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We aimed to investigate the impact of testosterone on the prognosis of heart failure (HF), as well as the underlying cardiac function, cardiac damage, and exercise capacity. We analyzed consecutive 618 men with HF (age 65.9 years). These patients were divided into quartiles based on their serum levels of total testosterone (TT): first (TT > 631 ng/dl, n = 154), second (462 < TT ≤ 631 ng/dl, n = 155), third (300 < TT ≤ 462 ng/dl, n = 156), and fourth (TT ≤ 300 ng/dl, n = 153) quartiles. In the Kaplan–Meier analysis (mean 1,281 days), all-cause mortality progressively increased throughout from the first to the fourth groups. In the multivariable Cox proportional hazard analysis, TT was found to be an independent predictor of all-cause mortality (hazard ratio 0.929, p = 0.042). In addition, we compared the parameters of echocardiography and cardiopulmonary exercise testing, as well as levels of B-type natriuretic peptide and cardiac troponin I, among the 4 groups. Left ventricular ejection fraction and B-type natriuretic peptide did not differ among the groups. In contrast, the fourth quartile, compared with the first, second, and third groups, had higher levels of troponin I and lower peak VO2 (p <0.05, respectively). Decreased serum testosterone is associated with myocardial damage, lower exercise capacity, and higher mortality in men with HF.
Testosterone affects multiple cardiovascular systems, including cardiomyocytes (protein synthesis, hypertrophy), cardiac electrophysiology (ion channel, arrhythmias), cardiac contractility (adrenoreceptor regulation, heavy myosin chain modification), and vascular function.
Thus, we aimed to clarify associations between testosterone levels and prognosis in men with HF while taking into consideration the underlying comprehensive clinical parameters (e.g., cardiac function, cardiac damage, arterial stiffness, and exercise capacity).
Methods
This was a prospective observational study of 702 decompensated men with HF who were discharged from the Fukushima Medical University Hospital between 2009 and 2015. The diagnosis of decompensated HF was made by several cardiologists based on the HF guidelines.
American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Patients who were prescribed androgenic steroids, glucocorticoid, thyroid hormone, and/or antithyroid drugs during follow-up were excluded. The patient flowchart is shown in Figure 1. Of the total of 702 patients, 618 were finally enrolled. The average total testosterone (TT) level of the study population was 479.2 ± 267.7 (range 6 to 2538 ng/dl), and the patients were divided into quartiles based on their TT levels: first (632 ng/dl ≤ TT, n = 154), second (463 ≤ TT ≤ 631, n = 155), third (462 ≤ TT ≤ 301, n = 156), and fourth quartiles (TT ≤ 300, n = 153). The TT of ≤ 300 ng/dl is generally considered as low TT levels.
We compared the clinical features and parameters of laboratory data, echocardiography, pulse wave velocity (PWV), and cardiopulmonary exercise testing. These assessments were performed within one week of hospital discharge.
The patients were followed up until 2017 for all-cause death. The status and/or dates of death of all patients were obtained from the patients' medical records or the attending physicians at the patient's referring hospital. We were able to follow up all patients. Survival time was calculated from the date of hospitalization until the date of death or last follow-up. Written informed consent was obtained from all study subjects at discharge. The study protocol was approved by the Ethics Committee of Fukushima Medical University and was carried out in accordance with the principles outlined in the Declaration of Helsinki. The reporting of the study conforms to the Strengthening the Reporting of Observational Studies in Epide along with references to Strengthening the Reporting of Observational Studies in Epide and the broader EQUATOR guidelines.
Blood samples were obtained at hospital discharge each morning, with the patients in a fasted state. Serum TT was measured by electrochemiluminescence immunoassay (ARCHITECT 2nd Generation Testosterone, Abbott Japan, Tokyo, Japan) using an analyzer (Architect i2000 analyzer; Abbott Diagnostics, Abbott Park, Illinois). High-sensitivity cardiac troponin I levels were measured in EDTA anticoagulated plasma using the refined assay (Abbott-Architect, Abbott Laboratories, Abbott Park, Illinois). These immunoassays were blindly performed by clinical laboratory technologists at Abott Japan Co. Ltd. B-type natriuretic peptide (BNP) levels were measured using a specific immunoradiometric assay (Shionoria BNP kit, Shionogi, Osaka, Japan).
Echocardiography was performed blindly by experienced echocardiographers using ultrasound systems (ACUSON Sequoia, Siemens Medical Solutions USA, Inc., Mountain View, California) with standard techniques.
American Society of Echocardiography's Nomenclature and Standards Committee, Task Force on Chamber Quantification, American College of Cardiology Echocardiography Committee, American Heart Association, European Association of Echocardiography, European Society of Cardiology Recommendations for chamber quantification.
American Society of Echocardiography's Nomenclature and Standards Committee, Task Force on Chamber Quantification, American College of Cardiology Echocardiography Committee, American Heart Association, European Association of Echocardiography, European Society of Cardiology Recommendations for chamber quantification.
An LVEF of less than 40% was considered as reduced LVEF, an LVEF of 40% to 49% was considered as midrange LVEF, and an LVEF of more than 50% was considered as preserved LVEF.
Authors/Task Force M 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
PWV was estimated using a Mobil-O-Graph PWA Monitor (I.E.M. GmbH, Stolberg, Germany), which is the automated self-measurement blood pressure monitoring device to estimate brachial and ankle PWV.
This device uses a transfer function-like method (ARCSolver algorithm) with brachial cuff-based waveform recordings.
The patients underwent incremental symptom-limited exercise testing before discharge using an upright cycle ergometer with a ramp protocol (Strength Ergo 8, Fukuda Denshi Co. Ltd., Tokyo, Japan). Breath-by-breath oxygen consumption (VO2), carbon dioxide production (VCO2), and minute ventilation (VE) were measured during exercise using an AE-300S respiratory monitor (Minato Medical Science, Osaka, Japan).
Peak VO2 was measured as an average of the last 30 seconds of exercise. Ventilatory response to exercise (slope of the relationship between ventilation and carbon dioxide production, VE/VCO2 slope) was calculated as the regression slope relating VE to CO2 from the start of exercise until the respiratory compensation point.
Parametric variables are presented as mean ± SD, nonparametric variables (e.g., ferritin, vitamin B12, erythropoietin, C-reactive protein, BNP, and troponin I) are presented as median and interquartile range, and categorical variables are expressed as numbers and percentages. The chi-square test was used for comparisons of categorical variables. We used the analysis of variance for continuous variables, followed by Tukey's post hoc test. We performed multiple regression analysis, allowing for interaction between serum TT level and clinical confounding factors: age, body mass index, New York Heart Association (NYHA) functional class, presence of ischemic etiology, hypertension, diabetes, dyslipidemia, chronic kidney disease (CKD), anemia, and atrial fibrillation. Correlations between serum TT levels and other parameters (e.g., laboratory data, echocardiography, PWV, and cardiopulmonary exercise test) were assessed using Spearman's correlation analysis. The Kaplan–Meier analysis was used for presenting the all-cause mortality, and the log-rank test was used for initial comparisons. The prognostic value was tested by univariate and multivariate Cox proportional hazard analyses. In the multivariate Cox proportional hazard analysis, to prepare for potential confounding, we considered the following clinical factors, which are generally known to affect the prognosis in HF patients: age, body mass index, presence of NYHA functional class III or IV, LVEF, ischemic etiology, hypertension, diabetes, dyslipidemia, CKD, anemia, atrial fibrillation, and TT levels. Univariate parameters with p values of <0.10 were included in the multivariate analysis. In addition, to assess the potential heterogeneity of associations between TT levels and all-cause mortality, we conducted subgroup analyses. Interactions between TT levels and clinically relevant variables that were known to be important prognostic factors in HF patients and/or were different clinical characteristics between the groups (age, body mass index, NYHA functional class, LVEF, ischemic etiology, hypertension, diabetes, dyslipidemia, CKD, anemia, atrial fibrillation, levels of total protein, albumin, C-reactive protein, BNP, and troponin I) were estimated by a Cox proportional hazard model. A p value of <0.05 was considered statistically significant for all comparisons. All analyses were performed using a statistical software package (SPSS version 24.0, IBM, Armonk, New York).
Results
The comparisons of the clinical features are shown in Table 1. Regarding factors that affect serum TT levels, multiple regression analysis (Table 2) showed that age and the presence of dyslipidemia and/or anemia are independent predictors of serum TT levels. In the laboratory data (Table 3), hemoglobin, iron, total protein, and albumin were lowest, and ferritin, C-reactive protein, and troponin I were highest in the fourth quartile. The PWV was highest, and the peak VO2 was lowest, in the fourth quartile (Table 3). Additionally, correlation analyses with the TT levels and other parameters are presented in Table 4. Although there was no significant correlation between serum TT levels and echocardiographic parameters, there were many significant correlations between TT levels and hemoglobin, iron, ferritin, unsaturated iron-binding capacity, total protein, albumin, log C-reactive protein, log troponin I, PWV, and peak VO2.
Table 1Comparisons of clinical features among testosterone quartiles (n = 618)
Variable
1st n = 154
2nd n = 155
3rd n = 156
4th n = 153
p-value
Testosterone (ng/dl)
827.2 ± 20.0 (632–2538 ng/dl)
546.6 ± 48.2 (463–631 ng/dl)
376.6 ± 47.6 (301–462 ng/dl)
165.1 ± 91.4 (6–300 ng/dl)
<0.001
Age (years)
63.8 ± 14.6
65.4 ± 12.9
68.1 ± 13.2
66.2 ± 15.4
0.059
Body mass index (kg/m2)
23.2 ± 3.6
24.0 ± 4.1
24.1 ± 4.0
23.5 ± 4.4
0.614
NYHA class III or IV
4 (2.6%)
4 (2.6%)
0 (0%)
7 (4.6%)
0.075
Left ventricular ejection fraction reduced/ mid-range/ preserved
86(55.8%)/18(11.7%)/50(32.5%)
75(48.4%)/23(14.8%)/57(36.8%)
69(44.2%)/10(6.4%)/77(49.4%)
76(49.7%)/16(10.5%)/61(39.9%)
0.037
Ischemic etiology
41 (26.6)
50 (32.3)
47 (30.1)
61 (39.9)
0.085
Hypertension
118 (76.6%)
122 (78.7%)
137 (87.8%)
120 (78.4%)
0.057
Diabetes mellitus
58 (37.7%)
78 (50.3%)
63 (40.4%)
84 (54.9%)
0.006
Dyslipidemia
118 (76.6%)
120 (77.4%)
124 (79.5%)
134 (87.6%)
0.063
Chronic kidney disease
91 (59.1%)
95 (61.3%)
104 (66.7%)
101 (66.0%)
0.442
Anemia
67 (43.5%)
74 (47.7%)
86 (55.1%)
94 (61.4%)
0.009
Atrial fibrillation
71 (46.1%)
71 (45.8%)
66 (42.3%)
57 (37.3%)
0.363
Medications
Renin-angiotensin aldosterone system inhibitors
135 (87.7%)
130 (83.9%)
133 (85.3%)
114 (74.5%)
0.013
Aldosterone antagonists
79 (51.3%)
58 (37.4%)
69 (44.2%)
77 (50.3%)
0.053
β-blockers
137 (89.0%)
138 (89.0%)
129 (82.7%)
123 (80.4%)
0.067
Diuretics
107 (30.5%)
98 (63.2%)
104 (66.7%)
114 (74.5%)
0.182
Inotropic agents
27 (17.5%)
17 (11.0%)
26 (16.7%)
23 (15.0%)
0.379
Hypertension was defined as the recent use of antihypertensive drugs, a systolic blood pressure of ≥140 mm Hg, and/or a diastolic blood pressure of ≥90 mm Hg. Diabetes mellitus was defined as the recent use of antidiabetic dugs, a fasting glucose value of ≥126 mg/dl, a casual glucose value of ≥200 mg/dl, and/or a HbA1c percentage of ≥6.5% (National Glycohemoglobin Standardization Program). Dyslipidemia was defined as the recent use of cholesterol-lowering drugs, a triglyceride value of ≥150 mg/dL, a low-density lipoprotein cholesterol value of ≥140 mg/dL, and/or a high-density lipoprotein cholesterol value of <40 mg/dL. Chronic kidney disease was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 cm2 according to the Modification of Diet in Renal Disease formula. Anemia was defined as hemoglobin levels of <13.0 g/dL. Atrial fibrillation was identified by an electrocardiogram performed during hospitalization and/or from medical records.
In the follow-up period (mean 1,281 days), there were 180 deaths (94 cardiac deaths and 86 noncardiac deaths). In the Kaplan–Meier analysis (Figure 2), all-cause mortality progressively increased from the first to the fourth quartiles (log-rank, p = 0.010). In the Cox proportional hazard analysis (Table 5), after adjusting for other confounding factors, TT level was an independent predictor of all-cause mortality in HF patients. To assess the potential heterogeneity of TT's impact on all-cause mortality, we also conducted subgroup analyses and examined interaction terms (Table 6). There were no interactions between TT levels and other important variables, including age, NYHA class, LVEF, co-morbidities, and other laboratory markers including total protein, albumin, C-reactive protein, BNP, and troponin I. Thus, the impact of TT levels was consistent in all subgroups.
Figure 2Kaplan–Meier analysis for all-cause mortality stratified by serum testosterone.
The present study is the first to report that men with HF with decreased TT levels (especially TT ≤300 ng/dl) experience a higher mortality accompanied by anemia, inflammation, myocardial damage, increased arterial stiffness, and impaired exercise capacity without association with impaired cardiac function.
Testosterone strongly stimulates erythropoiesis through mechanisms such as intestinal iron absorption, erythrocyte iron incorporation, hemoglobin synthesis, and bone marrow hematopoietic stem cells through the induction of insulin growth factor-I via androgen receptor–mediated mechanisms.
A recent study presented that testosterone supplementation significantly increased the hemoglobin levels in older men with low testosterone levels with any cause of anemia.
By modulating the activity of several ion channels and endothelial nitric oxide synthase, testosterone influences the tonus of vascular smooth muscle cells and leads to the vasodilation of systemic,
Low testosterone level is associated with increased levels of cholesterol, the production of inflammatory factors (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α),
Testosterone inhibits cardiac fibroblast migration and proliferation in addition to myofibroblast differentiation induced by transforming growth factor-β1.
Myocardial damage is reduced by the testosterone by upregulating cardiac α1 adrenoceptor and possibly by activating cardiac mitochondrial ATP-sensitive potassium channels.
Skeletal muscle strength is also influenced by the testosterone by stimulating change in muscle composition toward type I muscle fibers that are, compared with type II fibers, associated with enhanced physical capability, strength, and reduced exercise capacity and cachexia.
Although a previous report suggested that only dehydroepiandrosterone is correlated to peak VO2, and testosterone and insulin-like growth factor-1 were not significantly correlated,
A meta-analysis of testosterone supplementation in moderate to severe HF patients revealed that testosterone supplementation improves exercise capacity without any improvement in myocardial structure or function.
Thus, lower testosterone is associated with anemia, inflammation, myocardial damage, increased arterial stiffness, and impaired exercise capacity and represents chronic illness, and these mechanisms partly related to poor prognosis in men with HF in the present study.
The present study has several limitations. First, as a prospective cohort study of a single center with a relatively small number of patients, the present results may not be representative of a general population. Although we performed both multivariate Cox proportional hazard analysis and subgroup analysis under consideration with several confounding factors, we cannot rule out residual confounding variables, and the effects of differences in the backgrounds among the groups might not be completely adjusted. Second, because the present study included variables during hospitalization for decompensated HF without taking into consideration changes in medical parameters and postdischarge treatment, we should pay attention to extrapolating our findings to all men with HF. Third, although we encouraged cardiopulmonary exercise testing and PWV as much as possible, we were not able to perform these measurements in all patients for various reasons (e.g., patient refusal, medical reasons). Thus, there may be potential selection bias in these measurements. Fourth, because this was a cross-sectional and prospective observational study without intervention for decreased testosterone, the causal relationships and mechanisms of decreased testosterone on hypoalbuminemia, anemia, inflammation, myocardial damage, increased arterial stiffness, impaired exercise capacity, and worse prognosis could not be fully explained. Sixth, we did not examine other anabolic hormones (dehydroepiandrosterone sulfate and insulin-like growth factor-1excluded) in this study. Therefore, the present results should be viewed as preliminary, and further studies with a larger population are needed.
In conclusion, decreased testosterone is associated with adverse prognosis, accompanied by hypoalbuminemia, anemia, inflammation, myocardial damage, increased arterial stiffness, and impaired exercise capacity, in men with HF.
Disclosures
Serum TT and high-sensitivity cardiac troponin I were measured at Abott Japan Co. Ltd. The authors have no conflicts of interest to disclose.
Acknowledgment
The authors acknowledge the efforts of Kumiko Watanabe, Hitomi Kobayashi, and Tomiko Miura for their outstanding technical assistance.
References
Busic Z.
Culic V.
Central and peripheral testosterone effects in men with heart failure: an approach for cardiovascular research.
American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
American Society of Echocardiography's Nomenclature and Standards Committee, Task Force on Chamber Quantification, American College of Cardiology Echocardiography Committee, American Heart Association, European Association of Echocardiography, European Society of Cardiology
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
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