Bone mass loss in chronic heart failure is associated with secondary hyperparathyroidism and has prognostic significance




Chronic heart failure (CHF) is associated with increased risk of osteoporosis. We investigated the relationship between severity of CHF and bone loss, underlying pathophysiological mechanisms, and the prognostic significance of bone mass changes in heart failure.

Methods and results

Total body (TB) and femoral (F) bone mineral density (BMD), and T- and Z-scores in the femur were measured in 60 men with CHF (56 ± 11 years) and 13 age-matched men free from CHF. The composite study endpoint was death, implantation of a left ventricular assist device (LVAD), or inotrope dependency during a median 2-year follow-up. Parathyroid hormone (PTH) and vitamin D were measured in all subjects. TBBMD, FBMD, T-score, and Z-score were significantly lower in men with CHF. Their PTH levels were also significantly increased (111 ± 59 vs. 39 ± 14; P < 0.001). Patients in New York Heart Association classes III–IV compared with those in classes I–II demonstrated significantly lower TBBMD, FBMD, T-score, and Z-score, and higher PTH (136 ± 69 vs. 86 ± 31; P= 0.001). Increased PTH levels were correlated with reduced TBBMD (P = 0.003), FBMD (P = 0.002), and femur T-score (P = 0.001), reduced cardiac index (P = 0.01) and VO2 peak (P < 0.0001), and increased wedge pressure (P = 0.001). Low TBBMD [hazard ratio (HR) 0.003, 95% confidence interval (CI) 0.00–0.58; P = 0.03] and Z-score (HR 0.56, 95% CI 0.35–0.90; P = 0.017) were associated with adverse outcome.


Secondary hyperparathyroidism and reduction in bone density occur in CHF patients and are associated with disease severity. Increased bone mass loss in CHF has prognostic significance.


With a 2.2% prevalence in the general population, chronic heart failure (CHF) is the leading cause of hospitalizations for acute care and of death in patients >65 years of age.[1],[2] It is estimated that there are currently 6.5 million CHF patients in Europe, and the number is expected to increase because of the ageing of the population.[3] On the other hand, >200 million people worldwide have osteoporosis, a disease that exposes patients to the risk of non-traumatic fractures, particularly of the wrist, spine, and hip.[4] Over 1.7 million hip fractures, the most serious complication of osteoporosis associated with a 30% 1-year mortality, occur annually worldwide.[5],[6] In the European Union, in 2000, the number of osteoporotic fractures was estimated at 3.79 million, with the direct costs to health services reaching 32 billion Euros, and expected to double by 2050.[4] CHF has been associated with an increased risk of bone fractures.[5],[7],[8]

Both disorders are common causes of loss of function and independence, and of prolonged hospitalizations, presenting a heavy burden to the healthcare system. Several studies looking at the relationship and mutual interactions of the two conditions have been reported during the last decade. Increasing evidence suggests that secondary hyperparathyroidism and hypovitaminosis D, both well-known predisposing factors of osteoporosis, are associated with CHF, and serum levels of parathyroid hormone (PTH) and vitamin D have prognostic value in CHF.[9]−[11]

Bone remodelling is a life-long process, which is adversely affected by several chronic diseases, including hepatic and renal insufficiency, chronic obstructive lung disease, and Parkinson's disease. Despite the association of CHF with multiple factors that adversely influence bone metabolism, the bone status of patients suffering from CHF has rarely been studied.[12] A low bone mineral density (BMD) has been described in patients presenting with advanced CHF, particularly when they are cachectic or candidates for cardiac transplantation.[13],[14] In case series of patients with CHF evaluated for transplantation, >40% had low BMD.[14],[15] CHF is associated with several risk factors that predispose to the development of osteoporosis or osteopenia, including old age, post-menopausal status, sedentary lifestyle, limited exposure to sunlight, tobacco or alcohol abuse, and therapy with loop diuretics and anticoagulants. In addition, hepatic and intestinal congestion due to right ventricular failure may impair the absorption and synthesis of vitamin D.[15] Finally, renal insufficiency is an important cause of BMD loss in CHF.[16]

Whether CHF and osteoporosis are two common, though unrelated disorders with shared risk factors, or whether they are linked by a common underlying pathophysiological mechanism is unclear.[17] Despite the known effect of PTH as a stimulator of bone turnover and resorption, previous studies have shown only weak or no association between hyperparathyroidism and reduced BMD in CHF patients.[12],[18] Moreover, scarce and conflicting data have been published on the relationship between severity of CHF and bone mass loss.[12],[15] Finally, the prognostic significance of BMD in the setting of CHF has not been thoroughly studied. Therefore, we examined (i) bone mass status, PTH, and vitamin D levels in a population of CHF patients and their relationship with the severity of CHF; and (ii) the prognostic value of measurements of BMD, PTH, and vitamin D in men suffering from CHF. The BMD, used for the evaluation of bone status and expressed in g/cm2, reflects the planimetric density of bone tissue.


Between August 2007 and August 2009, we studied 60 Caucasian men, who were hospitalized or were followed in the CHF ambulatory services of our hospital for management of ischaemic (n = 31) or dilated (n = 29) cardiomyopathy (CHF group). Inclusion criteria were: (i) a≥6 month history of CHF due to coronary artery disease or idiopathic dilated cardiomyopathy; (ii) a left ventricular (LV) ejection fraction (EF) <40% measured by echocardiography; and (iii) a stable clinical status and medication regimen for ≥1 month preceding enrolment. We studied 13 Caucasian, age-matched, hypertensive men whose LVEF was ≥50%, and who had no history or manifestations of CHF, as controls (non-CHF group). The exclusion criteria for both groups were (i) a history of chronic, non-cardiac disease that may influence bone metabolism, including autoimmune diseases, cancer, multiple myeloma and other haematological malignancies, chronic obstructive pulmonary disease, advanced liver failure, hyperthyroidism, and Cushing's syndrome; (ii) a serum creatinine concentration >2.5 mg/dL or long-term haemodialysis; and (iii) current or previous therapy with bisphosphonates, calcitonin, oestrogen, or glucocorticoids, or supplementation with vitamin D or calcium. The study protocol was approved by our institutional ethics committee, and all study participants gave written informed consent.

Bone, lean, and fat tissue densitometry

The total body composition was assessed, using a DPX-MD dual-energy X-ray absorptiometry (DEXA) scan (Lunar Corporation, Madison, WI, USA). This total body scanner performs transverse scans at 1 cm intervals from head to toe, while the patient lies supine for ~20 min, projecting two beams of photon energy through the body. Because of a differential attenuation, the lean, fat, and bone tissue compartments can be studied separately. For a more precise assessment of the bone status, we also measured the femoral BMD (FBMD), and T- and Z-scores, using the DEXA scan, a widely applied, non-invasive, bone densitometric method, which results in exposure to minimal amounts of ionizing radiation.[19],[20] The total body composition of all study participants was evaluated, while BMD measurements of the femoral neck were made in 53 patients and 12 controls. The FBMD was also expressed as standardized T- and Z-scores, to compare measurements of individual bone density with those of young and age-matched normal subjects of the same gender. Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.[21],[22] According to the criteria defined by the World Health Organization, T-scores >2.5 standard deviations (SDs) below the mean represent osteoporosis, while scores between −1 and −2.5 SDs represent osteopenia or low bone mass.[21],[22]

Using the total body DEXA scan, apart from total body BMD (TBBMD), we also measured total body fat and lean tissue mass (expressed in g), as well as BMD, and lean and fat tissue for both arms, both legs, and the trunk separately.

Cardiovascular assessment

The New York Heart Association (NYHA) functional class was estimated at the time of initial evaluation. All study participants underwent transthoracic echocardiography. Cardiac catheterization was performed in 54 patients while on an optimal medical regimen during the initial evaluation. Exercise capacity was measured by the peak oxygen consumption (VO2) method during a symptom-limited, ramp incremental, treadmill cardiopulmonary exercise test. Peak VO2 was the mean oxygen uptake measured during the last 20 s of exercise.[23]

Blood tests

Venous blood was sampled in the morning, after an overnight fast. Serum sodium, calcium, phosphorus, albumin, creatinine, blood urea nitrogen, cholesterol, triglycerides, thyroid-stimulating hormone, haematocrit, and haemoglobin concentrations were measured. Brain natriuretic peptide (BNP) was measured immediately after the collection of the venous blood samples, using a Triage® analyser (BIOSITE, San Diego, CA, USA). The upper limit of normal concentration for this assay is 99 pg/mL. Intact PTH (1–84) was measured in pg/mL by a chemiluminescence immunometric assay (Advia Centaur Immunoassay System, Siemens, Bayer). The established normal range for this assay was 14–72 pg/mL. 25-Hydroxyvitamin D was also measured in nmol/L by an enzyme-linked immunosorbent assay (ELISA; Immunodiagnostic Systems, Bristol, UK). Since 25-hydroxyvitamin D levels are considered to be the most reliable parameter reflecting overall vitamin D status, values <50 nmol/L were used for vitamin D insufficiency diagnosis.

Study endpoints

The composite primary endpoint of the study was death, implantation of a left ventricular assist device (LVAD), or chronic administration of inotropes. This endpoint was ascertained at each follow-up visit.

Statistical analysis

Continuous variables are presented as means ± SD (median). The Kolmogorov–Smirnov test was used to assess distribution normality and the Student's t-test was used for comparisons when its underlying assumptions were not violated. For continuous variables not normally distributed, the Mann–Whitney test was used for comparisons. Correlations between variables were assessed using Pearson's or Spearman's correlation coefficient. The prognostic significance of variables was investigated by Cox regression analysis, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Receiver operator characteristics (ROC) curves were constructed to identify optimal discriminating prognostic thresholds. For all tests, a two-sided P-value <0.05 was considered significant.


Characteristics of the study groups

The CHF group comprised 31 men presenting with ischaemic and 29 with dilated cardiomyopathy, and the control group included 13 men presenting with hypertension. The median length of follow-up was 2 years. The baseline clinical and laboratory characteristics of the two groups are shown in Table 1, and the baseline characteristics of the CHF group divided into a group in NYHA functional classes I or II vs. classes III or IV are shown in Table 2.

Table 1. Baseline clinical and laboratory characteristics of the study groups
 CHF group (n = 60)Non-CHF group (n = 13)
  • aValues are means ± standard deviation.
  • *P < 0.05; all other between-groups differences are statistically non-significant.
  • cCHF, chronic heart failure.
Age, years57 ± 1157 ± 10
Body mass index, kg/m227.7 ± 4.328.1 ± 3.3
New York Heart Association functional class  
I15Not applicable
II15Not applicable
III16Not applicable
IV14Not applicable
Left ventricular ejection fraction, %26 ± 659 ± 4*
Serum concentrations  
Creatinine, mg/dL1.2 ± 0.30.8 ± 0.2*
Sodium, mEq/L139 ± 3141 ± 2
Calcium, mg/dL9.2 ± 0.69.3 ± 0.5
Phosphorus, mg/dL3.4 ± 0.52.8 ± 0.5*
Thyroid-stimulating hormone, µIU/mL2.6 ± 1.62.4 ± 0.4
Cholesterol, mg/dL169 ± 37223 ± 33*
Triglycerides, mg/dL125 ± 58167 ± 90
Albumin, mg/dL4.2 ± 0.54.4 ± 0.3
Haemoglobin, g/dL12.9 ± 1.414.6 ± 0.2
Table 2. Baseline characteristics of patients with mild/moderate vs. advanced/severe chronic heart failure
 New York Heart Association functional classP-value
 I or II (n = 30)III or IV (n = 30) 
  1. aValues are means ± standard deviation.
Dilated cardiomyopathy1217 
Ischaemic cardiomyopathy1813 
Left ventricular ejection fraction, %28 ± 724 ± 40.03
Peak VO2, mL/kg/min17.7 ± 511.5 ± 4<0.001
Pulmonary capillary wedge pressure, mmHg14 ± 923 ± 6<0.001
Cardiac index, mL/min2.2 ± 0.71.7 ± 0.40.01
Serum concentrations   
Brain natriuretic peptide, pg/mL478 ± 5581578 ± 1184<0.001
Creatinine, mg/dL1.1 ± 0.31.3 ± 0.30.03
Sodium, mg/dL140 ± 2138 ± 40.08
Albumin, g/dL4.4 ± 0.54.1 ± 0.50.07
Haemoglobin, g/dL13.4 ± 1.212.5 ± 1.40.01

Bone status and clinical indices

According to the criteria cited earlier, 12 patients (23%) in the CHF group suffered from osteoporosis, 27 (51%) from osteopenia, while 14 (26%) had normal femoral T-scores. No patient in the non-CHF group suffered from osteoporosis, 4 (31%) had osteopenia, and 9 (69%) had a normal bone status. The TBBMD (P = 0.001), FBMD (P = 0.006), T-score (P = 0.008), and Z-score (P = 0.004) were significantly lower in men with CHF. The bone densitometry data of the two study groups are shown in Table 3.

Table 3. Bone densitometry in the two study groups
 CHF group (n = 60)Non-CHF group (n = 13)P-value
  1. aValues are means ± standard deviation (medians).
  2. bCHF, chronic heart failure; NS, non-significant.
Bone mineral density, g/cm2   
Total1.214 ± 0.086 (1.220)1.300 ± 0.048 (1.308)0.001
Arms1.005 ± 0.106 (1.002)1.074 ± 0.072 (1.069)0.012
Legs1.339 ± 0.117 (1.338)1.454 ± 0.780 (1.460)0.001
Trunk0.961 ± 0.104 (0.958)1.014 ± 0.056 (1.017)0.067
Femur0.869 ± 0.147 (0.851)1.013 ± 0.137 (1.005)0.006
Femur score   
T−1.5 ± 1.2 (−1.7)−0.4 ± 0.9 (−0.7)0.008
Z−0.8 ± 1 (−1)+0.3 ± 1 (−0.2)0.004
Parathyroid hormone (pg/mL)111 ± 59 (103)39 ± 14 (41)<0.001
Vitamin D (nmol/L)53 ± 27 (48)63 ± 25 (57)NS

Patients in NYHA classes III–IV, compared with those in NYHA classes I–II, had significantly lower TBBMD (P = 0.004), FBMD (P = 0.008), T-score (P = 0.005), and Z-score (P = 0.02) (Table 4). We found significant, yet modest, correlations between NYHA functional class and (i) total body (r2 = 0.13, P = 0.004), arm (r2 = 0.19, P = 0.001), trunk (r2 = 0.10, P = 0.01), and femoral (r2 = 0.18, P = 0.003) BMD, and (ii) femoral T- (r2 = 0.20, P = 0.001) and Z- (r2 = 0.12, P = 0.01) scores. However, the bone densitometric measurements were not correlated with LVEF, BNP, peak VO2, pulmonary capillary wedge pressure, or cardiac index.

Table 4. Bone densitometry in mild to moderate vs advanced to severe chronic heart failure
 New York Heart Association functional classP-value
 I or II (n = 30)III or IV (n = 30) 
  1. aValues are means ± standard deviation (medians).
  2. bNS, non-significant.
Bone mineral density, g/cm2   
Total1.245 ± 0.070 (1.246)1.183 ± 0.092 (1.194)0.004
Arms1.047 ± 0.091 (1.038)0.962 ± 0.105 (0.965)0.001
Legs1.362 ± 0.098 (1.349)1.316 ± 0.130 (1.330)0.1
Trunk0.986 ± 0.095 (0.975)0.935 ± 0.107 (0.930)0.05
Femur0.925 ± 0.140 (0.929)0.819 ± 0.137 (0.818)0.008
Femur score   
T−1.1 ± 1.1 (−1)−1.9 ± 1.1 (−2)0.005
Z−0.3 ± 1.1 (−0.3)−1.1 ± 0.9 (−1.2)0.02
Parathyroid hormone (pg/mL)86 ± 31 (86)136 ± 69 (118)0.002
Vitamin D (nmol/L)60 ± 29 (56)47 ± 23 (42)NS

Lean and fat tissue mass measurements

The measurements of total body composition enabled the assessment of lean and fat tissue mass in the whole body and in the arms, legs, and trunk. The mean lean tissue mass in the arms of patients in NYHA functional classes III or IV was significantly lower (5970 ± 1400 g) than in that patients in functional classes I or II (7115 ± 1293 g; P = 0.002). Comparisons of lean tissue mass in other body parts between these two groups revealed similar trends, although the differences were not statistically significant. However, the decrease in lean tissue mass was correlated with decreased total body (r2 = 0.14, P = 0.001), arm (r2 = 0.07, P = 0.02), leg (r2 = 0.08, P = 0.02), and trunk (r2 = 0.20, P = 0.001) BMD. Similar trends were observed between BMD and fat tissue mass, though the only statistically significant relationship was with the trunk region (r2 = 0.12, P = 0.002).

Parathyroid hormone and vitamin D

Patients with CHF had significantly higher PTH levels compared with controls (P < 0.001), whereas vitamin D was lower in CHF patients, but the difference was not statistically significant (Table 3). Moreover, patients with advanced CHF (NYHA III–IV) demonstrated significantly higher PTH levels compared with those in NYHA classes I–II (P = 0.002) (Table 4, Figure 1A). In contrast, vitamin D levels were much lower in NYHA III–IV patients, but the difference did not reach statistical significance (Table 4). Vitamin D levels of patients in NYHA I–II were very close to those of the respective controls, but those of patients in NYHA III–IV were in the value range of vitamin D insufficiency (Table 4, Figure 1B). PTH levels were significantly correlated with NYHA class (r2 = 0.20, P < 0.0001), peak VO2 (r2 = 0.26, P < 0.0001) (Figure 2), wedge pressure (r2 = 0.20, P = 0.001), and cardiac index (r2 = 0.13, P = 0.01), but not with LVEF or BNP. Although vitamin D status was associated with the aforementioned clinical and laboratory parameters of CHF severity, the relationship was not significant. Finally, the increase in PTH levels was significantly correlated with the reduction of TBBMD (r2 = 0.12, P = 0.003), FBMD (r2 = 0.15, P = 0.002), and femoral T-score (r2 = 0.16; P = 0.001) (Figure 1A). Statistically significant correlations between vitamin D and bone densitometric parameters were not found, although a trend for association between vitamin D levels and FBMD and femoral T-score was identified.

Figure 1.

Figure 1. (A) Worsening heart failure is associated with higher parathyroid hormone (PTH) levels (columns) and lower femoral T-score (line). (B) PTH and vitamin D values in healthy subjects and heart failure patients according to New York Heart Association (NYHA) class

Figure 2.

Figure 2. High parathyroid hormone (PTH) levels are associated with low exercise capacity (VO2 peak) in chronic heart failure

Prognostic value of bone densitometry

During the median 2-year follow-up (August 2007–August 2009), (i) 11 patients died, of whom seven were in NYHA functional class IV, one was in class III, two were in class II, and one was in class I; (ii) LVADs were implanted in three patients in NYHA functional classes II, III, and IV, respectively; and (iii) five patients became inotrope dependent, of whom three were in NYHA functional class III and two were in class IV. Cox regression analysis identified low TBBMD (HR 0.003, 95% CI 0.00–0.58; P = 0.03) and femoral Z-score (HR 0.56, 95% CI 0.35–0.90; P = 0.0017) as significant predictors of death, LVAD implantation, or inotrope dependency. Neither PTH nor vitamin D had significant prognostic value in this patient cohort.


The main observations made in this study were: (i) TBBMD, FBMD, T-score, and Z-score are lower and PTH levels are higher in men suffering from CHF, compared with age-matched healthy subjects; (ii) TBBMD, FBMD, T-score and Z-score are significantly lower and PTH levels are significantly higher in patients in NYHA functional classes III or IV than in patients in functional classes I or II; (iii) increased PTH was correlated with NYHA class and haemodynamic indices of CHF severity, whereas reduced BMD was correlated solely with functional class; (iv) increased PTH levels were significantly associated with low BMD measurements; and (v) decreased TBBMD and femoral Z-score were associated with increased morbidity and mortality.

Chronic heart failure patients and particularly those in advanced stages demonstrate significant reduction in bone mass. Among multiple factors contributing to this reduction, secondary hyperparathyroidism may play a major role.[15],[18] Secondary hyperparathyroidism has been proposed as a principal mechanism in the pathogenesis of osteoporosis and hip fractures, while vitamin D deficiency may also contribute to these events.[24] Continuously high PTH serum levels accelerate bone turnover and bone catabolism, resulting in bone loss, especially of cortical bones such as the femur.[24] In CHF, the increased losses of urinary calcium and magnesium, due to long-term use of diuretics, the impaired absorption of these minerals and of vitamin D due to intestinal congestion, the decreased synthesis of 1,25-dihydroxyvitamin D secondary to liver congestion, renal insufficiency, and limited sunlight exposure, and finally the high aldosterone levels are all putative causes of secondary hyperparathyroidism.[10],[25],[26] Moreover, apart from stimulation of bone resorption, there is accumulating experimental evidence that PTH is a positive cardiac inotrope increasing heart rate and coronary blood flow.[27],[28] Therefore, secondary hyperparathyroidism may develop as a compensatory response to CHF.[15] Recent studies have reported an association of hyperparathyroidism with CHF,[9],[10],[25] as well as an association of reduced BMD with CHF[12],[13],[15],[18] or bone fracture risk and CHF.[5],[7],[29] In our study, hyperparathyroidism was correlated with both severity of heart failure and reduced bone density, implying that increased PTH levels in CHF might be an element of the underlying pathophysiological pathway leading patients to osteopenia or osteoporosis. To our knowledge, this is the first study where this association is so clearly demonstrated.

Although vitamin D levels were inversely correlated with PTH (Figure 1B), they were not associated with the reduction of BMD or severity of CHF. One possible explanation could be the fact that in CHF, hypovitaminosis D is only one component of the complex pathophysiological background of hyperparathyroidism. However, bone loss in heart failure is multifactorial. Many other hormonal changes, such as reduced testosterone,[12],[30] up-regulated pro-inflammatory mediators,[31] and other poorly identified mechanisms may contribute to bone resorption in CHF.

The decreased bone mass and BMD in the men included in our study was accompanied by a decrease in lean tissue mass of the whole body, as well as of the arms, legs, and trunk. A similar association, though mostly not statistically significant, was observed between BMD and fat tissue. These observations can lead to the assumption that decreased BMD may occur as part of general body wasting. Similar relationships between decreased bone densitometric measurements and a decrease in whole body or regional lean and fat tissue has also been described recently in men presenting with CHF.[12]

Last but not least, our study identified the predictive value of bone densitometry. Low TBBMD and femoral Z-scores were associated with high morbidity and mortality. This is consistent with the decreased bone mass observed in the advanced stages of CHF and in cachectic patients or transplant candidates, who are at high risk of dying.[13],[15],[32] To the best of our knowledge, the prognostic value of bone densitometry in CHF has not been described previously. Osteoporosis and bone fractures are an increasing problem in CHF, due to the growing prevalence of this syndrome and ageing of the population, and are related to increased morbidity, mortality, and cost for healthcare systems. In particular, BMD in the femur is easily and inexpensively obtained and provides the T-score (necessary for the diagnosis of osteopenia or osteoporosis) and Z-score, which could be used as an additional clinical prognostic tool in the management of CHF patients.

Study limitations

Our study was conducted at a single centre and enrolled a relatively small number of patients. Although our results are in agreement with previous observations, they need to be confirmed in a larger study, conducted at multiple centres, involving patients in different age groups, both sexes, and more ethnic backgrounds. The control group was also relatively small and no a priori power calculations were made in order to detect differences between CHF patients and control subjects. However, the principal aim of the study was to investigate the relationship of reduced bone density to the severity of CHF and its prognostic value. The bone densitometric measurements in the control group were, nevertheless, significantly higher, which is in agreement with the results of previous studies.[13],[18] Analyses of serum vitamin D were not controlled for seasonal variation, which may be considerable in our country. Finally, the pathophysiology of CHF and the pleiotropic effects of the applied therapies involve multiple complex processes that may potentially influence hormonal control of bone metabolism at several pathways. It was not possible to investigate all these interactions in this study. We identified a strong correlation of PTH levels with bone mass loss in CHF; however, other factors may also play a role in bone mass loss in CHF patients. A thorough investigation of all these potential contributors was beyond the scope of the present study.


CHF, particularly in advanced stages, is associated with an increased loss of bone mass and secondary hyperparathyroidism, a well-known predisposing factor for osteoporosis. Secondary hyperparathyroidism is a plausible candidate underlying the pathophysiological mechanism of reduced bone density observed in CHF patients. Total body BMD and femoral Z-score are significant predictors of prognosis in this patient population. Whether treating osteoporosis in patients suffering from CHF has positive effects on their quality of life and outcomes needs to be investigated in future studies.


The Hellenic Cardiological Society.

Conflict of interest: none declared.