Testosterone Deficiency Increases Hospital Readmission and Mortality Rates in Male Patients with Heart Failure

Abstracts

Background:

Testosterone deficiency in patients with heart failure (HF) is associated with decreased exercise capacity and mortality; however, its impact on hospital readmission rate is uncertain. Furthermore, the relationship between testosterone deficiency and sympathetic activation is unknown.

Objective:

We investigated the role of testosterone level on hospital readmission and mortality rates as well as sympathetic nerve activity in patients with HF.

Methods:

Total testosterone (TT) and free testosterone (FT) were measured in 110 hospitalized male patients with a left ventricular ejection fraction < 45% and New York Heart Association classification IV. The patients were placed into low testosterone (LT; n = 66) and normal testosterone (NT; n = 44) groups. Hypogonadism was defined as TT < 300 ng/dL and FT < 131 pmol/L. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography in a subpopulation of 27 patients.

Results:

Length of hospital stay was longer in the LT group compared to in the NT group (37 ± 4 vs. 25 ± 4 days; p = 0.008). Similarly, the cumulative hazard of readmission within 1 year was greater in the LT group compared to in the NT group (44% vs. 22%, p = 0.001). In the single-predictor analysis, TT (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.58–4.85; p = 0.02) predicted hospital readmission within 90 days. In addition, TT (HR, 4.65; 95% CI, 2.67–8.10; p = 0.009) and readmission within 90 days (HR, 3.27; 95% CI, 1.23–8.69; p = 0.02) predicted increased mortality. Neurohumoral activation, as estimated by MSNA, was significantly higher in the LT group compared to in the NT group (65 ± 3 vs. 51 ± 4 bursts/100 heart beats; p < 0.001).

Conclusion:

These results support the concept that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, increased MSNA was observed in patients with LT.

Heart Failure / mortality; Testosterone / deficiency; Patient Readmission; Men

Fundamento:

A deficiência de testosterona na insuficiência cardíaca (IC) está associada à diminuição da capacidade de exercício e mortalidade, mas o seu impacto sobre as readmissões é incerto. Além disso, sua relação com a ativação simpática é desconhecida.

Objetivo:

O presente estudo investigou o papel dos níveis de testosterona nas reinternações hospitalares, na mortalidade e na atividade nervosa simpática em pacientes com IC.

Métodos:

A testosterona total (TT) e a testosterona livre (TL) foram medidas em 110 pacientes do sexo masculino hospitalizados, com fração de ejeção < 45% eclassificação funcional da New York Heart Association (NYHA) IV, qualificados em dois grupos: 66 com baixos níveis de testosterona (BT) e 44 com testosterona normal (TN). Hipogonadismo foi definido como TT < 300 ng/dL e TL < 131 pmol/L. A atividade nervosa simpática muscular (ANSM) foi gravada por microneurografia em uma subpopulação de 27 pacientes.

Resultados:

O tempo de permanência hospitalar foi maior em pacientes BT em comparação com pacientes TN (37 ± 4 vs. 25 ± 4 dias; p = 0,008). Da mesma forma, o risco cumulativo de readmissão no período de um ano foi maior em pacientes BT (44% vs. 22%, p = 0,001). Na análise de uma única variável preditora, a testosterona total (HR = 2,77, IC 95% 1,58-4,85, p = 0,02) previu readmissão hospitalar no prazo de 90 dias. Na análise de uma única variável preditora, testosterona total (HR = 4,65, IC 95% 2,67-8,10, p = 0,009) e readmissão dentro de 90 dias (HR = 3,27, IC 95% 1,23-8,69, p = 0,02) previram aumento de mortalidade. Ativação neuro-humoral, estimada pela ANSM, foi significativamente maior nos pacientes BT em comparação aos do grupo TN (65 ± 3 vs. 51 ± 4 disparos/100BC; p < 0,001).

Conclusão:

Estes resultados sustentam o conceito de que BT é um fator de risco independente para a readmissão hospitalar dentro de 90 dias e para aumento de mortalidade em pacientes com IC. Além disso, observou-se aumento da ANSM em pacientes com baixos níveis de testosterona.

Insuficiência Cardíaca / mortalidade; Testosterona / deficiência; Readmissão do Paciente; Homens

Introduction

Symptoms attributable to heart failure (HF), including dyspnea, fatigue, and muscle weakness, lead to > 1 million hospitalizations per year in the United States and Brazil¹, with readmission rates within 90 days approaching 50%^2,3. Although the importance of HF-related costs as a major contributor to the healthcare spending crisis has been recognized, more than 20 pharmacological trials worldwide focusing on mortality as an endpoint have been negative². As a large proportion of patients with HF would trade increased length of life for increased quality of life⁴, which is directly linked to exercise capacity⁵, it may be reasonable to refocus therapeutic targets in patients with HF to improve exercise and functional capacity.

Testosterone deficiency is recognized in a large number of male patients with advanced HF and is correlated with decreased functional class, exercise capacity, and muscle strength^6-8, and in some studies⁹, but not all¹⁰, testosterone deficiency is associated with increased mortality. Testosterone therapy is recommended for men with a testosterone deficiency and symptoms of hypogonadism to increase exercise capacity. Testosterone therapy is associated with increased exercise tolerance in patients with HF compared with placebo, which is not explained by impaired cardiac function^8,11-14.

Considering that cardiac function does not improve following testosterone therapy, and the growing acceptance of the "muscle hypothesis," which argues that exercise limitations in patients with chronic HF are focused on the periphery, including abnormalities in the reflexes activated during exercise^15,16, testosterone therapy may have beneficial effects on the neurohumoral state in patients with HF. Indeed, decreased baroreceptor sensitivity and heart rate variability (HRV) have been reported in patients with a testosterone deficiency¹⁷.

The purpose of this study was to test the hypothesis that testosterone deficiency is associated with an increased risk for subsequent re-hospitalization within 30, 60, and 90 days. Additionally, we evaluated mortality rate in hospitalized male patients with HF due to decompensated HF. Moreover, we tested the hypothesis that patients with HF and testosterone deficiency have greater neurohumoral activation; i.e., increased levels of muscle sympathetic nerve activity (MSNA) compared to in patients with HF and normal testosterone (NT) levels to begin to understand the mechanisms underlying this potential inverse relationship.

Methods

Study Population

We prospectively evaluated 110 consecutive hospitalized male patients with HF who agreed to participate. Those who met the study inclusion criteria had acute decompensated HF and were functional class IV. Other study criteria were as follows: 1) age between 18 and 65 years old, 2) HF diagnosis > 6 months, and 3) left ventricular ejection fraction (LVEF) < 45%. Exclusion criteria were as follows: 1) history of coronary revascularization or myocardial infarction < 6 months before the study, 2) any hormonal treatment, including exogenous testosterone therapy, before or during the protocol, 3) advanced kidney disease, liver disease, or diabetes, 4) obesity (body mass index > 30 kg/m²), and 5) prostatic cancer or benign prostatic hyperplasia with or without anti-androgen therapy (finasteride, doxazosin, or tamsulosin). Written informed consent was obtained from all participants before the study; this study was approved by the local ethics committee and is registered at Clinical Trials (NCT01852994).

Laboratory Measurements

For all patients, blood samples for androgen testing were collected on the morning of hospital admission. If the patient was admitted during the afternoon or at night, androgen testing was done the next morning. Serum levels of total testosterone (normal range, 300-965 ng/dL; intra-assay coefficient of variation [CV] ≤ 7.5% and inter-assay CV ≤ 5.4%), sex hormone-binding globulin (SHBG; normal range, 12-75 nmol/L; intra-assay CV ≤ 2.3% and inter-assay CV ≤ 6%) were determined according to standard laboratory techniques in the clinical laboratory at the Hospital da Clínicas, University of Sao Paulo Medical School. Free testosterone (normal range, 131-640 pmol/L) was calculated using SHBG and total testosterone in the formula proposed by Vermeulen et al¹⁸. Hypogonadism was defined in the laboratory as total testosterone < 300 ng/dL and free testosterone < 131 pmol/L^19,20. B-type natriuretic peptide (BNP), C-reactive protein (CRP), hemoglobin, blood urea nitrogen (BUN), creatinine, sodium, potassium, and fasting blood glucose levels were also measured on the morning of hospital admission. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation recommended by the National Kidney Disease Education Program.

Muscle sympathetic nerve activity

Patients were stabilized on oral medication therapy and underwent microneurographic recording of MSNA. Microneurography of the peroneal nerve is a safe, precise, direct technique to record SNA directed to muscle²¹. MSNA was recorded in a subpopulation of 27 patients during hospitalization. In brief, a tungsten microelectrode was placed on the peroneal nerve, and a sympathetic neurogram was recorded. Nerve signals were amplified by 50,000-100,000 and band-pass filtered (700-2,000 Hz). Nerve activity for recording and analysis was rectified and integrated (time constant, 0.1 s) to obtain a mean voltage display. Muscle sympathetic bursts were identified by visual inspection (M.R.S.), who was blinded to the study protocol. MSNA was expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heart beats [HB]).

Echocardiography

LVEF was evaluated (Teicholz) using two-dimensional imaging according to standard methods²².

Follow-up

All patients were followed up after discharge by a dedicated research nurse through electronic health records and by periodic phone calls.

Statistical Analysis

The Kolmogorov-Smirnov test was used to verify that all data were normally distributed. Student's t-test and the Mann-Whitney U-test were used to compare parametric and non-parametric data, respectively. The chi-square (X²) test was used to analyze medications and the HF etiology data. The Cox proportional hazards model was used to test the associations between the analyzed variables and endpoints (readmissions within 30, 60, and 90 days and mortality). We included length of stay after the first hospital admission, age, LVEF, coronary artery disease (CAD) or no CAD, BNP, CRP, hemoglobin, urea, creatinine, eGFR, sodium, potassium, fasting blood glucose, total testosterone, free testosterone, and SHBG in the single-predictor analysis for readmission. We included the same variables as above in the single-predictor analysis for mortality, as well as readmission within 30, 60, and 90 days of discharge. Forward and backward stepwise multivariate model analyses (p = 0.10) were conducted to assess which factors independently predicted readmission and mortality in the single-predictor analysis. Survival was evaluated using a Kaplan-Meier analysis with 95% confidence intervals (CIs) between total testosterone and mortality within 1 year. Furthermore, a Kaplan-Meier analysis was used to evaluate the relationship between total testosterone level and readmission within 1 year. The Cox-Mantel log-rank test was used to evaluate differences in survival and readmission rates. A p value < 0.05 was considered statistically significant.

Results

Sixty-six patients were classified with low testosterone (LT), and 44 had NT during hospitalization. The characteristics of the LT and NT groups are compared in Table 1. The LT and NT groups were not different in age, etiology of HF, LVEF, or medications used, but BNP, CRP, BUN, creatinine, and fasting blood glucose levels were significantly higher in the LT group than those in the NT group. In contrast, hemoglobin, eGFR, sodium, and total and free testosterone levels were significantly lower in the LT group than those in the NT group.

Table 1
Physical, clinical, and hormonal characteristics of men with heart failure at the first admission

Variables	Low Testosterone (n = 66)	Normal Testosterone (n = 44)	p value
Age, y	52 ± 1	51 ± 2	0.70
Weight, kg	72 ± 2	71 ± 2	0.52
Height, m	1.70 ± 0.01	1.69 ± 0.01	0.78
BMI, kg/m2	25 ± 1	24 ± 1	0.54
LVEF, %	25 ± 1	27 ± 1	0.24
TT, ng/dL	237 ± 11	652 ± 41	< 0.001
FT, pmol/L	124 ± 9	323 ± 21	< 0.001
SHBG, nmol/L	60 ± 3	73 ± 5	0.037
Etiology of HF			0.81
CAD	17 (26%)	9 (20%)
Non CAD	49 (74%)	35 (80%)
Chagasic	17	14
Hypertensive	3	3
Idiopathic	29	18
Treatment, N (%)
ACE-I/ARB	29 (44%)	24 (55%)	0.28
β-blockers	51 (77%)	26 (59%)	0.04
Diuretics	57 (86%)	33 (75%)	0.13
Digoxin	13 (20%)	10 (23%)	0.70
Statin	18 (27%)	8 (18%)	0.27
Aspirin	26 (39%)	11 (25%)	0.12
Biomarkers
BNP, pg/mL	1725±153	804 ± 112	0.006
CRP, mg/L	35 ± 6	15 ± 3	0.007
BUN, mg/L	70 ± 4	56 ± 4	0.04
Creatinine, mg/L	1.66 ± 0.10	1.32 ± 0.05	0.02
Fasting glucose, mg/L	114 ± 3	94 ± 2	0.01
Hemoglobin, g/dL	12.30 ± 0.26	13.57 ± 0.30	0.007
GFR, mL min-1 1.73 m-2	49 ± 2	55 ± 1	0.03
Sodium, mEq/L	135 ± 1	137 ± 0.4	0.04
Potassium, mEq/L	4.38 ± 0.07	4.51 ± 0.08	0.29

• Six patients in the low testosterone group and two patients in the normal testosterone group died during the first admission and were excluded from subsequent analyses. BMI: body mass index; LVEF: left ventricular ejection fraction; TT: total testosterone; FT: free testosterone; SHBG:sex hormone-binding globulin; CAD: coronary artery disease; ACE-I/ARB: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BNP: B-type natriuretic peptide; CRP: C-reactive protein; BUN: blood urea nitrogen; GFR: glomerular filtration rate.

Length of hospital stay during the first admission

The LT group had a significantly longer hospital stay than the NT group (37 ± 4 vs. 25 ± 4 days, respectively) (Figure 1; p = 0.008). This relationship persisted even when outliers (values >2 standard deviations) were excluded. Six patients died in the LT group and two died in the NT group during this first admission.

Figure 1
Length of hospital stay in patients with heart failure and low testosterone (LT; n = 66) and normal testosterone (NT; n = 44). The LT group had a longer hospitalization stay than the NT group at the first admission. ^*Between group difference, p = 0.008.

Readmissions after the first admission

The medications at discharge were not different between the LT and NT groups (Table 2). The median times for the first readmission were 94 days (LT group) and 137 days (NT group). Readmission rate was greater in the LT compared to in the NT group when measured at 30, 60, and 90 days. However, readmission rates within 30 and 60 days were not related to any variable tested in the Cox regression. Total testosterone was the only variable related to this poor outcome in the single-predictor analysis for readmission within 90 days (hazard ratio [HR], 2.77; 95% CI, 1.58-4.85, p = 0.02; Table 3). All variables related to readmission within 90 days in the single-predictor analysis were included in the multivariate Cox proportional hazard model analyses. The final model after forward and backward stepwise analyses consisted of only total testosterone (forward: HR, 2.49; 95% CI, 1.33-4.65; p = 0.04 and backward: HR, 2.48; 95% CI, 1.33-4.65; p = 0.004) for readmission within 90 days. In addition, the cumulative hazard for readmission was higher in the LT group compared to in the NT group (Figure 2; n = 102; p = 0.001) at the 1-year follow-up.

Table 2
Medications and dally dosages at discharge (first admission) In men with heart failure

Variables	Low Testosterone (n = 60)	Normal Testosterone (n = 42)	p value
Treatment, N (%)
β-blocker	52 (87%)	39 (93%)	NS
ACE-I/ARB	41 (68%)	36 (86%)	NS
Spironolactone	25 (42%)	19 (45%)	NS
Diuretics	43 (72%)	34 (81%)	NS
Digoxin	10 (17%)	15 (36%)	NS
Hydralazine	36 (60%)	20 (48%)	NS
Statin	22 (37%)	8 (19%)	NS
Aspirin	19 (32%)	10 (24%)	NS

• Six patients in the low testosterone group and two patients in the normal testosterone group died during the first admission. ACE-I/ARB: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; NS: not significant.

Table 3
Single-predictor models of the Cox proportional hazard analysis for readmission within 90 days and mortality. Low testosterone group (n = 60) and normal testosterone group (n = 42)

Readmission within 90 days	Hazard ratio	95% CI	p value
Total testosterone, ng/dL	2.77	1.58-4.85	0.02
Mortality	Hazard ratio	95% CI	p value
Sodium, mEq/L	0.89	0.81-0.97	0.01
Total testosterone, ng/dL	4.65	2.67-8.10	0.009
Readmission - 90 days	3.27	1.23-8.69	0.02

• Six patients in the low testosterone group and two patients in the normal testosterone group were excluded from the single-predictor models due to mortality during the first admission. CI: confidence interval.

Figure 2
Kaplan–Meier readmission curves within the 1-year follow-up in patients with heart failure. The low testosterone group showed more cumulative readmissions than the normal testosterone group within the year (p = 0.001). The 1-year follow-up started at hospital discharge (time zero).

Mortality at the 1-year follow-up

Following first discharge, the LT group had significantly higher mortality compared than the NT group (Figure 3; n = 102; p = 0.001) at the 1-year follow-up: 24 patients in the LT group and seven in the NT group died within 1 year after hospital discharge. In the single-predictor analysis, total testosterone (HR, 4.65; 95% CI, 2.67-8.10; p = 0.009; Table 3) and readmission within 90 days (HR, 3.27; 95% CI, 1.23-8.69; p = 0.02; Table 3) were predictors of mortality. All variables that were related to mortality in the single-predictor analysis were included in the multivariate Cox proportional hazard model analyses. The final model after the forward stepwise analysis included total testosterone (forward: HR, 3.86; 95% CI, 2.06-7.21; p < 0.001) and readmission within 90 days (forward: HR, 3.08; 95% CI, 1.57-6.04; p = 0.001) for mortality. The backward stepwise analysis for mortality included total testosterone (HR, 3.86; 95% CI, 2.06-7.21; p < 0.0001), eGFR (HR, 0.97; 95% CI, 0.95-0.9; p = 0.034), readmission within 90 days (HR, 2.39; 95% CI, 1.05-5.45; p = 0.038), and readmission within 60 days (HR, 2.96; 95% CI, 1.01-8.67; p = 0.047).

Figure 3
Kaplan–Meier survival curves within the 1-year follow-up in patients with heart failure. The low testosterone group had a higher mortality rate than the normal testosterone group within the year (p = 0.001). The 1-year follow-up started at hospital discharge (time zero).

Muscle sympathetic nerve activity

MSNA was significantly higher in the LT group compared to in the NT group when calculated as bursts/100 HB, (65 ± 3 vs. 51 ± 4 bursts/100 HB, p < 0.001). MSNA tended to be higher in the LT group compared to in the NT group when calculated as bursts/min (47 ± 3 vs. 43 ± 4 bursts/min, p > 0.05), but was not statistically significant.

Discussion

Although testosterone deficiency is associated with heart disease and elevated mortality²³, testosterone level is not commonly used in clinical practice to measure the severity and prognosis in patients with HF. Our findings extend the observation that LT is associated with an increased cardiac risk by demonstrating that LT is associated with increased mortality in a cohort with HF. Furthermore, deficiency in total testosterone was an independent risk factor for increased morbidity as evidenced by the increase in hospital readmissions within 90 days.

The stepwise analysis for mortality was strongly related to readmission within 90 days (forward) and readmission within 60 days (backward), as well as total testosterone and eGFR. One review reported that later hospital readmission (> 30 days) is associated with renal insufficiency and elevated BNP level². Interestingly, we did not find an association between earlier readmission (within 30 days) and a testosterone deficiency in our patients. This result is consistent with the notion that a 30-day readmission may be related to poor social support and low socioeconomic status rather than to an increase in clinical comorbidities². In fact, we found that a testosterone deficiency was associated with greater activation of the sympathetic nervous system, and increased sympathetic nerve activity is a risk factor for increased mortality in patients with HF²⁴. The increased sympathetic activation may provide a potential mechanism, which will be discussed below.

Some studies have reported an inconsistent association between testosterone and mortality in patients with HF. Jankowska et al⁹found that low total testosterone is associated with increased mortality. In contrast, Guder et al¹⁰ reported that LT is not an independent risk factor for decreased survival in patients with HF. These disparate findings can be explained by differences in the HF populations; the population studied by Guder et al¹⁰ included a large proportion (~50%) of patients with HF and preserved LVEF, unlike those in the study by Jankowska et al⁹ In addition, they speculated that their findings differed from those of Jankowska et al. because they included additional prognostic variables, such as medication use, inflammatory markers, and others. Importantly, the additional variables included by Guder et al¹⁰ as well as several others were included in our study, and LT remained an independent predictor of increased mortality in patients with advanced HF and systolic dysfunction in our study.

We found that total testosterone, not free testosterone, was associated with poor outcomes. Total testosterone consists of free testosterone plus testosterone bound to SHBG and albumin; free testosterone is the active fraction. A meta-analysis reported that a decrease in total testosterone is associated with 35% and 25% increased risks of all-cause and cardiovascular disease mortality in men, respectively²⁵. Another study on patients with HF showed that a deficiency in SHBG is associated with a higher risk of cardiac death²⁶. In contrast, high levels of SHBG lead to a lower bioavailability of free testosterone and has been linked to increased mortality in men when augmented by SHBG²⁷. Although we found a significant difference in SHBG levels between the LT and NT groups, the result remained within the normal range in our laboratory (20.6-76.7 nmol/L). SHBG levels can be altered by non-cardiac medications, diet, and specific illnesses but the relative importance of these factors in our patients is not known.

Although a deficiency in androgens has been previously associated with increased morbidity, particularly a decrease in exercise capacity, our study is the first to examine the association between LT and hospital readmissions, a critically important endpoint in this era of skyrocketing medical costs. The patients with HF and LT had similar LVEF, New York Heart Association functional class, HF etiology, and discharge medications, as those of patients with HF and NT. Interestingly, LT was accompanied by several markers of increased HF severity, including higher BNP and CRP levels, more severe renal dysfunction, and anemia, yet testosterone deficiency remained an independent predictor of readmission within 90 days of hospital discharge.

It is unknown if a testosterone deficiency is only a strong marker for poor prognosis in patients with HF, or whether LT contributes directly to increased morbidity and mortality. Testosterone deficiency is associated with many signs and symptoms, several of which are indistinguishable from normal aging, including declining libido, increased body fat, osteoporosis, mild anemia, depression, and fatigue²⁸. The most easily recognizable manifestation of a testosterone deficiency is a decline in muscle strength and bulk, which is associated with a decline in exercise capacity²⁸. Exogenous testosterone improves exercise capacity^29,30. Baseline testosterone levels were directly related to exercise capacity in five small, controlled trials of testosterone treatment in patients with HF, including those with LT, NT, and one trial of women with HF. Furthermore, 3-month testosterone therapy compared with placebo is associated with increased exercise capacity in many studies^8,11-14. As hospitalization for HF is often prompted by increased fatigue and shortness of breath and the mechanisms underlying these symptoms vary^31-33 but includes progressive muscle weakness, it is tempting to speculate that testosterone deficiency may be an important contributor to the ongoing peripheral muscle decline, and thereby is a direct contributor to re-hospitalization risk. A controlled trial of testosterone therapy in patients with advanced HF would clarify this issue.

According to the muscle hypothesis, exercise limitations in patients with HF reside in the periphery, specifically in skeletal muscles^15,16,34,35. Furthermore, skeletal muscle abnormalities in patients with HF may contribute to abnormal neurohumoral activation, including exaggerated increases in sympathetic nerve activity^35-38. In a study of male rats with HF, castration was associated with changes in cardiac sympathetic nerve activity and increased plasma norepinephrine levels³⁹. This sympatho-excitation was reversed by testosterone replacement therapy, as observed by decreased plasma norepinephrine, increased myocardial norepinephrine, the density of tyrosine hydroxylase (TH) protein-labeled nerve fibers, and upregulated expression of myocardial TH protein. In a recent study of patients with mild HF, Rydlewska et al¹⁷ reported that testosterone deficiency is directly related to lower baroreceptor sensitivity and HRV. Similarly, castration significantly attenuates baroreceptor control of reflex bradycardia versus no effect on reflex tachycardia in rats. Testosterone replacement increases baroreflex sensitivity and restores reflex bradycardic responses⁴⁰. In our study, resting MSNA was higher in patients with LT; it is intriguing to speculate that testosterone therapy may have a modulating effect on sympathetic activation in patients with HF, which may be mediated by ameliorating abnormal reflexes originating in peripheral muscles and/or potentially through an effect on the baroreceptors themselves.

Limitations

We recognize several limitations in our study. Androgen levels were only measured at one time point during the index admission for decompensated HF. It is not known whether androgen levels fluctuate in patients with HF based on their clinical status. All patients with HF were decompensated at the time testosterone levels were obtained; it is unknown whether testosterone provides similar important prognostic information in less ill patients with HF.

MSNA was recorded in 25% of the patients during hospitalization after they were stabilized because we could not conduct this procedure during acute decompensation. Our MSNA results are representative of only a small subgroup of patients; thus, the results need to be confirmed in a larger group.

We did not have exercise data on our patients, and peak VO₂ is known to provide important prognostic information in patients with advanced HF. However, all patients were decompensated at the time of enrollment, and all were too ill to perform a CPX, which is a uniformly poor prognostic sign. Importantly, within this group of patients with HF who were too ill to provide exercise data, testosterone levels provided important prognostic information. The incidence of sleep apnea was not assessed in this group, which is another important risk factor that should be assessed in the future.

Finally, this study was conducted at a single institution (Heart Institute at the University of São Paulo, Brazil) and we only included males with HF. It is unknown whether testosterone therapy would be beneficial in females with HF, but it is an intriguing possibility.

Conclusion

Our results support the notion that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, we observed a possible modulating effect of LT on sympathetic activation in patients with HF.

• Sources of Funding
  This study was funded by FAPESP (2010/50048-1) and Capes.
• Study Association
  This article is part of the thesis of Doctoral submitted by Marcelo Rodrigues dos Santos, from Faculdade de Medicina da Universidade de São Paulo.

Funding and Acknowledgments

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2010/50048-1). MRS and RVRG were supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). ALCS was supported by Conselho Nacional de Pesquisa (CNPq #141856/2012-2). CEN was supported by Conselho Nacional de Pesquisa (CNPq #301867/2010-0). All foundations are in São Paulo-SP, Brazil. The authors sincerely thank the hormone and molecular genetics laboratory (Endocrinology - Hospital das Clínicas, University of Sao Paulo School) for measuring testosterone. We have no relationships with industry.

References

• ¹
  Rohde LE, Clausell N, Ribeiro JP, Goldraich L, Netto R, William Dec G, et al. Health outcomes in decompensated congestive heart failure: a comparison of tertiary hospitals in Brazil and United States. Int J Cardiol. 2005;102(1):71-7.
• ²
  Butler J, Fonarow GC, Gheorghiade M. Strategies and opportunities for drug development in heart failure. JAMA. 2013;309(15):1593-4.
• ³
  Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61(4):391-403.
• ⁴
  Stevenson LW, Hellkamp AS, Leier CV, Sopko G, Koelling T, Warnica JW, et al. Changing preferences for survival after hospitalization with advanced heart failure. J Am Coll Cardiol. 2008;52(21):1702-8.
• ⁵
  Dracup K, Walden JA, Stevenson LW, Brecht ML. Quality of life in patients with advanced heart failure. J Heart Lung Transplant. 1992;11(2 Pt 1):273-9.
• ⁶
  Agapitou V, Dimopoulos S, Kapelios C, Karatzanos E, Manetos C, Georgantas A, et al. Hormonal imbalance in relation to exercise intolerance and ventilatory inefficiency in chronic heart failure. J Heart Lung Transplant. 2013;32(4):431-6.
• ⁷
  Jankowska EA, Filippatos G, Ponikowska B, Borodulin-Nadzieja L, Anker SD, Banasiak W, et al. Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure. J Card Fail. 2009;15(5):442-50.
• ⁸
  Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006;27(1):57-64.
• ⁹
  Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114(17):1829-37.
• ¹⁰
  Guder G, Frantz S, Bauersachs J, Allolio B, Ertl G, Angermann CE, et al. Low circulating androgens and mortality risk in heart failure. Heart. 2010;96(7):504-9.
• ¹¹
  Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009;54(10):919-27.
• ¹²
  Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010;56(16):1310-6.
• ¹³
  Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004;90(4):446-7.
• ¹⁴
  Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, et al. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J. 2012;164(6):893-901.
• ¹⁵
  Coats AJ, Clark AL, Piepoli M, Volterrani M, Poole-Wilson PA. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J. 1994;72(2 Suppl):S36-9.
• ¹⁶
  Middlekauff HR. Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failure. Circ Heart Fail. 2010;3(4):537-46.
• ¹⁷
  Rydlewska A, Maj J, Katkowski B, Biel B, Ponikowska B, Banasiak W, et al. Circulating testosterone and estradiol, autonomic balance and baroreflex sensitivity in middle-aged and elderly men with heart failure. Aging Male. 2013;16(2):58-66.
• ¹⁸
  Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666-72.
• ¹⁹
  Huhtaniemi IT, Tajar A, Lee DM, O'Neill TW, Finn JD, Bartfai G, et al; EMAS Group. Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol. 2012;166(6):983-91.
• ²⁰
  Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab. 2004;89(2):534-43.
• ²¹
  Fagius J, Wallin BG. Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade. Clin Auton Res. 1993;3(3):201-5.
• ²²
  Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358-67.
• ²³
  Tirabassi G, Gioia A, Giovannini L, Boscaro M, Corona G, Carpi A, et al. Testosterone and cardiovascular risk. Intern Emerg Med. 2013;8 Suppl 1:S65-9.
• ²⁴
  Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, et al. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol. 2009;135(3):302-7.
• ²⁵
  Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007-19.
• ²⁶
  Pascual-Figal DA, Tornel PL, Nicolas F, Sanchez-Mas J, Martinez MD, Gracia MR, et al. Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure. Rev Esp Cardiol. 2009;62(12):1381-7.
• ²⁷
  Wehr E, Pilz S, Boehm BO, Marz W, Grammer TB, Obermayer-Pietsch B. Sex steroids and mortality in men referred for coronary angiography. Clin Endocrinol (Oxf). 2010;73(5):613-21.
• ²⁸
  Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5(3):427-48.
• ²⁹
  Harman SM, Blackman MR. The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and men. Horm Res. 2003;60(Suppl 1):121-4.
• ³⁰
  Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 1995;269(5 Pt 1):E820-6.
• ³¹
  Mancini DM, Henson D, LaManca J, Levine S. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation. 1992;86(3):909-18.
• ³²
  Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation. 1992;85(4):1364-73.
• ³³
  Witte KK, Clark AL. Why does chronic heart failure cause breathlessness and fatigue? Prog Cardiovasc Dis. 2007;49(5):366-84.
• ³⁴
  Coats AJ. Origin of symptoms in patients with cachexia with special reference to weakness and shortness of breath. Int J Cardiol. 2002;85(1):133-9.
• ³⁵
  Piepoli M, Ponikowski P, Clark AL, Banasiak W, Capucci A, Coats AJ. A neural link to explain the "muscle hypothesis" of exercise intolerance in chronic heart failure. Am Heart J. 1999;137(6):1050-6.
• ³⁶
  Middlekauff HR, Chiu J, Hamilton MA, Fonarow GC, Maclellan WR, Hage A, et al. Muscle mechanoreceptor sensitivity in heart failure. Am J Physiol Heart Circ Physiol. 2004;287(5):H1937-43.
• ³⁷
  Middlekauff HR, Chiu J, Hamilton MA, Fonarow GC, Maclellan WR, Hage A, et al. Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure. Am J Physiol Heart Circ Physiol. 2008;294(4):H1956-62.
• ³⁸
  Middlekauff HR, Sinoway LI. Increased mechanoreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure. J Appl Physiol (1985). 2007;102(1):492-4.
• ³⁹
  Han Y, Fu L, Sun W, Cao J, Xie R, Zhou P, et al. Neuroprotective effects of testosterone upon cardiac sympathetic function in rats with induced heart failure. Eur J Pharmacol. 2009;619(1-3):68-74.
• ⁴⁰
  El-Mas MM, Afify EA, Mohy El-Din MM, Omar AG, Sharabi FM. Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components. J Cardiovasc Pharmacol. 2001;38(5):754-63.

Publication Dates

• Publication in this collection
  21 July 2015
• Date of issue
  Sept 2015

History

• Received
  13 Feb 2015
• Reviewed
  14 May 2015
• Accepted
  15 May 2015