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Relation of Testosterone Levels to Mortality in Men With Heart Failure

Open AccessPublished:March 01, 2018DOI:https://doi.org/10.1016/j.amjcard.2018.01.052
      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.
      • Busic Z.
      • Culic V.
      Central and peripheral testosterone effects in men with heart failure: an approach for cardiovascular research.
      It has been reported that deficiency of the anabolic hormone is associated with poor prognosis in men with heart failure (HF).
      • Jankowska E.A.
      • Biel B.
      • Majda J.
      • Szklarska A.
      • Lopuszanska M.
      • Medras M.
      • Anker S.D.
      • Banasiak W.
      • Poole-Wilson P.A.
      • Ponikowski P.
      Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival.
      In contrast, low testosterone levels are associated with low mortality from ischemic heart disease.
      • Araujo A.B.
      • Kupelian V.
      • Page S.T.
      • Handelsman D.J.
      • Bremner W.J.
      • McKinlay J.B.
      Sex steroids and all-cause and cause-specific mortality in men.
      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.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • Butler J.
      • Casey Jr, D.E.
      • Drazner M.H.
      • Fonarow G.C.
      • Geraci S.A.
      • Horwich T.
      • Januzzi J.L.
      • Johnson M.R.
      • Kasper E.K.
      • Levy W.C.
      • Masoudi F.A.
      • McBride P.E.
      • McMurray J.J.
      • Mitchell J.E.
      • Peterson P.N.
      • Riegel B.
      • Sam F.
      • Stevenson L.W.
      • Tang W.H.
      • Tsai E.J.
      • Wilkoff B.L.
      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.
      • Kloner R.A.
      • Carson 3rd, C.
      • Dobs A.
      • Kopecky S.
      • Mohler 3rd., E.R.
      Testosterone and cardiovascular disease.
      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.
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      • Initiative S.
      Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      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.
      • Lang R.M.
      • Bierig M.
      • Devereux R.B.
      • Flachskampf F.A.
      • Foster E.
      • Pellikka P.A.
      • Picard M.H.
      • Roman M.J.
      • Seward J.
      • Shanewise J.
      • Solomon S.
      • Spencer K.T.
      • St John Sutton M.
      • Stewart W.
      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.
      Left ventricular ejection fraction (LVEF) was calculated using Simpson's method in a 4-chamber view.
      • Lang R.M.
      • Bierig M.
      • Devereux R.B.
      • Flachskampf F.A.
      • Foster E.
      • Pellikka P.A.
      • Picard M.H.
      • Roman M.J.
      • Seward J.
      • Shanewise J.
      • Solomon S.
      • Spencer K.T.
      • St John Sutton M.
      • Stewart W.
      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.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • Bueno H.
      • Cleland J.G.
      • Coats A.J.
      • Falk V.
      • Gonzalez-Juanatey J.R.
      • Harjola V.P.
      • Jankowska E.A.
      • Jessup M.
      • Linde C.
      • Nihoyannopoulos P.
      • Parissis J.T.
      • Pieske B.
      • Riley J.P.
      • Rosano G.M.
      • Ruilope L.M.
      • Ruschitzka F.
      • Rutten F.H.
      • van der Meer P.
      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.
      • Wei W.
      • Tolle M.
      • Zidek W.
      • van der Giet M.
      Validation of the mobil-O-Graph: 24 h-blood pressure measurement device.
      • Wassertheurer S.
      • Kropf J.
      • Weber T.
      • van der Giet M.
      • Baulmann J.
      • Ammer M.
      • Hametner B.
      • Mayer C.C.
      • Eber B.
      • Magometschnigg D.
      A new oscillometric method for pulse wave analysis: comparison with a common tonometric method.
      • Weber T.
      • Wassertheurer S.
      • Rammer M.
      • Maurer E.
      • Hametner B.
      • Mayer C.C.
      • Kropf J.
      • Eber B.
      Validation of a brachial cuff-based method for estimating central systolic blood pressure.
      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).
      • Kanno Y.
      • Yoshihisa A.
      • Watanabe S.
      • Takiguchi M.
      • Yokokawa T.
      • Sato A.
      • Miura S.
      • Shimizu T.
      • Nakamura Y.
      • Abe S.
      • Sato T.
      • Suzuki S.
      • Oikawa M.
      • Saitoh S.
      • Takeishi Y.
      Prognostic significance of insomnia in heart failure.
      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.
      • Kanno Y.
      • Yoshihisa A.
      • Watanabe S.
      • Takiguchi M.
      • Yokokawa T.
      • Sato A.
      • Miura S.
      • Shimizu T.
      • Nakamura Y.
      • Abe S.
      • Sato T.
      • Suzuki S.
      • Oikawa M.
      • Saitoh S.
      • Takeishi Y.
      Prognostic significance of insomnia in heart failure.
      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)
      Variable1st n = 1542nd n = 1553rd n = 1564th n = 153p-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 ± 14.665.4 ± 12.968.1 ± 13.266.2 ± 15.40.059
      Body mass index (kg/m2)23.2 ± 3.624.0 ± 4.124.1 ± 4.023.5 ± 4.40.614
      NYHA class III or IV4 (2.6%)4 (2.6%)0 (0%)7 (4.6%)0.075
      Left ventricular ejection fraction reduced/ mid-range/ preserved86(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 etiology41 (26.6)50 (32.3)47 (30.1)61 (39.9)0.085
      Hypertension118 (76.6%)122 (78.7%)137 (87.8%)120 (78.4%)0.057
      Diabetes mellitus58 (37.7%)78 (50.3%)63 (40.4%)84 (54.9%)0.006
      Dyslipidemia118 (76.6%)120 (77.4%)124 (79.5%)134 (87.6%)0.063
      Chronic kidney disease91 (59.1%)95 (61.3%)104 (66.7%)101 (66.0%)0.442
      Anemia67 (43.5%)74 (47.7%)86 (55.1%)94 (61.4%)0.009
      Atrial fibrillation71 (46.1%)71 (45.8%)66 (42.3%)57 (37.3%)0.363
      Medications
      Renin-angiotensin aldosterone system inhibitors135 (87.7%)130 (83.9%)133 (85.3%)114 (74.5%)0.013
      Aldosterone antagonists79 (51.3%)58 (37.4%)69 (44.2%)77 (50.3%)0.053
      β-blockers137 (89.0%)138 (89.0%)129 (82.7%)123 (80.4%)0.067
      Diuretics107 (30.5%)98 (63.2%)104 (66.7%)114 (74.5%)0.182
      Inotropic agents27 (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.
      Table 2Multiple regression analysis to determine serum testosterone levels
      FactorsUnivariateMultivariate
      β coefficientp-valueβ coefficientp-value
      Age−0.152<0.001−0.1210.003
      Body mass index−0.0350.391
      NYHA functional class−0.0900.025−0.0260.522
      Ischemic etiology−0.0900.025−0.0350.399
      Hypertension−0.0310.439
      Diabetes−0.1050.009
      Dyslipidemia−0.1020.011−0.0980.017
      Chronic kidney disease−0.0760.059
      Anemia−0.147<0.001−0.1090.009
      Atrial fibrillation0.0400.320
      Table 3Comparisons of laboratory data, echocardiography, cardiopulmonary exercise testing and pulse wave velocity among quartile (n = 618)
      1st2nd3rd4thp-value
      Laboratory data
      Testosterone (ng/dl)827.2 ± 20.0546.6 ± 48.2376.6 ± 47.6165.1 ± 91.4<0.001
      Hemoglobin (g/dl)13.6 ± 2.013.5 ± 2.012.8 ± 2.3
      p < 0.05 and †p < 0.01 vs. 1st quartile; ‡p < 0.05 and §p < 0.01 vs. 2nd quartile; ¶p < 0.05 and ‖p < 0.01 vs. 3rd quartile.
      12.4 ± 2.7 ,§<0.001
      Iron (µg/dl)91.3 ± 32.889.9 ± 40.179.5 ± 39.676.8 ± 45.50.030
      Ferritin (ng/ml)
      Data are presented as median (interquartile range).
      104.0 (53.3–220.3)124.0 (59.0–268.0)150.0
      p < 0.05 and †p < 0.01 vs. 1st quartile; ‡p < 0.05 and §p < 0.01 vs. 2nd quartile; ¶p < 0.05 and ‖p < 0.01 vs. 3rd quartile.
      (62.5–245.0)
      165.0 , (84.5–297.8)0.003
      Unsaturated iron binding capacity (µg/dl)222.7 ± 69.7224.4 ± 63.9215.3 ± 62.3205.6 ± 75.00.250
      Vitamin B12 (pg/ml)
      Data are presented as median (interquartile range).
      405.0 (271.0–562.0)408.0 (286.0–599.5)429.0 (348.0–558.0)516.0 (321.3–742.8)0.615
      Folic acid (ng/ml)6.1 ± 2.77.6 ± 3.56.7 ± 4.47.1 ± 3.60.115
      Erythropoietin (mIU/ml)
      Data are presented as median (interquartile range).
      22.7 (13.1–39.8)15.4 (9.7–26.1)20.5 (11.8–33.3)17.8 (12.5–46.6)0.460
      Glomerular filtration rate (ml/min./1.73 cm2)56.1 ± 24.157.9 ± 22.052.9 ± 23.354.1 ± 25.90.287
      Sodium (mmol/l)139.0 ± 3.1138.7 ± 3.1139.1 ± 3.6138.3 ± 4.80.273
      Total protein (g/dl)7.1 ± 0.77.2 ± 0.77.0 ± 0.76.7 ± 0.8 ,§,<0.001
      Albumin (g/dl)3.9 ± 0.53.9 ± 0.53.7 ± 0.53.4 ± 0.6 ,§,<0.001
      C-reactive protein (mg/dl)
      Data are presented as median (interquartile range).
      0.16 (0.07–0.52)0.12 (0.06–0.74)0.23 (0.08–0.76)0.56 (0.14–1.84) ,§,<0.001
      B-type natriuretic peptide (pg/ml)
      Data are presented as median (interquartile range).
      98.5 (44.3–179.0)75.2 (41.2–164.3)114.8 (40.4–241.6)103.3 (47.1–232.9)0.342
      Troponin I (pg/ml)
      Data are presented as median (interquartile range).
      21.4 (10.4–49.8)21.7 (10.2–97.3)33.4 (12.2–92.5)57.4 (22.3–258.9) ,§,0.018
      Echocardiography
      Left ventricular ejection fraction (%)43.7 ± 16.047.2 ± 14.647.7 ± 14.945.9 ± 16.10.145
      Right ventricular fractional area change (%)41.3 ± 15.940.8 ± 14.540.8 ± 15.741.6 ± 14.00.986
      Tricuspid valve regurgitation pressure gradient (mm Hg)28.7 ± 13.426.7 ± 15.828.6 ± 12.728.8 ± 13.50.676
      Cardio-pulmonary exercise testing (n = 299)
      Peak VO2 (ml/kg/min)16.4 ± 5.116.5 ± 4.515.8 ± 4.714.5 ± 4.9
      p < 0.05 and †p < 0.01 vs. 1st quartile; ‡p < 0.05 and §p < 0.01 vs. 2nd quartile; ¶p < 0.05 and ‖p < 0.01 vs. 3rd quartile.
      0.034
      VE-VCO2 slope34.3 ± 7.034.0 ± 7.734.8 ± 8.235.9 ± 10.20.593
      Pulse wave velocity (n = 156)7.9 ± 2.78.6 ± 2.09.5 ± 1.89.9 ± 2.1,§,<0.001
      * p < 0.05 and p < 0.01 vs. 1st quartile; p < 0.05 and §p < 0.01 vs. 2nd quartile; p < 0.05 and p < 0.01 vs. 3rd quartile.
      # Data are presented as median (interquartile range).
      Table 4Correlation analyses with serum testosterone levels and other parameters
      Rp value
      Laboratory data
       Hemoglobin0.229<0.001
       Iron0.1390.008
       Ferritin−0.1740.002
       Unsaturated iron binding capacity0.1430.007
       Vitamin B12−0.0090.879
       Folic acid−0.0660.270
       Erythropoietin−0.0650.277
       Glomerular filtration rate0.0600.154
       Sodium0.0500.237
       Total protein0.209<0.001
       Albumin0.315<0.001
       Log C-reactive protein−0.238<0.001
       Log B-type natriuretic peptide−0.0190.649
       Log troponin I−0.241<0.001
      Echocardiography
       Left ventricular ejection fraction−0.1020.128
       Right ventricular fractional area change0.0030.962
       Tricuspid valve regurgitation pressure gradient−0.0020.966
      Cardiopulmonary exercise test
       Peak VO20.1530.041
       VE/VCO2 slope−0.0860.136
      Pulse wave velocity−0.2280.004
      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 2
      Figure 2Kaplan–Meier analysis for all-cause mortality stratified by serum testosterone.
      Table 5Cox proportional hazard model for All-cause mortality (event 180, n = 618)
      Univariate analysisMultivariate analysis
      HR95% CIp valueHR95% CIp value
      Age1.0491.034–1.063<0.0011.0401.024–1.057<0.001
      Body mass index0.8840.849–0.921<0.0010.9250.879–0.9730.003
      NYHA class III or IV3.3161.751–6.279<0.0012.1951.046–4.6090.038
      Left ventricular ejection fraction0.9970.986–1.0080.581
      Ischemic etiology1.2630.934–1.7090.130
      Hypertension0.9590.650–1.4140.832
      Diabetes1.1360.848–1.5220.393
      Dyslipidemia1.2010.811–1.7770.361
      Chronic kidney disease1.8311.306–2.566<0.0011.3930.934–2.0760.104
      Anemia2.2881.666–3.143<0.0011.3590.924–1.9970.119
      Atrial fibrillation1.3030.973–1.7460.0760.9880.700–1.3940.943
      Testosterone0.8890.836–0.944<0.0010.9290.865–0.9970.042
      Table 6Subgroup analysis for all-cause mortality: impact of testosterone levels (per 1 ng/dl increase)
      FactorSubgroupnHR95% CIp valueInteraction p value
      TotalTotal6180.8890.836–0.944<0.001-
      Age≥703030.9020.835–0.9750.0090.941
      <703150.9120.826–1.0080.071
      Body mass index≥23.23090.9170.855–0.9830.0140.165
      <23.23090.8370.749–0.9360.002
      NYHA class III or IVIII or IV150.8680.708–1.0640.1740.594
      I or II6030.9000.845–0.9590.001
      Left ventricular ejection fractionReduced3060.8660.799–0.939<0.0010.225
      Mid-range670.8670.732–1.0270.099
      Preserved2450.9430.847–1.0490.280
      Ischemic etiologyPresent1990.8390.752–0.9360.0560.213
      Absent4190.9140.850–0.9820.015
      HypertensionPresent4970.8840.826–0.947<0.0010.785
      Absent1210.9050.793–1.0320.135
      DiabetesPresent2830.8980.822–0.9800.0160.679
      Absent3350.8790.807–0.9580.003
      DyslipidemiaPresent4960.8680.812–0.929<0.0010.079
      Absent1220.9940.870–1.1360.933
      Chronic kidney diseasePresent3910.8930.830–0.9600.0020.824
      Absent2270.8760.781–0.9830.025
      AnemiaPresent3210.9180.854–0.9870.0210.666
      Absent2970.8980.804–1.0030.057
      Atrial fibrillationPresent2650.8610.790–0.9390.0010.508
      Absent3530.9050.831–0.9860.022
      Total protein≥7.03150.8580.791–0.930<0.0010.090
      <7.03030.9560.869–1.0510.354
      Albumin≥3.62900.8690.803–0.9410.0010.070
      <3.63280.9760.884–1.0760.123
      C-reactive protein≥0.173050.8830.811–0.9610.0040.575
      <0.173130.9070.831–0.9910.031
      B-type natriuretic peptide≥92.23090.8870.829–0.9500.0010.974
      <92.23090.8090.786–1.0080.067
      Troponin I≥29.63090.9520.880–1.0300.2200.085
      <29.63090.8520.771–0.9420.002

      Discussion

      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.
      • Busic Z.
      • Culic V.
      Central and peripheral testosterone effects in men with heart failure: an approach for cardiovascular research.
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • Montori V.M.
      Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.
      Testosterone deficiency causes resistance to erythropoiesis-stimulating agents in men with CKD.
      • Stenvinkel P.
      • Barany P.
      Hypogonadism in males with chronic kidney disease: another cause of resistance to erythropoiesis-stimulating agents?.
      A recent study presented that testosterone supplementation significantly increased the hemoglobin levels in older men with low testosterone levels with any cause of anemia.
      • Roy C.N.
      • Snyder P.J.
      • Stephens-Shields A.J.
      • Artz A.S.
      • Bhasin S.
      • Cohen H.J.
      • Farrar J.T.
      • Gill T.M.
      • Zeldow B.
      • Cella D.
      • Barrett-Connor E.
      • Cauley J.A.
      • Crandall J.P.
      • Cunningham G.R.
      • Ensrud K.E.
      • Lewis C.E.
      • Matsumoto A.M.
      • Molitch M.E.
      • Pahor M.
      • Swerdloff R.S.
      • Cifelli D.
      • Hou X.
      • Resnick S.M.
      • Walston J.D.
      • Anton S.
      • Basaria S.
      • Diem S.J.
      • Wang C.
      • Schrier S.L.
      • Ellenberg S.S.
      Association of testosterone levels with anemia in older men: a controlled clinical trial.
      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,
      • Kang S.M.
      • Jang Y.
      • Kim J.
      • Chung N.
      • Cho S.Y.
      • Chae J.S.
      • Lee J.H.
      Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease.
      coronary,
      • Webb C.M.
      • McNeill J.G.
      • Hayward C.S.
      • de Zeigler D.
      • Collins P.
      Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease.
      and pulmonary
      • Jones R.D.
      • English K.M.
      • Pugh P.J.
      • Morice A.H.
      • Jones T.H.
      • Channer K.S.
      Pulmonary vasodilatory action of testosterone: evidence of a calcium antagonistic action.
      vessels.
      • Culic V.
      Androgens in cardiac fibrosis and other cardiovascular mechanisms.
      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),
      • Oskui P.M.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      and the thickness of the arterial wall, and contributes to endothelial dysfunction
      • Traish A.M.
      • Saad F.
      • Feeley R.J.
      • Guay A.
      The dark side of testosterone deficiency: III. Cardiovascular disease.
      and arterial stiffness.
      • Oskui P.M.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      • Kyriazis J.
      • Tzanakis I.
      • Stylianou K.
      • Katsipi I.
      • Moisiadis D.
      • Papadaki A.
      • Mavroeidi V.
      • Kagia S.
      • Karkavitsas N.
      • Daphnis E.
      Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients.
      • Kelly D.M.
      • Jones T.H.
      Testosterone: a vascular hormone in health and disease.
      Testosterone inhibits cardiac fibroblast migration and proliferation in addition to myofibroblast differentiation induced by transforming growth factor-β1.
      • Chung C.C.
      • Hsu R.C.
      • Kao Y.H.
      • Liou J.P.
      • Lu Y.Y.
      • Chen Y.J.
      Androgen attenuates cardiac fibroblasts activations through modulations of transforming growth factor-beta and angiotensin II signaling.
      Testosterone affects cardiac efferent vagal activity
      • El-Mas M.M.
      • Afify E.A.
      • Mohy El-Din M.M.
      • Omar A.G.
      • Sharabi F.M.
      Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components.
      and induces the hypertrophy of both type I and type II muscle fibers.
      • El-Mas M.M.
      • Afify E.A.
      • Mohy El-Din M.M.
      • Omar A.G.
      • Sharabi F.M.
      Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components.
      Myocardial damage is reduced by the testosterone by upregulating cardiac α1 adrenoceptor and possibly by activating cardiac mitochondrial ATP-sensitive potassium channels.
      • Busic Z.
      • Culic V.
      Central and peripheral testosterone effects in men with heart failure: an approach for cardiovascular research.
      • Tsang S.
      • Wu S.
      • Liu J.
      • Wong T.M.
      Testosterone protects rat hearts against ischaemic insults by enhancing the effects of alpha(1)-adrenoceptor stimulation.
      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.
      • Volterrani M.
      • Rosano G.
      • Iellamo F.
      Testosterone and heart failure.
      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,
      • Pastor-Perez F.J.
      • Manzano-Fernandez S.
      • Garrido Bravo I.P.
      • Nicolas F.
      • Tornel P.L.
      • Lax A.
      • de la Morena G.
      • Valdes M.
      • Pascual-Figal D.A.
      Anabolic status and functional impairment in men with mild chronic heart failure.
      another report presented that lowered circulating testosterone and its changes relate to peak VO2.
      • Jankowska E.A.
      • Filippatos G.
      • Ponikowska B.
      • Borodulin-Nadzieja L.
      • Anker S.D.
      • Banasiak W.
      • Poole-Wilson P.A.
      • Ponikowski P.
      Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure.
      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.
      • Toma M.
      • McAlister F.A.
      • Coglianese E.E.
      • Vidi V.
      • Vasaiwala S.
      • Bakal J.A.
      • Armstrong P.W.
      • Ezekowitz J.A.
      Testosterone supplementation in heart failure: a meta-analysis.
      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.

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