicted the presence of PAF. Area under the receiver operating characteristic curve to diagnose PAF was highest for LAVI/a′ (0.813 [0.738; 0.889]). A previously suggested cut-off of LAVI/a′ <2.3 had 92% sensitivity, 55.8% specificity, and 98% negative predictive value for PAF. Conclusions— LAVI/a′ <2.3 can effectively rule out PAF in patients with cerebral ischemia.

Impact of obstructive sleep apnoea on diastolic function

We investigated whether obstructive sleep apnoea (OSA) independently affects diastolic function in a primary care cohort of patients with cardiovascular risk factors. 378 study participants with risk factors for diastolic dysfunction were prospectively included and a polygraphy was performed in all patients. Diastolic dysfunction was assessed by comprehensive echocardiography including tissue Doppler. Sleep apnoea was classified according to apnoea/hypopnoea index (AHI) as none (AHI <5 events·h−1), mild (AHI ≤5 to <15 events·h−1) or moderate-to-severe (AHI ≥15 events·h−1). Patients with central sleep apnoea (n=14) and patients with previously diagnosed sleep apnoea (n=12) were excluded. In the remaining 352 subjects, 21.6% had an AHI ≥15 events·h−1. The prevalence of diastolic dysfunction increased with the severity of sleep apnoea from 44.8% (none) to 56.8% (mild) to 69.7% (moderate-to-severe sleep apnoea) (p=0.002). The degree of diastolic dysfunction also increased with sleep apnoea severity (p=0.004). In univariate regression analysis, age, desaturation index, AHI, cardiac frequency, angiotensin receptor 1 antagonist therapy, body mass index (BMI) and left ventricular mass were associated with diastolic dysfunction. In multivariate regression analysis, only age, BMI, AHI and cardiac frequency were independently associated with diastolic dysfunction. Moderate-to-severe OSA is independently associated with diastolic dysfunction in patients with classical risk factors for diastolic dysfunction.

Impaired physical quality of life in patients with diastolic dysfunction associates more strongly with neurohumoral activation than with echocardiographic parameters: Quality of life in diastolic dysfunction

BACKGROUND Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure. METHODS In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. RESULTS Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association. CONCLUSIONS Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

Excessive Supraventricular Ectopic Activity Is Indicative of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia

Background Detecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run24 h), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a’ (left atrial volume index/late diastolic tissue Doppler velocity). Methods Retrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively. Results PAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run24 h. PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤4 (p<0.001); 17.0% vs. 4.9% for SV-run24 h >5 vs. ≤5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run24 h = 10 [5]; [21] vs. 0 [0; 8] beats (both p<0.001). Both markers discriminated between the PAF- and the Non-PAF-group (area under receiver-operator-characteristics-curve 0.763 [95% CI 0.667; 0.858] and 0.716 [0.600; 0.832]). In multivariate analyses log(PAC/h) and log(SV-run24 h) were independently indicative of PAF. In Patients with PAC/h ≤4 and normal LAVI/a’ PAF was excluded, whereas those with PAC/h >4 and abnormal LAVI/a’ showed high PAF-rates. Conclusions ESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a’ in patients with cerebral ischemia. Normal LAVI/a’+PAC/h ≤4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a’+PAC/h >4.

Finding atrial fibrillation in stroke patients: Randomized evaluation of enhanced and prolonged Holter monitoring—Find-AFRANDOMISED —rationale and design

BACKGROUND Detecting paroxysmal atrial fibrillation (AF) in patients with ischemic strokes presenting in sinus rhythm is challenging because episodes are often short, occur randomly, and are frequently asymptomatic. If AF is detected, recurrent thromboembolism can be prevented efficiently by oral anticoagulation. Numerous uncontrolled studies using various electrocardiogram (ECG) devices have established that prolonged ECG monitoring increases the yield of AF detection, but most established procedures are time-consuming and costly. The few randomized trials are mostly limited to cryptogenic strokes. The optimal method, duration, and patient selection remain unclear. Repeated prolonged continuous Holter ECG monitoring to detect paroxysmal AF within an unspecific stroke population may prove to be a widely applicable, effective secondary prevention strategy. STUDY DESIGN Find-AFRANDOMISED is a randomized and controlled prospective multicenter trial. Four hundred patients 60 years or older with manifest (symptoms ≥24 hours or acute computed tomography/magnetic resonance imaging lesion) and acute (symptoms ≤7 days) ischemic strokes will be included at 4 certified stroke centers in Germany. Those with previously diagnosed AF/flutter, indications/contraindications for oral anticoagulation, or obvious causative blood vessel pathologies will be excluded. Patients will be randomized 1:1 to either enhanced and prolonged Holter ECG monitoring (10 days at baseline and after 3 and 6 months) or standard of care (≥24-hour continuous ECG monitoring, according to current stroke guidelines). All patients will be followed up for at least 12 months. OUTCOMES The primary end point is newly detected AF (≥30 seconds) after 6 months, confirmed by an independent adjudication committee. We plan to complete recruitment in autumn 2014. First results can be expected by spring 2016.

Clinical predictors to identify paroxysmal atrial fibrillation after ischaemic stroke

Detection of paroxysmal atrial fibrillation (pAF) after an ischaemic cerebrovascular event is of imminent interest, because oral anticoagulation as a highly effective secondary preventive treatment is available. Whereas permanent atrial fibrillation (AF) can be detected during routine electrocardiogram (ECG), longer detection duration will detect more pAF but might be resource consuming. The current study tried to identify clinical predictors for pAF detected during long‐term Holter ECG and clinical follow‐up.

High-sensitivity troponin assay improves prediction of cardiovascular risk in patients with cerebral ischaemia

Background and purpose Clinical scores are recommended for predicting cardiovascular risk in patients with cerebral ischaemia to inform secondary prevention. Blood biomarkers may improve prediction beyond clinical scores. Methods Within the observational Find-AF trial (ISRCTN46104198), 197 patients >18 years of age with cerebral ischaemia and without atrial fibrillation had blood sampled at baseline. The predictive value of five biomarkers for a combined vascular endpoint (acute coronary syndrome, stroke, cardiovascular death) and all-cause mortality was determined, alone and in addition to the Essen Stroke Risk Score (ESRS), Stroke Prognostic Instrument 2 (SPI-2) and National Institutes of Health Stroke Scale (NIH-SS). Results There were 23 vascular events (11.7%) and 13 deaths (6.6%) to 1 year follow-up. In multivariate analyses of all markers, only high-sensitivity troponin T (hsTropT) remained independently predictive for vascular events (p=0.045) and all-cause mortality (p=0.004). hsTropT was higher in patients with a vascular event (median 12.7 ng/ml vs 5.1 ng/ml), and patients with hsTropT above the median of 6.15 ng/ml had vascular events more frequently (HR 3.86, p=0.008). For prediction of vascular events as well as all-cause mortality, hsTropT significantly improved multivariate Cox regression models with ESRS, SPI-2 or NIH-SS. The c-statistic increased non-significantly from 0.695 (ESRS) or 0.710 (hsTropT) to 0.747 (ESRS+hsTropT) and from 0.699 (SPI-2) to 0.763 (SPI-2+hsTropT). No patient with a low-risk ESRS and an hsTropT below the median had a vascular event or died. Conclusions hsTropT predicts vascular events and all-cause mortality in patients with acute cerebral ischaemia and improves prediction beyond established clinical scores.