Association of P-Wave Abnormalities With Sudden Cardiac and Cardiovascular Death: The ARIC Study.

Abstract

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 14, No. 2Association of P-Wave Abnormalities With Sudden Cardiac and Cardiovascular Death Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBAssociation of P-Wave Abnormalities With Sudden Cardiac and Cardiovascular DeathThe ARIC Study Ankit Maheshwari, MD, MS Faye L. Norby, MS, PhD; MPH Elsayed Z. Soliman, MD, MSc, MS Alvaro Alonso, MD, PhD Nona Sotoodehnia, MD, MPH Lin Y. ChenMD, MS Ankit MaheshwariAnkit Maheshwari Correspondence to: Ankit Maheshwari, MD, MS, Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3096-3372 Heart and Vascular Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA (A.M.). Search for more papers by this author , Faye L. NorbyFaye L. Norby https://orcid.org/0000-0002-1975-0405 School of Public Health (F.L.N.), University of Minnesota, Minneapolis. Search for more papers by this author , Elsayed Z. SolimanElsayed Z. Soliman https://orcid.org/0000-0001-5632-8150 Epidemiological Cardiology Research Center, Wake Forest University, Winston-Salem, NC (E.Z.S.). Search for more papers by this author , Alvaro AlonsoAlvaro Alonso https://orcid.org/0000-0002-2225-8323 Department of Epidemiology, Emory University, Atlanta, GA (A.A.). Search for more papers by this author , Nona SotoodehniaNona Sotoodehnia Department of Medicine, University of Washington, Seattle (N.S.). Search for more papers by this author , and Lin Y. ChenLin Y. Chen https://orcid.org/0000-0002-0700-814X Department of Medicine (L.Y.C.), University of Minnesota, Minneapolis. Search for more papers by this author Originally published16 Feb 2021https://doi.org/10.1161/CIRCEP.120.009314Circulation: Arrhythmia and Electrophysiology. 2021;14:e009314Electrocardiographic assessment of cardiovascular risk has primarily relied on analysis of ventricular depolarization and repolarization.1 Atrial cardiomyopathy is increasingly recognized as an independent contributor to poor cardiovascular outcomes. It is characterized by adverse structural, architectural, contractile, or electrophysiological atrial remodeling,2 which manifests electrocardiographically3 as abnormal P-wave indices (aPWIs). We aimed to determine whether aPWIs are associated with sudden cardiac death (SCD) and cardiovascular death independent of clinical cardiovascular risk factors from the American College of Cardiology/American Heart Association pooled cohort equation4 and established electrocardiographic1 cardiovascular risk markers. We also aimed to determine whether use of multiple electrocardiographic markers could improve prediction models for SCD and cardiovascular death.We utilized ARIC Study (Atherosclerosis Risk in Communities) data. Details on study protocols including covariate and outcome adjudication have been previously reported3,5 and are included in Methods in the Data Supplement. Informed participant consent and institutional review board approval from each participating institution was obtained. ARIC study participant consent does not allow for public release of data. Data, with some restriction, can be accessed by contacting the ARIC coordinating center (www2.cscc.unc.edu/aric/). We evaluated 13 580 participants at baseline without prevalent cardiovascular disease (stroke, heart failure, coronary heart disease [CHD], atrial fibrillation) or missing ECG/covariate data.ECGs variables were obtained during the first 4 study visits (1987–1998). We evaluated abnormal P-wave axis (<0°, >75°), prolonged P-wave duration (>120 ms), and abnormal P-wave terminal force in lead V1 (≤−4000 μV×ms), as well as previously reported electrocardiographic SCD and cardiovascular risk markers1—resting heart rate >75 bpm, prolonged QTc interval (>450 ms for men, >460 for women), QRS-T angle >90°, QRS transition zone >V4, left ventricular (LV) hypertrophy (sex-specific Cornell product), Tpeak to Tend >89 ms, and QRS duration >100 ms. Clinical covariates were selected from the American College of Cardiology/American Heart Association pooled cohort equation including age, sex, systolic blood pressure, use of antihypertensive medications, smoking status, total cholesterol, and high-density lipoprotein. We also included race/study center and incident heart failure, CHD, and atrial fibrillation.All fatal CHD events through 2012 were reviewed by a panel of physicians to adjudicate SCDs. Cardiovascular deaths were defined as deaths associated with International Classification of Diseases, Tenth Revision I codes or International Classification of Diseases, Ninth Revision codes 401 to 459.We used Cox proportional hazard models (models 1–4′) to estimate hazard ratios of each aPWI for SCD and cardiovascular death. All PWIs and covariates were time-varying. To account for mediation by development of cardiovascular diseases associated with SCD and cardiovascular death, selected covariates (atrial fibrillation, CHD, and heart failure) were updated to the end of follow-up (Table 1).Table 1. Association of P-Wave Indices With Sudden Cardiac Death and Cardiovascular DeathHazard ratios (95% CI) of SCD and CV death for aPWIP-wave index*Model†SCD‡CV death‡aPWA (<0°, >75°)14.27 (3.44–5.30)3.99 (3.56–4.48)23.94 (3.17–4.90)3.80 (3.38–4.26)33.77 (3.03–4.69)3.61 (3.21–4.06)43.80 (3.05–4.73)3.64 (3.23–4.10)4′2.84 (2.27–3.57)2.79 (2.48–3.15)PPWD (>120 ms)11.86 (1.51–2.30)2.00 (1.78–2.25)21.78 (1.44–2.20)1.90 (1.69–2.14)31.70 (1.37–2.11)1.82 (1.62–2.05)41.67 (1.34–2.07)1.79 (1.59–2.02)4′1.32 (1.06–1.64)1.38 (1.22–1.55)aPTFV1 (≤−4000 μV×ms)12.46 (1.98–3.05)2.35 (2.09–2.65)22.00 (1.60–2.48)1.91 (1.69–2.15)31.82 (1.46–2.28)1.73 (1.53–1.95)41.79 (1.43–2.24)1.69 (1.50–1.92)4′1.58 (1.26–1.99)1.44 (1.27–1.62)ACC indicates American College of Cardiology; AHA, American Heart Association; aPTFV1, abnormal P-wave terminal force in V1; aPWA, abnormal P-wave axis; aPWIs, abnormal P-wave indices; CV, cardiovascular; PPWD, prolonged P-wave duration; and SCD, sudden cardiac death.* P-wave indices and covariates (models 1–4) are time-varying.† Model 1: Cox proportional hazard model adjusted for age, sex, and race/study center. Model 2: model 1+ hypertension medications, systolic blood pressure, diabetes, smoking status, total cholesterol, high-density lipoprotein (clinical covariates from the ACC/AHA pooled cohort equation). Model 3: model 2+ ECG left ventricular hypertrophy, QTc>450 ms (men)/460 ms (female), resting heart rate >75 bpm, Frontal QRS-T angle >90°, QRS transition >V4, QRS duration >100 ms, TpTe>89 ms (previously reported ECG markers of CV risk). Model 4: model 3+ atrial fibrillation, coronary heart disease, heart failure. Model 4′: model 4 with atrial fibrillation, coronary heart disease, heart failure updated to end of follow-up.‡ All P<0.01 for 1A.Benchmark models predicting 10-year SCD and cardiovascular death risk were built using baseline variables from the American College of Cardiology/American Heart Association pooled cohort equation (model A4) and previously established SCD risk scores (models B,1 and C5).Improvement in risk prediction by the addition of ECG markers to benchmarks (models A+, B+, and C+) was evaluated by calculating the C statistic, categorical net reclassification improvement, and relative integrated discrimination improvement. We used the Hosmer-Lemeshow χ2 statistic to evaluate model calibration (Table 2).Table 2. Prediction of SCD and CV Death Utilizing Multivariable ECG AnalysisPrediction model performance for 10-year SCD and CV death riskOutcomeModel*C statistic (95% CI)Calibration X2 (P value)Category-based NRI† (95% CI)rIDI (95% CI)SCDA0.815 (0.781–0.848)10.1 (0.34)ReferenceReferenceA+0.832 (0.798–0.865)5.89 (0.75)0.087 (0.013–0.162)0.338 (0.145–0.559)B0.814 (0.782–0.846)8.44 (0.49)ReferenceReferenceB+0.822 (0.790–0.855)14.3 (0.11)0.079 (0.004–0.150)0.100 (0.006–0.232)C0.838 (0.807–0.868)5.97 (0.74)ReferenceReferenceC+0.848 (0.818–0.879)8.43 (0.49)0.078 (0.018–0.143)0.222 (0.069–0.412)CV deathA0.816 (0.794–0.839)7.81 (0.55)ReferenceReferenceA+0.830 (0.808–0.853)9.51 (0.39)0.072 (0.017–0.128)0.239 (0.097–0.415)B0.802 (0.778–0.825)13.6 (0.14)ReferenceReferenceB+0.808 (0.784–0.832)10.9 (0.28)0.058 (0.011–0.101)0.094 (0.032–0.171)C0.822 (0.799–0.845)6.67 (0.67)ReferenceReferenceC+0.833 (0.811–0.856)5.82 (0.76)0.085 (0.037–0.133)0.215 (0.088–0.375)ACC indicates American College of Cardiology; AHA, American Heart Association; aPTFV1, abnormal P-wave terminal force in V1; aPWA, abnormal P-wave axis; CV, cardiovascular; HDL, high-density lipoprotein; NRI, categorical net reclassification improvement; PPWD, prolonged P-wave duration; rIDI, relative integrated discrimination improvement; SCD, sudden cardiac death; and TpTe, Tpeak-Tend.* Model A: Cox proportional hazard model adjusted for age, sex, race/study center, hypertension medications, systolic blood pressure, diabetes, smoking status, total cholesterol, HDL (variables from the ACC/AHA pooled cohort equation). Model A+: model A+ECG variables (aPWA, aPFTV1, PPWD, ECG left ventricular hypertrophy, QTc>450 ms (men)/460 ms (female), resting heart rate >75 bpm, QRS-T angle >90° QRS transition >V4, QRS duration >100 ms, TpTe>89 ms). Model B: Cox proportional hazard model adjusted for age, sex, hypertension, diabetes, body mass index, smoking status, ECG left ventricular hypertrophy, QRS transition >V4, resting heart rate >75 bpm, frontal QRS-T angle >90°, QTc>450 ms (men)/460 ms (female), TpTe>89 ms. Model B+: model B+remaining ECG variables (aPWA, aPTFV1, PPWD, QRS duration >100 ms). Model C: Cox proportional hazard model adjusted for age, sex, race, diabetes, smoking status, systolic blood pressure, hypertension medications, potassium, albumin, HDL, estimated glomerular filtration rate, QTc>450 ms (men)/460 ms (female). Model C+: model C+remaining ECG variables (aPWA, PPWD, aPTFV1, ECG left ventricular hypertrophy, QRS transition >V4, resting heart rate >75 bpm, Frontal QRS-T angle >90°, TpTe>89 ms, QRS duration >100 ms).† NRI categories: SCD: <1%, 1%–2%, >2%; CV death: <2.5%, 2.5%–5%, >5%.We identified 386 SCDs and 1296 cardiovascular deaths in our cohort of 13 580 participants over a mean follow-up period of 21.1 years. Baseline demographic data are displayed in Table I in the Data Supplement.All PWIs were independently associated with SCD and cardiovascular death after adjustment for age, sex, and race/study center (model 1). These associations were attenuated but remained significant after adjustment for clinical risk factors from the American College of Cardiology/American Heart Association pooled cohort equation (model 2), electrocardiographic cardiovascular risk factors (model 3), cardiovascular diseases (model 4), and cardiovascular diseases updated to the end of follow-up (model 4′).For prediction of 10-year SCD and cardiovascular death risk, the addition of ECG markers to our benchmarks resulted in an improvement in model discrimination measured by C statistic for SCD and cardiovascular death. This corresponded to accurate reclassification of risk measured by relative integrated discrimination improvement and net reclassification improvement for SCD and cardiovascular death. All models were well calibrated for SCD and cardiovascular death (Table 2).aPWIs have been linked with atrial remodeling/enlargement and reduced atrial contractility. These elements of atrial cardiomyopathy can have diverse consequences including impaired ventricular filling/hemodynamics and arrhythmia, such as atrial fibrillation.2 Ultimately, development of increased cardiac remodeling, pulmonary hypertension, heart failure, and myocardial ischemia can occur. In fact, aPWIs have been independently associated with increased LV end-diastolic diameter, lower LV systolic function,3 and increased LV fibrosis. By rigorously characterizing the association of aPWIs with cardiovascular death and SCD, this article expands current understanding of the impact of atrial cardiomyopathy on cardiovascular disease. Because the majority of SCDs occur in people with subclinical CHD disease and normal LV ejection fraction, identifying novel predictors and improving general cardiovascular risk assessment is paramount. This is especially true as multivariable SCD prediction models have not been able to meaningfully discriminate between SCD and non-SCD. Our findings illustrate the potential of improvement in cardiovascular risk prediction with multimarker ECG analysis. Further validation and evaluation of clinical utility is needed.Nonstandard Abbreviations and AcronymsaPWIabnormal P-wave indicesARICAtherosclerosis Risk in CommunitiesCHDcoronary heart diseaseLVleft ventricularPPWDprolonged P-wave durationSCDsudden cardiac deathAcknowledgmentsWe thank the staff and participants of the ARIC study (Atherosclerosis Risk in Communities) for their important contributions.Sources of FundingThe Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I).Disclosures None.FootnotesThe Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCEP.120.009314.For Sources of Funding and Disclosures, see page 218.Correspondence to: Ankit Maheshwari, MD, MS, Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033. Email [email protected]psu.edu