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 μU/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 <0.001) were significantly associated with occurrence of the composite end point; 53.6% of patients with hypothyroidism at baseline developed the composite end point compared with 39.8% of those with euthyroidism (p = 0.02). In conclusion, hypothyroidism is associated with a worse prognosis after CRT implantation.
Previous studies have identified predictors of response to CRT including demographics, origin of cardiomyopathy, biomarkers, QRS width and morphology, lead location, and postimplant care provided to these patients. Notably, hypothyroidism is a frequent co-morbid condition for patients with heart failure (HF), but to our knowledge, it has not been previously specifically evaluated for its impact on CRT response. Persistent subclinical hypothyroidism has been associated with the development of HF in patients with and without underlying heart disease. The Health, Aging, and Body Composition population-based study showed that participants with thyroid-stimulating hormone (TSH) ≥7 μU/ml had 3 times higher HF events than patients with euthyroid. The Cardiovascular Health Study showed a greater incidence of HF events in participants >65 years with TSH ≥10 μU/ml 3 . However, there are also studies with contradictory findings where no relation was established between hypothyroidism and cardiovascular risk. The prevalence of hypothyroidism in patients with HF has been reported from 7% for overt hypothyroidism to 14% for subclinical hypothyroidism. Guidelines from the American College of Cardiology recommend workup for all cases of HF to include screening with thyrotropin levels. 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. 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 μU/ml. TSH level ≥5.00 μU/ml was defined as uncontrolled hypothyroidism (if previously diagnosed); 6 patients had TSH level ≥5 and ≤10 μU/ml and were defined as having subclinical hypothyroidism and included in the hypothyroid group. There were 3 patients with hyperthyroidism, which was too small a number for relevant analysis, and so these patients were excluded from the study; 1 of these 3 patients was on amiodarone. TSH levels within 2 weeks of CRT device implantation were analyzed and were measured in outpatient settings. Other laboratory values of interest that were recorded included serum sodium and creatinine. Hyponatremia was defined as sodium level <135 mEq/L. Patients had a transthoracic echocardiogram before implant and a follow-up echocardiogram within a year of baseline echocardiogram (Philips iE33, SONOS 5500/7500, Andover, Massachusetts, and General Electric Vivid 7, Milwaukee, Wisconsin). LVEF was calculated using the biplane method of discs from the apical 4- and 2-chamber views.
All patients were followed up for a period of 3 years (median follow-up duration 21.9 months) for a combined end point comprising all-cause mortality, HF hospitalizations, left ventricular assist device implantation, and cardiac transplant. HF hospitalization was defined as inpatient admission with signs and/or symptoms of HF, including dyspnea, peripheral edema, and/or congestion on the chest radiograph. Notably, clinical outcomes were confirmed with review of the electronic medical record and comparison with the social security death index.
Statistical analyses were performed using SPSS, version 21.0 (SPSS Inc., Chicago, Illinois). Results are presented as mean ± SD for continuous variables. Categorical data were summarized as frequencies and percentages. For the assessment of differences, the chi-square test was applied, where appropriate. Continuous variables were compared by independent sample t test. Kaplan-Meier curves were constructed to compare event rates in hypothyroid and euthyroid groups with respect to the composite end point of HF hospitalization, left ventricular assist device, cardiac transplant, and all-cause death. Cox proportional hazard models were used for cumulative risk assessment of composite end point as described earlier, and backward stepwise selection was applied. The models were adjusted for clinical variables, which were shown as significant univariate predictors. However, parameters with p <0.10 were selected for multivariate analysis. All statistical tests were considered significant at p ≤0.05.
Results
Of 511 patients who met study criteria, 84 had a history of hypothyroidism before CRT placement; 60 of these 84 patients with a known history of hypothyroidism had TSH within 2 weeks of CRT implant. Baseline characteristics for the 511 patients in the study cohort are presented in Table 1 . Patients with hypothyroid were significantly older compared with those with euthyroid (73.2 ± 10.8 vs 67.5 ± 12.4 years, p <0.001) and were more likely to be women. They also had significant difference in baseline serum creatinine. The baseline LVEF was significantly greater in the hypothyroid group with significantly smaller left ventricular internal diameters, both diastolic and systolic. Patients with hypothyroid were significantly less frequently treated with angiotensin-converting enzyme inhibitors and more frequently treated with digoxin. There were no other significant differences in other co-morbidites or medication use. There was no significant difference between the included and excluded population regarding baseline characteristics.
| Characteristic | Whole cohort (N=511) | Hypothyroid (N= 84) | Euthyroid N=427 | p value |
|---|---|---|---|---|
| Age (years) | 68.5±12.4 | 73.2±10.8 | 67.5±12.4 | <0.001 |
| Female | 116 (23%) | 32 (38%) | 74 (17%) | <0.001 |
| Creatinine (mg/dL) | 1.5±0.8 | 1.7±0.7 | 1.47±0.80 | 0.018 |
| New York Heart Association class: III/IV | 387 (76%) | 61 (73%) | 326 (76%) | 0.495 |
| Left ventricular ejection fraction | 24±7(%) | 26±7 | 24±7 | 0.014 |
| LVIDd (mm) | 62.1±8.9 | 58.8±8.4 | 62.0±8.8 | 0.001 |
| LVIDs (mm) | 54.2±9.4 | 50.2±8.7 | 54.0±9.3 | <0.001 |
| QRS duration (msec) | 161±28 | 162±23 | 161±28.5 | 0.795 |
| Coronary artery bypass graft | 209 (41%) | 42(50%) | 167 (39%) | 0.063 |
| Chronic atrial fibrillation | 146 (29%) | 29 (35%) | 117 (27%) | 0.186 |
| Paroxysmal atrial fibrillation | 152 (30%) | 26 (31%) | 126 (30%) | 0.791 |
| Diabetes Mellitus | 205(40%) | 39 (46%) | 166 (39%) | 0.197 |
| Hypertension | 381(75%) | 64 (76%) | 317 (74%) | 0.707 |
| Coronary artery disease | 379(74%) | 61 (73%) | 274 (64%) | 0.093 |
| Ischemic Cardiomyopathy | 294 (58%) | 52 (62%) | 242 (57%) | 0.623 |
| Baseline Sodium (mEq/L) | 137.6±3.51 | 137.4±3.1 | 137.6±3.6 | 0.655 |
| Hyponatremia | 102 (20%) | 16 (19%) | 86 (20%) | 0.804 |
| Angiotensin converting enzyme inhibitor | 310 (61%) | 42 (50%) | 268 (63%) | 0.029 |
| Angiotensin II receptor blocker | 102 (20%) | 20 (24%) | 82 (19%) | 0.334 |
| Aldosterone antagonist | 164(32%) | 23 (27%) | 141 (33%) | 0.189 |
| Beta-blockers | 448 (88%) | 69 (82%) | 379 (89%) | 0.92 |
| Digoxin | 194 (38%) | 40 (48%) | 154 (36%) | 0.046 |
| Diuretics | 449 (88%) | 74 (88%) | 375 (88%) | 0.55 |
| Antiarrhythmics | 95 (19%) | 18 (21%) | 77 (18%) | 0.561 |
| Amiodarone | 74 (15%) | 18(21%) | 56 (13%) | 0.01 |
| TSH ( μU/mL) | 3.8±8.3 | 8.5±15.7 | 2.3±1.6 | 0.003 |
Univariate predictors of the composite outcome with p <0.10 (i.e., female gender, hypothyroidism, creatinine, diabetes mellitus, digoxin, and angiotensin-converting enzyme inhibitors use) were considered for multivariate analysis, which demonstrated that creatinine, female gender, and hypothyroidism were significantly associated with the composite outcome ( Table 2 ). Kaplan-Meier curve for event-free survival showed that patients with a history of hypothyroidism had a significantly higher incidence of the composite end point compared with those with euthyroid ( Figure 1 ). The chi-square comparison between the 2 groups demonstrated that 53.6% of patients with hypothyroid compared with 39.8% of those with euthyroid (p = 0.02) reached the composite end point; 215 total events meeting the composite end point were noted at the end of 3 years (hazard ratio [HR] for hypothyroidism = 1.48, 95% confidence interval [CI] 1.06 to 2.05, p = 0.02). When the composite end point was broken into individual components, there were significantly greater rates of mortality and of heart failure hospitalization in patients with hypothyroid: 33 patients had died during this time period (HR 1.48, 95% CI 1.01 to 2.18, p = 0.046) and 38 patients had heart failure hospitalizations (HR 1.51, 95% CI 1.06 to 2.17, p = 0.022). In regard to the other components of the composite end point, there were no significant differences in LVAD implant (3 events = 0.7% in normothyroid and 2 events = 2.4% in hypothyroid, p = 0.191) or in heart transplant (17 events = 4% in normothyroid and 0 events in hypothyroid, p = 0.089). There was no significant difference between echocardiographic responses to CRT implantation in hypothyroid compared with patients with euthyroid in regard to change in LVEF after CRT placement (change in LVEF: patients with hypothyroid 10.1 ± 10.5, euthyroid 7.3 ± 10.5, p = 0.09; % change in LVEF: hypothyroid 42.5 ± 50.7, euthyroid 35.9 ± 52.1, p = 0.426).
| Characteristic | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95%CI) | p value | HR (95%CI) | p value | |
| Age | 1.01 (0.997-1.019) | 0.137 | – | – |
| Creatinine | 1.29 (1.183-1.405) | <0.001 | 1.26 (1.142-1.381) | <0.001 |
| Hypothyroidism | 1.47 (1.064-2.052) | 0.020 | 1.46 (1.027-2.085) | 0.035 |
| Left ventricular ejection fraction | 0.98 (0.970-1.007) | 0.237 | – | – |
| Diabetes mellitus | 1.34 (1.025-1.789) | 0.052 | 1.29 (0.971-1.708) | 0.080 |
| Female gender | 0.69 (0.48-0.998) | 0.049 | 0.64 (0.428-0.963) | 0.032 |
| Angiotensin converting enzyme inhibitor | 0.79 (0.604-1.037) | 0.09 | 0.86 (0.642-1.150) | 0.309 |
| Digoxin | 1.42 (1.100-1.847) | 0.010 | 1.26 (0.946-1.675) | 0.114 |
| Amiodarone | 1.30(0.651-2.605) | 0.455 | – | – |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
