There are well-documented changes in thyroid hormone metabolism that accompany heart failure (HF). However, the frequency of thyroid hormone abnormalities in HF with preserved ejection fraction (HFpEF) is unknown, and no studies have investigated the association between triiodothyronine (T 3 ) and markers of HF severity (B-type natriuretic peptide [BNP] and diastolic dysfunction [DD]) in HFpEF. In this study, 89 consecutive patients with HFpEF, defined as symptomatic HF with a left ventricular ejection fraction >50% and a left ventricular end-diastolic volume index <97 ml/m 2 , were prospectively studied. Patients were dichotomized into 2 groups on the basis of median T 3 levels, and clinical, laboratory, and echocardiographic data were compared between groups. Univariate and multivariate linear regression analyses were performed to determine whether BNP and DD were independently associated with T 3 level. We found that 22% of patients with HFpEF had reduced T 3 . Patients with lower T 3 levels were older, were more symptomatic, more frequently had hyperlipidemia and diabetes, and had higher BNP levels. Severe (grade 3) DD, higher mitral E velocity, shorter deceleration time, and higher pulse pressure/stroke volume ratio were all associated with lower T 3 levels. T 3 was inversely associated with log BNP (p = 0.004) and the severity of DD (p = 0.039). On multivariate analysis, T 3 was independently associated with log BNP (β = −4.7 ng/dl, 95% confidence interval −9.0 to −0.41 ng/dl, p = 0.032) and severe DD (β = −16.3 ng/dl, 95% confidence interval −30.1 to −2.5 ng/dl, p = 0.022). In conclusion, T 3 is inversely associated with markers of HFpEF severity (BNP and DD). Whether reduced T 3 contributes to or is a consequence of increased severity of HFpEF remains to be determined.
Heart failure (HF) with preserved ejection fraction (HFpEF) is common and associated with high morbidity and mortality. Finding dedicated treatments for HFpEF has been challenging, and novel therapeutic pathways are necessary. Given the hormonal alterations that occur in HF, interest in endocrine dysregulation as a potential avenue for intervention is growing. Thyroid hormone, specifically triiodothyronine (T 3 ), is known to have beneficial cardiovascular effects, including facilitating myocardial relaxation and lowering peripheral vascular resistance. Derangement of the thyroid axis can thus lead to a spectrum of cardiovascular manifestations. This relation has been studied in HF with reduced ejection fraction, but the frequency of thyroid hormone abnormalities in HFpEF is unknown. Furthermore, no previous studies have investigated the association between T 3 and markers of HF severity (e.g., B-type natriuretic peptide [BNP] and left ventricular (LV) diastolic dysfunction [DD]) in patients with HFpEF. We therefore sought to (1) define the prevalence of thyroid-axis abnormalities in HFpEF and (2) investigate associations between T 3 and laboratory and echocardiographic data in HFpEF. We hypothesized that reduced T 3 is common in HFpEF and may independently contribute to increased BNP and worse DD in these patients, similar to that observed in classic hypothyroidism.
Methods
Consecutive patients were prospectively enrolled from the outpatient clinic of the Northwestern University HFpEF program as part of a systematic observational study of HFpEF ( ClinicalTrials.gov identifier NCT01030991 ). Patients were initially identified by an automated daily query of the inpatient electronic medical record at Northwestern Memorial Hospital using the following search criteria: (1) diagnosis of HF or the phrase “heart failure” anywhere in the hospital notes, (2) BNP >100 pg/ml, or (3) administration of ≥2 doses of intravenous diuretics. The list of patients generated was screened daily, and only those patients with LV ejection fraction >50% who met Framingham criteria for HF were offered postdischarge follow-up in a specialized HFpEF outpatient program. Once patients were evaluated as outpatients in the HFpEF clinic, the diagnoses of HF were confirmed by a board-certified HF specialist. All study participants gave written informed consent, and the institutional review board at Northwestern University approved the study.
We defined HFpEF as symptomatic HF with an LV ejection fraction >50% and an LV end-diastolic volume index <97 ml/m 2 . On the basis of previously published guidelines, we additionally required evidence of either significant DD (grade 2 or 3) on echocardiography or evidence of elevated LV filling pressures. In patients in whom DD was graded as normal or grade 1 (mild), we performed invasive hemodynamic testing and required evidence of elevated LV end-diastolic pressure (i.e., pulmonary capillary wedge pressure >15 mm Hg or LV end-diastolic pressure >15 mm Hg). In line with a large population-based study in HFpEF, patients with hemodynamically significant valvular disease (defined as greater than moderate in severity), previous cardiac transplantation, history of overt LV systolic dysfunction (LV ejection fraction <40%), or diagnosis of constrictive pericarditis were excluded. Patients were also excluded if they had known hypothyroidism or hyperthyroidism.
We collected and analyzed demographics, clinical data (including co-morbidities and medications), and laboratory data, including BNP, thyroid stimulating hormone (TSH), free T 4 , and total T 3 . Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) equation. Hypertension was defined by systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, physician-documented history of hypertension, or current use of antihypertensive medications. Diabetes mellitus was defined by the presence of physician-documented history of diabetes or the use of oral hypoglycemic agents or insulin for the treatment of hyperglycemia. Coronary artery disease was defined by the presence of physician-documented history of coronary artery disease, known coronary stenosis >50%, history of myocardial infarction, percutaneous intervention, coronary artery bypass grafting, or abnormal stress test results consistent with myocardial ischemia. Obesity was defined by a body mass index >30 kg/m 2 . Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m 2 .
All study participants underwent comprehensive 2-dimensional echocardiography with Doppler and tissue Doppler imaging. All standard echocardiographic views were obtained. Echocardiography was performed using commercially available ultrasound systems with harmonic imaging (Philips iE33 or 7500, Philips Medical Systems, Andover, Massachusetts; or Vivid 7, GE Healthcare, Waukesha, Wisconsin). Cardiac structure and systolic function were quantified as recommended by the American Society of Echocardiography. Diastolic function was graded in accordance with criteria published previously. All echocardiographic measurements were made by an experienced research sonographer blinded to all other clinical data using ProSolv version 4.0 echocardiographic analysis software (ProSolv CardioVascular, Indianapolis, Indiana) and were verified by a board-certified echocardiographer.
For descriptive purposes, we dichotomized participants into 2 groups on the basis of the median T 3 level (T 3 ≥108 ng/dl [n = 46] vs T 3 <108 ng/dl [n = 43]). The reference range for normal T 3 values in the Northwestern Memorial Hospital laboratory is 87 to 178 ng/dl. We chose to dichotomize study participants by median T 3 level (108 ng/dl) instead of the clinical cut point for reduced T 3 (87 ng/dl) to preserve statistical power in our 2 comparison groups.
Demographics, clinical characteristics, laboratory data, and echocardiographic parameters were compared between groups using t tests for normally distributed continuous variables (or nonparametric equivalent when appropriate). Chi-square tests (or Fisher’s exact test when appropriate) were used to compare categorical variables between groups. Two-sided p values <0.05 were considered statistically significant. Continuous data with normal distributions are expressed as mean ± SD. Right-skewed data were log transformed and are expressed as medians with 25th and 75th percentiles.
To determine associations between thyroid function tests and cardiac data (echocardiographic variables and BNP), we performed Pearson’s correlation analyses to determine the strength of correlation and significance for any bivariate associations (variables that were right skewed [i.e., TSH and BNP] were log transformed before analysis). Next, we performed univariate and multivariate linear regression analyses to determine whether BNP (the independent variable) was associated with T 3 level (the dependent variable). We performed similar analyses to determine the association between severe (grade 3) DD and T 3 . Candidate covariates were selected for inclusion in our multivariate linear regression models if they differed between the T 3 ≥108 ng/dl and T 3 <108 ng/dl groups at a significance level of p <0.05. Furthermore, because obesity correlates inversely with BNP, and β-blocker use has been linked to worsening HFpEF severity, these variables were also included in the multivariate analyses. All analyses were performed using Stata version 10.1 (StataCorp LP, College Station, Texas).
Results
Demographic and clinical characteristics of the 89 study participants were consistent with previous epidemiologic and large observational studies of HFpEF, with an observed sample mean age of 67 ± 14 years and female predominance (69%). Ethnicities represented a mixed urban population: 49% were white, 42% were African American, and 9% were other ethnicities. Most patients (52%) had New York Heart Association functional class III or IV symptoms, and co-morbidities were common. The distribution of medication use reflected standard medical therapy in those with HFpEF who have multiple cardiovascular co-morbidities. Notably, only 6% of patients were taking amiodarone at the time of thyroid function testing. Echocardiographic variables were consistent with expected findings in HFpEF: preserved LV ejection fraction, normal LV end-diastolic volume index, increased left atrial volume index, and increased E/e′ ratio reflective of increased LV filling pressures. In addition, most patients had either moderate or severe DD.
On the basis of clinical cutoffs, T 3 was low (i.e., T 3 <87 ng/dl) in 20 of 89 patients (22%) and elevated (i.e., T 3 >178 ng/dl) in 3 of 89 patients (3%). In addition, 6 of 89 (7%) had low free T 4 (<0.7 ng/dl), 2 of 89 (2%) had elevated free T 4 (>1.5 ng/dl), 12 of 89 (13%) had low TSH (<0.4 μIU/ml), and 9 of 89 (10%) had elevated TSH (>4 μIU/ml). Patients with lower T 3 levels were more likely to be older, were more symptomatic with higher New York Heart Association functional class, more frequently had hyperlipidemia and diabetes, and had higher BNP levels ( Table 1 ). These patients also had lower diastolic blood pressure, but this association was no longer significant after adjusting for age (p = 0.26). No differences in gender, ethnicity, medication use (including amiodarone), systolic blood pressure, body mass index, hemoglobin, TSH, and free T 4 values were observed compared to patients with T 3 ≥108 ng/dl. Patients with lower T 3 levels had a higher prevalence of grade 3 DD, higher early mitral inflow velocity, and shorter early mitral inflow deceleration time ( Table 2 ). A higher pulse pressure/stroke volume ratio, indicative of increased arterial stiffness, was also noted. There were no observed differences in LV structure, the LV ejection fraction, E/A ratio, and septal e′ velocity. Patients with lower T 3 had higher E/e′ ratios (i.e., higher LV filling pressures) and longer isovolumic relaxation times (i.e., lusitropic impairment), though these findings were not statistically significant (p = 0.14 and p = 0.24, respectively).
| Characteristic | All Patients (n = 89) | T 3 (ng/dl) | p Value | |
|---|---|---|---|---|
| ≥108 (n = 46) | <108 (n = 43) | |||
| T 3 (ng/dl) | 111 ± 31 | 134 ± 24 | 86 ± 14 | |
| Age (years) | 67 ± 14 | 63 ± 14 | 70 ± 13 | 0.012 |
| Women | 61 (69%) | 32 (70%) | 29 (67%) | 0.83 |
| Ethnicity | 0.74 | |||
| White | 44 (49%) | 23 (50%) | 21 (49%) | |
| African American | 37 (42%) | 20 (44%) | 17 (40%) | |
| Other | 8 (9%) | 3 (7%) | 5 (12%) | |
| New York Heart Association functional class | 0.014 | |||
| I or II | 43 (48%) | 28 (61%) | 15 (35%) | |
| III or IV | 46 (52%) | 18 (39%) | 28 (65%) | |
| Coronary artery disease | 31 (35%) | 15 (33%) | 16 (37%) | 0.65 |
| Hypertension ⁎ | 73 (82%) | 36 (78%) | 37 (86%) | 0.34 |
| Hyperlipidemia † | 49 (55%) | 20 (44%) | 29 (67%) | 0.023 |
| Diabetes mellitus | 28 (32%) | 9 (20%) | 19 (44%) | 0.012 |
| Chronic kidney disease | 35 (39%) | 14 (30%) | 21 (49%) | 0.08 |
| Current smoker | 35 (39%) | 18 (39%) | 17 (40%) | 0.97 |
| Atrial fibrillation | 23 (26%) | 10 (22%) | 13 (30%) | 0.36 |
| Obesity | 53 (60%) | 28 (61%) | 25 (58%) | 0.79 |
| Chronic obstructive pulmonary disease or asthma | 21 (24%) | 10 (22%) | 11 (26%) | 0.67 |
| Heart rate (beats/min) | 74 ± 15 | 75 ± 16 | 73 ± 14 | 0.55 |
| Systolic blood pressure (mm Hg) | 128 ± 21 | 129 ± 20 | 128 ± 23 | 0.85 |
| Diastolic blood pressure (mm Hg) | 72 ± 13 | 74 ± 12 | 69 ± 13 | 0.043 |
| Pulse pressure (mm Hg) | 57 ± 17 | 55 ± 15 | 59 ± 19 | 0.20 |
| Body mass index (kg/m 2 ) | 33.0 ± 8.3 | 34.0 ± 9.0 | 32.0 ± 7.5 | 0.27 |
| Serum sodium (mEq/L) | 138 ± 3 | 138 ± 3 | 139 ± 3 | 0.48 |
| Blood urea nitrogen (mg/dl) | 25 ± 17 | 22 ± 18 | 27 ± 16 | 0.19 |
| Serum creatinine (mg/dl) | 1.56 ± 1.34 | 1.51 ± 1.45 | 1.63 ± 1.22 | 0.68 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 57 ± 26 | 61 ± 27 | 52 ± 25 | 0.10 |
| Serum glucose (mg/dl) | 119 ± 53 | 117 ± 61 | 121 ± 44 | 0.71 |
| Hemoglobin (g/dl) | 12.0 ± 1.8 | 12.3 ± 1.9 | 11.6 ± 1.6 | 0.07 |
| BNP (pg/ml) | 214 (66–603) | 133 (46–318) | 326 (115–874) | 0.009 |
| TSH (μIU/ml) | 1.7 (0.9–2.6) | 1.6 (0.9–2.6) | 1.9 (1.0–2.9) | 0.48 |
| Free T4 (ng/dl) | 0.97 ± 0.27 | 0.93 ± 0.23 | 1.02 ± 0.30 | 0.11 |
| Medications | ||||
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 56 (63%) | 30 (65%) | 26 (61%) | 0.64 |
| β blockers | 60 (67%) | 27 (59%) | 33 (76%) | 0.07 |
| Calcium channel blockers | 30 (34%) | 17 (37%) | 13 (30%) | 0.50 |
| Loop diuretics | 54 (61%) | 25 (54%) | 29 (67%) | 0.21 |
| Thiazide diuretics | 21 (24%) | 11 (24%) | 10 (23%) | 0.94 |
| Statins | 43 (48%) | 19 (41%) | 24 (56%) | 0.17 |
| Aspirin | 31 (35%) | 18 (39%) | 13 (30%) | 0.38 |
| Warfarin | 18 (20%) | 7 (15%) | 11 (26%) | 0.22 |
| Amiodarone | 5 (6%) | 2 (4%) | 3 (7%) | 0.59 |
⁎ Blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, physician-documented history of hypertension, or current use of antihypertensive medications.
† Physician-documented history of hyperlipidemia or current use of lipid-lowering medications.
| Characteristic | All Patients (n = 89) | T 3 (ng/dl) | p Value | |
|---|---|---|---|---|
| ≥108 (n = 46) | <108 (n = 43) | |||
| LV end-systolic volume index (ml/m 2 ) | 15 ± 6 | 16 ± 7 | 15 ± 5 | 0.46 |
| LV end-diastolic volume index (ml/m 2 ) | 40 ± 11 | 41 ± 13 | 39 ± 9 | 0.44 |
| LV ejection fraction (%) | 62 ± 7 | 62 ± 7 | 62 ± 7 | 0.85 |
| LV mass index (g/m 2 ) | 105 ± 37 | 104 ± 45 | 106 ± 26 | 0.77 |
| Stroke volume (ml) | 93 ± 63 | 91 ± 27 | 96 ± 87 | 0.70 |
| Cardiac index (L/min/m 2 ) | 3.4 ± 2.3 | 3.3 ± 1.1 | 3.5 ± 3.2 | 0.65 |
| Pulse pressure/stroke volume ratio (mm Hg/ml) | 0.69 ± 0.25 | 0.64 ± 0.22 | 0.75 ± 0.28 | 0.03 |
| LV diastolic function | ||||
| Normal | 8 (9%) | 5 (11%) | 3 (7%) | 0.71 |
| Grade 1 (impaired relaxation) | 8 (9%) | 5 (11%) | 3 (7%) | 0.71 |
| Grade 2 (pseudonormal) | 41 (46%) | 24 (52%) | 17 (40%) | 0.19 |
| Grade 3 (restrictive) | 29 (33%) | 10 (22%) | 19 (44%) | 0.027 |
| Indeterminate | 3 (3%) | 2 (4%) | 1 (2%) | 0.99 |
| Left atrial volume index (ml/m 2 ) | 33 ± 13 | 31 ± 11 | 35 ± 15 | 0.23 |
| Early mitral inflow, E velocity (cm/s) | 101 ± 33 | 93 ± 27 | 110 ± 36 | 0.012 |
| Late mitral inflow, A velocity (cm/s) | 86 ± 31 | 86 ± 30 | 86 ± 33 | 0.98 |
| E/A ratio | 1.4 ± 0.8 | 1.2 ± 0.6 | 1.5 ± 1.0 | 0.14 |
| E deceleration time (ms) | 219 ± 48 | 231 ± 47 | 206 ± 47 | 0.016 |
| Isovolumic relaxation time (ms) | 88 ± 24 | 85 ± 21 | 91 ± 27 | 0.24 |
| Septal e′ velocity (cm/s) | 6.6 ± 2.0 | 6.5 ± 2.1 | 6.8 ± 2.1 | 0.59 |
| E/e′ ratio | 16.8 ± 8.6 | 15.5 ± 6.2 | 18.2 ± 10.4 | 0.14 |
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