Association of Hypothyroidism With Adverse Events in Patients With Heart Failure Receiving Cardiac Resynchronization Therapy Ajay K. Sharma, MD, Eszter Vegh, MD, Mary Orencole, ANP, Alexandra Miller, MA, Dan Blendea, MD, PhD, Stephanie Moore, MD, Gregory D. Lewis, MD, Jagmeet P. Singh, MD, PhD, Kimberly A. Parks, DO, and E. Kevin Heist, MD, PhD* Hypothyroidism is associated with an adverse prognosis in cardiac patients in general and in particular in patients with heart failure (HF). The aim of this study was to evaluate the impact of hypothyroidism on patients with HF receiving cardiac resynchronization therapy (CRT). Additionally, the impact of level of control of hypothyroidism on risk of adverse events after CRT implantation was also evaluated. We included consecutive patients in whom a CRT device was implanted from April 2004 to April 2010 at our institution with sufficient follow-up data available for analysis; 511 patients were included (age 68.5 – 12.4 years, women 20.4%); 84 patients with a clinical history of hypothyroidism, on treatment with thyroid hormone repletion or serum thyroid-stimulating hormone level ‡5.00 mU/ml, were included in the hypothyroid group. The patients were followed for up to 3 years after implant for a composite end point of hospitalization for HF, left ventricular assist device placement, or heart transplant and cardiac death; 215 composite end point events were noted in this period. In a multivariate model, hypothyroidism (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.027 to 2.085, p [ 0.035), female gender (HR 0.64, 95% CI 0.428 to 0.963, p [ 0.032), and creatinine (HR 1.26, 95% CI 1.145 to 1.382, p 65 years with TSH
10 mU/ml3. However, there are also studies with contradictory findings where no relation was established between hypothyroidism and cardiovascular risk.6,7 The prevalence of hypothyroidism in patients with HF has been Cardiology Division, Massachusetts General Hospital Heart Center, Harvard Medical School, Boston, Massachusetts. Manuscript received October 20, 2014; revised manuscript received and accepted January 29, 2015. See page 1252 for disclosure information. *Corresponding author: Tel: (617) 726-4959; fax: (617) 726-3852. E-mail address: [email protected] (E.K. Heist). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.559

reported from 7% for overt hypothyroidism to 14% for subclinical hypothyroidism.3,8 Guidelines from the American College of Cardiology recommend workup for all cases of HF to include screening with thyrotropin levels.9 The purpose of this study was to determine how hypothyroidism in patients with HF affected response to CRT. Methods This is a single-center retrospective study of a database comprising consecutive patients who underwent CRT device implantation from April 2004 to April 2010. Patients were followed up after implant in a multidisciplinary clinic by integrated care visits with HF, echocardiography, and electrophysiology specialists. The physicians belonging to this group were responsible for defining New York Heart Association class, cause of HF, calculating left ventricular ejection fraction (LVEF), and implanting CRT device according to standard implantation criteria.10 Information collected in the database consisted of patients’ demographic characteristics, medical history, disease course after device implantation, diagnostic testing before and after device implantation, and drug therapies. Hypothyroidism was defined by clinical history obtained by reviewing electronic medical record, treatment with thyroid hormone repletion, and serum TSH around the time of device implantation. Reference range for TSH was 0.40 to 5.00 mU/ml. TSH level
5.00 mU/ml was defined www.ajconline.org

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Table 1 Baseline characteristics for the whole cohort, hypothyroid and euthyroid patients Characteristic Age (years) Female Creatinine (mg/dL) New York Heart Association class: III/IV Left ventricular ejection fraction LVIDd (mm) LVIDs (mm) QRS duration (msec) Coronary artery bypass graft Chronic atrial fibrillation Paroxysmal atrial fibrillation Diabetes Mellitus Hypertension Coronary artery disease Ischemic Cardiomyopathy Baseline Sodium (mEq/L) Hyponatremia Angiotensin converting enzyme inhibitor Angiotensin II receptor blocker Aldosterone antagonist Beta-blockers Digoxin Diuretics Antiarrhythmics Amiodarone TSH ( mU/mL)

Whole cohort (N¼511)

Hypothyroid (N¼ 84)

Euthyroid N¼427

p value

68.512.4 116 (23%) 1.50.8 387 (76%) 247(%) 62.18.9 54.29.4 16128 209 (41%) 146 (29%) 152 (30%) 205(40%) 381(75%) 379(74%) 294 (58%) 137.63.51 102 (20%) 310 (61%) 102 (20%) 164(32%) 448 (88%) 194 (38%) 449 (88%) 95 (19%) 74 (15%) 3.88.3

73.210.8 32 (38%) 1.70.7 61 (73%) 267 58.88.4 50.28.7 16223 42(50%) 29 (35%) 26 (31%) 39 (46%) 64 (76%) 61 (73%) 52 (62%) 137.43.1 16 (19%) 42 (50%) 20 (24%) 23 (27%) 69 (82%) 40 (48%) 74 (88%) 18 (21%) 18(21%) 8.515.7

67.512.4 74 (17%) 1.470.80 326 (76%) 247 62.08.8 54.09.3 16128.5 167 (39%) 117 (27%) 126 (30%) 166 (39%) 317 (74%) 274 (64%) 242 (57%) 137.63.6 86 (20%) 268 (63%) 82 (19%) 141 (33%) 379 (89%) 154 (36%) 375 (88%) 77 (18%) 56 (13%) 2.31.6