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ECG left atrial abnormality: a marker of stroke prediction in hypertension

Cuspidi, Cesarea,b; Sala, Carlac; Grassi, Guidoa,d

doi: 10.1097/HJH.0000000000001026
EDITORIAL COMMENTARIES

aDepartment of Medicine and Surgery, University of Milano-Bicocca

bIstituto Auxologico Italiano

cDepartment of Clinical Sciences and Community Health, University of Milano and Fondazione Ospedale Maggiore Policlinico di Milano

dIstituto di Ricerche a Carattere Scientifico Multimedica, Milan, Italy

Correspondence to Prof Cesare Cuspidi, MD, Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +0039 0362 772433; fax: +0039 0362 772416; e-mail: cesare.cuspidi@unimib.it

Stroke is a major cause of mortality and morbidity worldwide [1]; in Europe, it is the second cause of mortality accounting for approximately 15% of all deaths in women and 10% in men [2]. Hypertension is regarded as the single most relevant risk factor for stroke; cardiac disease, atherosclerosis, diabetes mellitus, cigarette smoking, obesity and dyslipidemia have been reported to be strongly associated with stroke [3,4].

Since the end of the 1990s, international hypertension guidelines recommend cardiovascular risk stratification in the population based on blood pressure (BP) levels, modifiable and nonmodifiable risk factors, cardiac and extracardiac organ damage, diabetes mellitus and established cardiovascular or renal disease [5–7].

As for the assessment of target organ damage, recent 2013 ESH/ESC Guidelines [8] re-emphasize the role of ECG as first-line examination for detection of subclinical cardiac damage. ECG left ventricular hypertrophy (LVH), indeed, is a powerful marker of increased cerebrovascular as well as cardiac mortality and morbidity in the general and hypertensive population.

Historical evidence on this issue has been recently confirmed and expanded by large studies. The association between baseline ECG-LVH by Solokow–Lyon criterion and ischemic stroke has been prospectively assessed in 24 948 participants (mean age 65 ± 9 years; 40% black; 55% women) over a 7.6 years mean follow-up by the REasons for Geographic And Racial Differences in Stroke study [9]. After adjustment for stroke risk factors and confounders, an increased risk of ischemic stroke was observed among participants with ECG-LVH [hazard ratio = 1.40, 95% confidence interval (CI) = 1.13–1.75] compared with counterparts without ECG-LVH. The value of ECG-LVH by Cornell voltage criterion in predicting stroke was examined among 4008 participants to the Cardiovascular Health Study over a 13-year period [10]. Findings from multivariable Cox regression analysis, adjusted for stroke risk factors, demonstrated that ECG-LVH (hazard ratio = 1.68; 95% CI = 1.23–2.28) was associated with increased risk of stroke. Of note, similar results were obtained for LVH diagnosed by ECG criteria (hazard ratio = 1.58; 95% CI = 1.17–2.14).

In addition to identification of LVH, ECG provides relevant clues for the management of hypertensive patients such as signs of ventricular overload or ‘strain’, ischemia, left atrial enlargement, conduction defects or arrhythmias, all conditions associated with an adverse prognosis and specific diagnostic or treatment indications. In recent years, several investigations have addressed the value of established and new ECG markers in detecting subclinical cardiac damage and predicting cardiovascular outcomes.

In this issue of the Journal, Okin et al. [11] report the results of a retrospective analysis in a subset of the LIFE population aimed at assessing the value of abnormal P-wave on baseline ECG in predicting ischemic stroke; in particular, the authors examined the prognostic value of the amplitude times duration greater than 4000 μs mm of the terminal negative component of biphasic P-wave in precordial lead V1 (PTFV1).

During a mean follow-up of 4.8 years, stroke occurred in approximately 2.5% of the sample. Abnormal PTFV1 was associated with a two-fold increased risk of incident stroke; the relation persisted highly significant after adjusting for baseline covariates including sex, previous cardiovascular disease, diabetes, renal function and a time-varying covariate such as in-treatment SBP. Before commenting these findings, some general considerations on available evidence in this research area may be useful.

Several longitudinal studies identified left atrial size as an independent predictor of incident atrial fibrillation [12], stroke [13], congestive heart failure and cardiovascular death [14]. Furthermore, the extent of dilatation has been linked to severity of ischemic stroke or pattern of ischemic lesions in cross-sectional analyses conducted in patients with nonvalve atrial fibrillation; left atrial size, indeed, turned out to be directly related to the degree of neurologic deficit evaluated according to the National Institutes of Health Stroke Scale [15].

In the majority of these studies, anatomical left atrial abnormalities were investigated by assessing echocardiographic anteroposterior left atrial diameter by M-mode technique under two-dimensional (2-D) control or, less frequently, by measuring left atrial volume on 2-D imaging.

To date, scant information is available on the link between left atrial electrical alterations assessed by standard ECG and cardiovascular outcomes. P-wave abnormalities in lead V1 such as P-wave amplitude higher than 3 mm, total duration longer than 110 ms and P-wave/PR-segment duration ratio greater than 1.6 are currently accepted ECG markers of left atrial dysfunction and enlargement in clinical and research settings.

In the middle of 1960s, Morris et al. [16] were the first to document the value of PTFV1 as an index of interatrial conduction defects due to left atrial morphological abnormalities in patients with cardiac valve disease. For many years after this pioneering observation, abnormal PTFV1 was merely considered a sign of left atrial dilatation secondary to LVH. Subsequent investigations established that interatrial conduction defects may be related to a variety of cardiovascular diseases. Alteration in left atrial texture due to fibrosis, indeed, is associated with a wide spectrum of cardiac diseases and may affect atrial conduction resulting in a prevalent antero-to-posterior direction of left atrial activation leading to a deep negative terminal P-wave component [17]. Despite these important physiopathological observations, a limited number of reports provided clinical and prognostic correlates of this ECG marker of atrial damage, in particular its relation with stroke.

Prevalence rates of abnormal PTFV1 have been reported to largely vary in cross-sectional studies carried out in patients with ischemic stroke. In a population-based, case–control study including 146 patients with first ischemic stroke (69 ± 11 years, 48% men), more than half of the sample (54%) fulfilled diagnostic criteria for abnormal PTFV1 [18]. In the Helsinki Young Stroke Registry [19], collecting data from 690 ischemic strokes in patients aged 15–49 years, an abnormal PTFV1 was found in a marginal fraction of cases (4%). Finally, Yaghi et al. [20] evaluated the prevalence of three biomarkers of atrial damage in 40 patients with cryptogenetic stroke and found that in 63% of cases at least one of the following markers of atrial cardiopathy was present: elevated N-terminal prohormone of brain natriuretic peptide (49%), PTFV1 greater than 5000 μs mm (20%) and severe ECG left atrial enlargement (5%).

Demographic and clinical characteristics of patients with pathological PTFV1 have been analyzed in different settings. Angeli et al. [21] reported that abnormal PTFV1 (diagnosed at the first antenatal visit) in pregnant women was associated with higher levels of maternal weight, BMI and clinic BP and, more importantly, to a 4-fold increased risk of hypertensive disorders during late pregnancy.

In line with previous reports, the Atherosclerosis Risk in Communities (ARIC) study showed that participants with abnormal PTFV1 were more likely to be older and have a higher prevalence of risk factors such as hypertension, diabetes, smoking as well as ECG abnormalities (i.e. prolonged P-wave and QT interval, and greater Cornell product) than counterparts [22].

Prospective studies have shown that abnormal PTFV1 is predictive of atrial fibrillation, stroke, heart failure hospitalizations and death in general population samples [23] as well as in patients with prior myocardial infarction. In the above-mentioned ARIC study [22] including 15 375 participants (54.1 ± 5.8 years, 45% men, 73% whites), this marker was independently associated with sudden cardiac death in individuals with and without prior cardiovascular events, even after adjustment for traditional coronary risk factors. Notably, the risk of sudden cardiac death associated with abnormal PTFV1 exceeded the risk of nonfatal coronary heart disease, heart failure and stroke.

The article by Okin et al. adds a new piece of information to previous evidence by showing that an abnormal PTFV1 may be an independent predictor of stroke in treated hypertensive patients with ECG-LVH.

It is worth noting that in a preliminary analysis including all LIFE participants on persistent sinus rhythm (n = 7778, mean age 67 ± 7 years, 37% with abnormal PTFV1), the authors failed to demonstrate an independent association between PTFV1 and stroke, probably due to the significant interaction between age more than 60 years and this marker of atrial damage. The authors restricted the assessment of PTFV1 prognostic significance to 1879 patients aged 55–60 years (mean age 57 ± 2 years) and found a similar prevalence of left atrial abnormality (36%) in this subset of younger patients as in the total population. Patients with abnormal PTFV1 compared with their counterparts had similar age and sex distribution, but were more frequently blacks, smokers and more likely to have a history of heart failure and subclinical cardiac and renal damage, as assessed by Cornell product and microalbuminuria, respectively. An ischemic stroke occurred in 45 patients during a 4.8 years follow-up; analyses addressed to explore the relationship between this outcome and PTFV1 demonstrated that patients with baseline abnormal PTFV1 had a two-fold greater risk of developing stroke than their counterparts without left atrial abnormality. The strength of this association was not weakened after introducing several baseline and time-varying (BP and ECG-LVH changes) stroke risk factors in Cox regression models. Thus, findings provided by Okin et al. [11] based on a retrospective analysis of a middle-aged subset of LIFE study convey the notion that ECG left atrial abnormalities may stratify the risk of ischemic stroke in systemic hypertension. These conclusions, however, should be taken with caution; in particular, their extension to the general hypertensive population is not allowed. Major limitations of the study are represented by the small number of ischemic events recorded in participants aged 55–60 years during the follow-up period. More importantly, abnormal PTFV1 failed to predict incident stroke in the overall LIFE population on sinus rhythm. Some other aspects of this study deserve to be briefly discussed. Unfortunately, the study did not address the effective contribution of PTFV1 in improving discrimination of incident stroke risk in addition to established predictors including baseline microalbuminuria, ECG-LVH (treated as continuous variable), ECG parameters such as left atrial diameter and left ventricle mass. The relation between PTFV1 (more strongly related to cardioembolic stroke) and subtypes of ischemic strokes in 364 patients from the general LIFE population was not analyzed and this may be regarded as a limitation of study design. Finally, it should be remarked that PTFV1 was measured manually; nonetheless, information on inter-reader and intrareader variability was not provided.

In conclusion, the value of PTFV1 in predicting ischemic stroke documented by this study conducted in middle-aged hypertensive patients with ECG-LVH needs to be confirmed in larger studies representative of unselected hypertensive population.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

The authors alone are responsible for the content and writing of the article.

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