Abstract
Context.
The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) is high.
Objective.
To analyze the role of NT-pro-BNP levels in the evaluation of diabetic patients with heart failure.
Design.
Retrospective comparative cohort study.
Subjects and Methods.
A total of 174 patients admitted to our Cardiology Department, previously diagnosed with HF, were enrolled. Among these patients, 47.7% had DM. HF was defined according to the 2016 ESC criteria. The NT-pro BNP levels above 126 pg/mL indicate a high probability of heart failure.
Results.
In diabetic patients there were significant correlations between NT-pro-BNP values and the following parameters: hemoglobin (rho=-0.28, p=0.01), hematocrit (rho= -0.27, p=0.014), total cholesterol (rho= -0.21, p=0.048), triglycerides (rho= -0.283, p=0.01), ejection fraction (rho= -0.465, p<0.0001), end-diastolic volume (rho= 0.253, p= 0.026), end-systolic volume (rho= 0.29 p=0.01). Only the following 3 parameters: ejection fraction (p= 0.0009), hemoglobin (p= 0.0092) and triglycerides (p= 0.0380) were independent predictive factors for elevated NT-pro-BNP values.
Conclusion.
In diabetic heart failure patients, the value of NT-pro-BNP holds a pivotal role in the evaluation of their overall status, facilitating the establishment of correct management and follow-up.
Keywords: NT-pro-BNP, diabetes mellitus, heart failure
INTRODUCTION
Diabetic patients have a high cardiovascular (CV) morbidity and mortality (1). The Framingham Heart Study showed that the presence of DM is associated with a fourfold increase in the odds of developing heart failure for women, and a twofold increase for males, irrespective of the presence of other CV risk factors (2). At the same time, 30% of patients diagnosed with symptomatic heart failure had DM preceding this cardiac complication (3). On the other hand, in patients admitted for decompensated HF this prevalence was even higher, at around 40-44% (4). The presence of heart failure in diabetic patients leads to a 40% increase in overall three-year mortality, being three times greater than for non-diabetic patients (5).
In the Studies of Left Ventricular Dysfunction (SOLVD) and Candesartan Heart Failure Assessment of Reduction (CHARM) Registries the overall risk of hospitalization for HF was higher in diabetic patients compared to non-diabetic ones (6, 7).
Nowadays we benefit from an array of biomarkers that hold prognostic value for heart failure patients (8). But the most studied is, by far, the N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), which is recommended by the current practice guidelines not only for the positive diagnosis of heart failure, but also for prognosis and treatment monitoring (8). There are few studies aiming to clarify the role of this neuro-hormone in diabetic patients. These have shown that in subjects with DM, NT-pro-BNP is a direct predictor of adverse outcome and cardiovascular mortality (9-11). In light of the above, this research aims to evaluate the role of NT-pro-BNP in a special category of patients, namely those with DM.
METHODS
A total of 174 patients admitted to the Cardiology Department of the Rehabilitation Hospital in Cluj-Napoca, Romania, previously diagnosed with symptomatic heart failure, NYHA class II-IV, were enrolled. All of these patients were hospitalized for decompensated heart failure, meaning they had clinical signs and symptoms of heart failure and an elevated NT pro-BNP value on admission. The mean age was 70.04±10.14 years, and 55.2% of the patients were women. Among our study subjects, 47.7% had known DM. The diagnostic criteria used for defining DM were the ones proposed in the 2017 American Diabetes Association guidelines, and included: fasting plasma glucose levels ≥126 mg/dL or 2-hour plasma glucose levels ≥200 mg/dL or random plasma glucose levels in a patient (with symptoms of hyperglycemia) ≥200 mg/dL (12).
HF was defined according to the 2016 ESC criteria (8). Patients were evaluated for additional cardiovascular risk factors, NT-pro-BNP levels were recorded and an echocardiographic study was also performed in all subjects. The EF was obtained by applying the modified Simpson’s method in the apical 4 and 2 chamber views of the left ventricle on 2D echo. A final percentage was obtained by calculating an arithmetic mean of the two initial values.
Circulating NT-proBNP concentration was determined from heparinized whole venous blood using the Roche Cardiac Reader POC (point of care) instrument. The pro-BNP cartridge used in this system enabled the measuring of NT-proBNP levels ranging between 60 and 3000 pg/mL. NT-proBNP levels were measured in all patients on the first day of admission. According to the ESC guidelines and the kit producer, it was deemed that NT-pro BNP levels above 125 pg/mL indicate a high probability of heart failure (8). NT-proBNP values < 125 pg/mL exclude cardiac dysfunction with a high level of certainty in patients with symptoms suggestive of heart failure (8).
All subjects included in the final analysis were consecutive patients admitted to our clinic for decompensated heart failure between March 2015 and April 2017.
Statistical analysis was carried out using SPSS for Windows (v 16.0, IBM Corporation, Armonk, NY, USA) and MedCalc (v 10.3.0.0, MedCalc Software, Ostend, Belgium) software programs. Normal or abnormal distribution was assessed using Kolmogorov–Smirnov test. For descriptive statistics, mean+/- standard deviation and median values are presented as numbers or percentages respectively. Comparative statistics was performed using Student and Mann–Whitney U tests and also χ2 test. For correlations, Pearson and Spearman coefficients were used. Univariate and multivariate analysis was performed in order to identify independent predictive factors. A p < 0.05 was considered statistically significant.
The selected patients were informed about the study protocol and gave their signed informed consent. The study was carried out in agreement with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.
RESULTS
The patients’ general characteristics are summarized in Table 1.
Table 1.
Patients’ characteristics
| Total | DM | Non DM | P | ||
|---|---|---|---|---|---|
| Number | 174 | 83(47.7%) | 91 (52.3%) | - | |
| Age | Mean±SD | 70.04±10.14 | 69.65±7.96 | 70.39±11.82 | NS |
| Women | No (%) | 96(55.2) | 44 (53.01%) | 52(57.14) | NS |
| Men | No (%) | 78(44.8) | 39(46.98) | 39 (42.85) | |
| NT-pro- BNP**- global pg/mL | Mean±SD (median) | 2848± 2867.10 (1573) | 2926±2906.38 (1590) | 2776.92 ±2845.01 (1523) | NS |
| NT-pro- BNP- women pg/mL | Mean±SD (median) | 2479.9±2669 (1296) | 2711± 2828 (1351) | 2284±2538 (1296) | NS |
| NT-pro- BNP men - pg/mL | Mean±SD (median) | 3302±3049 (1957) | 3170±3009 (1948) | 3433±3122 (2100) | NS |
| NYHA class | |||||
| II | No (%) | 67(38.5) | 33 (39.8) | 34 (37.4) | NS |
| III | 85(48.8) | 40 (48.2) | 45 (49.5) | NS | |
| IV | 22(12.6) | 10 (12) | 12 (13.2) | NS | |
| Ischemic heart disease | No (%) | 92(52.8) | 50 (60.24) | 42 (46.2) | 0.088 |
| Valvulopathies | 81(46.5) | 37(44.6) | 44 (48.4) | NS | |
| Cor pulmonale | 14(8.0) | 8 (9.87) | 6(6.6) | NS | |
| Toxic dilatative cardiomyopathy | 5(2.8) | 2 (2.40) | 3(3.3) | NS | |
| Other etiologies | 48(27.5) | 22 (26.5) | 26(28.6) | NS | |
| Hemoglobin g/dL | Mean±SD | 13.06±1.91 | 13.07±1.95 | 13.06 ±1.88 | NS |
| Total Chol. mg/dL | Mean±SD | 165.34 ± 45.37 | 163.98 ±4714 | 166.56±43.93 | NS |
| LDL – Chol. mg/dL | Mean±SD | 97.30 ±36.32 | 94.65 ±. 37.3 | 99.65±35.46 | NS |
| HDL - Chol. mg/dL | Mean±SD | 41.16± 12.38 | 37.86±11.20 | 44.13±12.71 | 0.0008 |
| Uric acid mg/dL | Mean±SD | 7.95 ± 2.84 | 8.6±2.92 | 7.38±2.66 | 0.004 |
| TG ** mg/dL | Mean±SD (median) | 138.83±73.53 (118) | 162.48±90.95 (136) | 117.52±43.8(108) | 0.0001 |
| Glycemia ** mg/dL | Mean±SD (median) | 121.36±46.13 (105) | 144.90 ± 56 (127) | 99.90 ± 15.83 (97) | <0.0001 |
| Hypertension | No (%) | 93 (47.7) | 62 (74.7) | 53(58.24) | 0.033 |
| Obesity | No (%) | 68 (39.08) | 40 (48.1) | 28 (30.7) | 0.028 |
| Ejection fraction ** – Global- % | Mean±SD (median) | 47.41±9.78 (50) | 45.43 ±9.73 (50) | 49.17 ± 9.53 (50) | 0.01 |
| Ejection fraction global interval – No (%) | <40 | 31(18.2) | 19(23.75) | 12(13.33) | 0.05 |
| 40-49 | 36(21.2) | 20(25) | 16(17.77) | ||
| >=50 | 103(60.6) | 41(51.25) | 62(68.88) | ||
| Ejection fraction women ** - % | Mean±SD (median) | 49.23±8.8 (50) | 47.83 ± 8.71 (50) | 50.41 ± 8.79 (50) | NS |
| Ejection fraction interval – No (%) | <40 | 13 (13.8) | 7(16.27) | 6(11.76) | NS |
| 40-49 | 14(14.9) | 8(18.6) | 6(11.76) | ||
| >=50 | 67(71.3) | 28(65.11) | 39(76.47) | ||
| Ejection fraction men **- % | Mean±SD (median) | 45.11 ±10.49 (45) | 42.64±10.22 (45) | 47.56 ±10.31 (50) | 0.04 |
| Ejection fraction interval – No (%) | <40 | 18(23.7) | 12(32.43) | 6 (15.38) | 0.08 |
| 40-49 | 22(28.9) | 12(32.43) | 10 (25.64) | ||
| >=50 | 36(47.4) | 13 (35.13) | 23 (58.97) | ||
| Diuretics | No (%) | 150(86.2) | 76(91.56) | 74(81.31) | 0.08 |
| Nitrates | No (%) | 78(44.8) | 43(51.8) | 35(38.46) | NS |
| ACEI | No (%) | 94(54) | 46(55.42) | 48(52.74) | NS |
| Beta blockers | No (%) | 129(74.1) | 70(84.33) | 59(64.83) | 0.005 |
| Antiplatelets | No (%) | 72(41.4) | 41(49.39) | 31(34.06) | 0.05 |
| Anticoagulant therapy | No (%) | 96(55.2) | 45(54.21) | 51(56.04) | NS |
| Sartans | No (%) | 30(17.2) | 17(20.48) | 13(14.28) | NS |
| Spironolactone/eplerenone | No (%) | 115(66.0) | 55 (66.26) | 60 (65.9) | NS |
| Statins | No (%) | 88(50.5) | 49 (59) | 39 (42.9) | 0.04 |
| Insulin | No (%) | 32(18.8) | 32 (38.55) | - | - |
| Oral antidiabetes drugs | No (%) | 51(30) | 51(61.44) | - | - |
**do not respect normality distribution.
Legend: NT-pro BNP: N-terminal pro-B-type natriuretic peptide; LDL-Chol.: low density lipoprotein cholesterol; HDL-Chol.: high density lipoprotein cholesterol; TG: Triglycerides.
There was no statistical difference between the two groups concerning gender distribution - women: 53.01% vs. 57.14 %, p=NS; men: 46.98 vs. 42.85%, p=NS.
We found no significant statistical difference in total cholesterol (163.98±47.14 vs. 166.56±43.93 mg/dL, p=NS) and LDL-cholesterol (94.65±37.3 vs. 99.65±35.46 mg/dL, p=NS) levels, but HDL-cholesterol values were significantly lower (37.86±11.20 vs. 44.13±12.71 mg/dL, p=0.0008), with triglycerides considerably higher (162.48±90.95 vs. 117.52±43.8 mg/dL, p=0.0001) in diabetic patients.
Patients with DM displayed significantly higher uric acid values (8.6±2.92 vs. 7.38±2.66 mg/dL, p=0.004) compared to non-diabetic ones. Spearman’s coefficient of rank correlation (rho) was: -0.132, p=0.2303 in diabetic patients and 0.0726, p=0.4932 in patients without diabetes.
However, uric acid levels were not influenced by NYHA class or the presence of renal failure (Table 2).
Table 2.
The correlation between uric acid and NT-pro-BNP in NYHA II-IV heart faiure patients with or without renal failure-- Spearman’s coefficient of rank correlation (rho)
| NYHA II | NYHA III | NYHA IV | ||
| Diabetic patients | With renal failure | Rho=0.527 p=0.1137 |
Rho= 0.148 p=0.6073 |
0.112 p=0.8231 |
| Without renal failure | 0.167 p=0.4347 |
0.205 p=0.2969 |
-0.354 p=0.4795 |
|
| Non-diabetic patients | With renal failure | Rho=0.3 p=0.5485 |
-0.212 p=0.5245 |
0.975 p=0.0513 |
| Without renal failure | 0.341 p=0.0885 |
0.296 p=0.0940 |
-0.516 p=0.2485 |
The mean NT-pro-BNP value for both groups was 2848±2867.10 pg/mL: 2926±2906.38 pg/mL in the patients with DM and 2776.92 ±2845.01 pg/mL in those without DM, p=NS.
The ejection fraction was significantly lower in diabetes patients: 45.43 ±9.73 vs. 49.17 ± 9.53%, p=0.01.
As a general remark, we found a significant negative correlation between NT-pro-BNP levels and ejection fraction, irrespective of glycemic status (r= -0.465, p<0.0001 vs. r= -0.349, p=0.0010), except for women without DM, where this correlation was lost: r=-0.437, p=0.0047 vs. r=-0.0597, p=NS; men: r=-0.455, p=0.0064 vs. r=-0.633, p=0.0001 (Table 3, Figs 1, 2). Moreover, we found that in patients with diabetes there is no correlation between the degree of diastolic dysfunction and NT pro-BNP values (atrial fibrillation subjects included): no diastolic dysfunction on echocardiography 2873.45±2928.37 pg/mL, atrial fibrillation patients-3933.80±3237.97 pg/mL, mild diastolic dysfunction-2175.88±2858.24 pg/mL and restrictive diastolic dysfunction-3718.60±3433.27 pg/mL (p=0.283). The same applies even if we merge the last three categories and compare them with subjects with normal diastolic function, p=0.137.
Figure 1.
Relationship between NT-pro-BNP and ejection fraction in diabetic heart failure patients.
Table 3.
Correlations between ejection fraction and NT-pro-BNP values in patients with DM vs. patients without DM - Spearman’s coefficient of rank correlation (rho)
| Heart failure patients | With diabetes | Without diabetes | |
|---|---|---|---|
| GLOBAL | -0.41 p<0.0001 |
-0.465 p<0.0001 |
-0.349 p=0.0010 |
| women | -0.239 p=0.0214 |
-0.437 p=0.0047 |
-0.0597 p=NS |
| men | -0.548 p<0.0001 |
-0.455 p=0.0064 |
-0.633 p=0.0001 |
Figure 2.
Relationship between NT-pro-BNP and ejection fraction in heart failure non-diabetic patients.
In order to establish the determinants of NT-pro-BNP values, uni- and multivariate analyses were performed in both groups (diabetic vs. nondiabetic patients).
Therefore, in diabetic patients there were significant correlations between NT-pro-BNP values and the following parameters: hemoglobin (rho=-0.28, p=0.01), haematocrit (rho= -0.27, p=0.014), total cholesterol (rho= -0.21, p=0.048), triglycerides (rho= -0.283, p=0.01), ejection fraction (rho= -0.465, p<0.0001), end-diastolic volume (rho= 0.253, p= 0.026), end-systolic volume (rho= 0.29 p=0.01).
Basically, by using the stepwise method for multivariate analysis, we found as independent predictive factors for elevated NT-pro-BNP values only the following 3 parameters: ejection fraction (p= 0.0009), hemoglobin (p= 0.0092) and triglycerides (p= 0.0380).
In the case of diabetic women, significant correlations were found between NT-pro-BNP values and: ejection fraction (rho= -0.437, p=0.0047), end-diastolic volume (rho= 0.295, p=0.05), end-systolic volume (rho= 0.334, p=0.034), hemoglobin (rho= -0.464, p=0.0023) and hematocrit (rho= -0.419, p=0.006) values.
There were two independent determinants of NT-pro-BNP values, those being ejection fraction (p=0.0075) and hemoglobin (p=0.04).
For diabetic men, on the other hand, NT-pro-BNP correlated well with ejection fraction (rho= -0.455, p=0.0064) and triglycerides (rho= -0.33, p=0.04), respectively, with only the former being an independent determinant at stepwise multivariate analysis.
Regarding patients with HF but without diabetes, univariate analysis demonstrated the existence of positive correlations between NT-pro-BNP and total cholesterol (rho= -0.407, p<0.001), LDL cholesterol (rho= -0.28, p=0.005), HDL cholesterol (rho= -0.315, p=0.0028), triglycerides (rho= -0.313, p=0.003), ejection fraction (rho= -0.349, p=0.001), end-diastolic volume (rho= 0.246, p=0.02) and end-systolic volume (rho= 0.363, p=0.0008) values.
When applying the stepwise multivariate analysis, only ejection fraction (p= 0.0237), end-systolic volume (p= 0.0050), total cholesterol (p= 0.0060) and LDL cholesterol (p= 0.0429) levels were found to be independent determinants of NT-pro-BNP values.
Non-diabetic women exhibited significant correlations between NT-pro- BNP levels and hemoglobin (rho= -0.279, p=0.04), hematocrit (rho= -0.275, p=0.049), total cholesterol (rho= -0.385, p=0.006), triglycerides (rho= -0.38, p=0.006), LDL cholesterol (rho= -0.278, p=0.047) and end-systolic volume (rho= 0.242, p=0.09), with only total cholesterol levels (p=0.017) and end-diastolic volume (p= 0.0089) proving to be independent determinants on multivariate analysis.
Non-diabetic men had a good correlation between NT-pro-BNP values and total cholesterol (rho= -0.34, p=0.031), HDL cholesterol (rho= -0.35, p=0.03), ejection fraction (rho= -0.63, p=0.0001) and end-systolic volume (rho= 0.475, p=0.004) levels.
As well as for their diabetic counterparts, they had only one independent determinant on multivariate stepwise analysis, that being ejection fraction (p <0.0001).
There was no difference concerning the prescription of various HF drug classes (diuretics: 91.56% vs. 81.31%, p=NS; mineralocorticoid receptor antagonists: 66.26% vs. 65.9%, p-NS; angiotensin converting enzyme inhibitors: 55.42% vs. 52.74%, p=NS; angiotensin receptor blockers: 20.% vs. 14.28%, p=NS), with the exception of beta-blockers, which were prescribed to a higher extent to patients with DM: 84.33 vs. 64.83%, p=0.005. At the same time, antiplatelets were prescribed more often in patients with DM, compared to those without DM: 49.39 vs. 34.06%, p=0.05. Also, statin therapy was used to a higher extent in diabetic patients: 59% vs. 39%, p=0.048. Table 4 shows the correlation between statin therapy and lipid levels in the two groups.
Table 4.
Correlation between statin therapy and lipid fractions
| Total-cholesterol (mg/dL) | HDL-cholesterol (mg/dL) | LDL-cholesterol (mg/dL) | |||
|---|---|---|---|---|---|
| Diabetes heart failure patients | Statins | + | 160.02±46.06 | 38.89±12.88 | 87.08±33.29 |
| - | 172.05±49.73 | 36.38±7.9 | 108.02±39.98 | ||
| p | NS | NS | p = 0.0112 | ||
| Non-diabetes heart failure patients | Statins | + | 170.66±42.54 | 45.02±10.66 | 100.38±33.97 |
| - | 163.48±45.11 | 43.46±14.11 | 99.11±36.85 | ||
| p | p = 0.44 | p = 0.5643 | NS |
DISCUSSION
Diabetic cardiomyopathy was first described by Ruben in 1972, during post-mortem examinations of 4 diabetic patients. Their hearts showed extensive myocardial hypertrophy and fibrosis, in the absence of other cardiovascular disease (13). Nowadays diabetic cardiomyopathy is defined as left ventricular dysfunction in diabetic patients without a history of hypertension, ischemic heart disease or significant valvular disease. The pathophysiological mechanism that leads to diabetic cardiomyopathy is still not fully understood. Factors like alteration in the lipid metabolism, with cardiac lipid accumulation, oxidative stress, mitochondrial dysfunction, inflammation and RAAS activation, have all been proven to play an important role in diabetic cardiomyopathy, eventually leading to hypertrophy, apoptosis and necrosis of the myocardium, which in turn leads to diastolic dysfunction (14.).
In our study the mean age of the subjects was 70.04±10.14 years, while the prevalence of DM was 47.7%. Other research reported a much lower prevalence of DM in patients aged over 65 years (around 22%) (15). Sitar Taut et al. reported in their study a mean age of 71.26 ± 9.14 for subjects with DM and HF (16).
Obviously, the natural evolution of HF and DM is to a greater extent influenced by the presence of other cardiovascular risk factors (hypertension, dyslipidemia, obesity, metabolic syndrome, etc.)(17).
Systemic arterial hypertension is frequently associated with the presence of diabetes. It seems like over 71% of diabetic patients have concomitant arterial hypertension, defined as ambulatory values greater than 140/85mmHg (18). In Romania this percentage is around 63% (19), given that the overall prevalence of hypertension is on the rise (20). The current study found a slightly higher prevalence of systemic arterial hypertension than the national average (74.7%). In general, a high percentage of diabetic individuals have associated obesity. In our country over 65% of diabetic patients are either overweight or obese (15). Weight loss, apart from improving the lipid profile, also lowers HbA1c values and reduces the risk of adverse CV events (21).
Concerning patients with HF, there is a growing debate about the so-called ‘obesity paradox’, which means that obese patients have a better long term prognosis and improved overall survival compared to normal weight patients (22). However, this theory does not seem to apply for patients with concomitant DM and HF (23). In our study 48.1% of diabetic patients were obese.
Dyslipidemia is another condition frequently encountered in diabetic patients. The association of multiple risk factors obviously leads to an increase in overall CV risk (24). In Romania, approximately 81% of patients with DM have concomitant dyslipidemia (19). We found no significant statistical difference in our study between total cholesterol and LDL-cholesterol values in the two groups. However, HDL-cholesterol values were significantly lower, while triglycerides were considerably higher in diabetic patients.
Basically, although patients with HF generally exhibit low serum lipids (as shown in Table 1), comparable to the ones seen in the general population, those with diabetes have lower HDL- cholesterol and higher TG levels. This must be integrated in the well known context of an overall lowering, through various pathological pathways, of total cholesterol, LDL- cholesterol and TG level, even in the absence of statin therapy, in symptomatic HF patients (25).
In our study patients with DM displayed significantly higher uric acid levels. There was an inverse association between plasma uric acid levels and ejection fraction, but statistical significance was lost when correlating with NT pro-BNP levels, NYHA class or the degree of renal failure.
However, recent studies suggest that type 2 diabetes mellitus prevalence seems to be increased in gouty patients (26). A series of prospective studies have demonstrated that high uric acid levels increase the risk of developing DM (27).
Therefore, we analyzed the association between the most important HF biomarker - NT-pro-BNP and other common cardiovascular risk factors, but also their relationship with left ventricular function. It is worth mentioning that even in diabetic individuals free of cardiovascular disease, NT-pro-BNP is still an accurate predictor of adverse cardiovascular events (28).
In that sense, it has been proven to hold a better predictive value than albuminuria (29). The PONTIAC trial showed that this neuropeptide can be utilized to identify diabetic patients who require primary prevention measures (30).
In our study there were no significant differences between the mean NT-pro-BNP values in patients with or without DM. We also found a significant inverse correlation between NT-pro-BNP values and ejection fraction, with the exception of diabetic women, where this association was present, but did not reach statistical significance.
In diabetic patients there were significant correlations between NT-pro-BNP values and those of hemoglobin, hematocrit, total cholesterol, triglycerides, but also between natriuretic peptides and certain echocardiographic parameters like end-diastolic volume and end-systolic volume of left ventricle.
Basically, we found ejection fraction, hemoglobin, and triglyceride level to be independent determinants for NT-pro-BNP values. Regarding patients with HF but without diabetes, our univariate analysis demonstrated the existence of a significant correlation between NT-pro-BNP values and those of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, ejection fraction, end-diastolic volume and end-systolic volume. Previous studies have shown an indirect correlation between NT-pro-BNP values and those of lipid fractions in patients with symptomatic HF (31).
A research published in 2015 demonstrated that even a low total cholesterol level on admission was a strong and independent predictor of BNP nonresponse in patients admitted with acute HF (32).
In our study, the stepwise multivariate analysis found in non-diabetic patients, as independent determinants of NT-pro-BNP, the levels of total and LDL- cholesterol, unlike diabetic subjects where triglycerides level is also a determinant factor. To our knowledge, there is no published research analyzing this relationship in patients with diabetes and HF. The drop in serum lipids observed in HF patients might be explained through various mechanisms: hepatic congestion, systemic inflammation, intestinal endotoxin translocation, and increased levels of TNFα, IL-6, IL-1, plus those of soluble receptors of TNF α- sTNFR-I and sTNFR-II (33).
The same chronic inflammatory state, as mentioned above, was associated with reduced erythropoietin synthesis, iron deficiency and hemodilution, all of which are responsible for anemia in chronic HF patients (34). The prevalence of anemia in HF patients is 30-50%, depending on NYHA class, compared to <10 % in patients without HF, and is associated with worse outcomes and a poor clinical status (35).
As reported by other studies, we found an inverse correlation between NT- pro-BNP values and EF, irrespective of glycemic status (with the exception of non-diabetic women, as mentioned before) (36).
At the same time, decreasing NT-pro-BNP values may be an important parameter for monitoring the increase in exercise capacity in heart failure patients (37).
DM is present in about 30% of patients with HF and a preserved EF (38). The association between the two comorbidities is constantly growing due to the ageing of the general population. At the same time, the relationship between DM and HF is bidirectional, each condition increasing the risk for developing the other. In this study the mean EF in diabetic patients with HF was 42.64 ±10.22%, significantly lower than that of patients without DM. Of course, it is well known that diastolic dysfunction leads to elevated end-diastolic pressures in the LV, which increases the left atrial pressure and predisposes to atrial fibrillation. This is the reason why, in general, patients with atrial fibrillation tend to have higher NT pro-BNP values than the ones in sinus rhythm (16).
In our study, there was no difference regarding prescription of HF medication (diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers), with the exception of beta-blockers, antiplatelet agents and statins, which, as mentioned before, were prescribed to a greater extent in patients with DM. Diabetic patients on previous statin treatment had significantly lower LDL-cholesterol levels, with mean values close to guideline recommended targets (<70 mg/dL)(12).
Regarding diabetes treatment, in our study 38.55% of the patients were receiving insulin therapy and 61.44% were on oral anti-diabetic agents. In patients with HF and DM the administration of metformin is preferred for glycemic control. However, this drug is contraindicated in cases of severe renal or hepatic impairment (39).
Sulfonylureas may worsen HF symptoms, that is why their administration in HF diabetics should be closely monitored. Insulin therapy is prescribed not only for type I diabetes, but also in type II for symptomatic management of hyperglycemia (8).
Regarding natriuretic peptides use in DM subjects, our study shows that NT-pro BNP has the same diagnostic and predictive value in diabetic patients with heart failure as in non-diabetic ones. It should be an important diagnostic and stratification tool in this category of patients, and the glycemic status of the patient does not alter that. Basically, heart failure is a consequence of structural cardiac abnormalities, irrespective of their nature. The same is true for diabetics. The causes of their heart failure may be particular, but the diagnosis and management is the same as for non-diabetic patients.
In conclusion, although NT pro-BNP values were not significantly different in diabetic patients compared to non-diabetics, this biomarker still holds a pivotal role in the evaluation of subjects with heart failure and DM, facilitating the establishment of correct management and follow-up.
Conflict of interest
The authors declare that they have no conflict of interest.
References
- 1.Domanski M, Krause-Steinrauf H, Deedwania P, Follmann D, Ghali JK, Gilbert E, Haffner S, Katz R, Lindenfeld J, Lowes BD, Martin W, McGrew F, Bristow MR, BEST Investigators The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol. 2003;42:914–922. doi: 10.1016/s0735-1097(03)00856-8. [DOI] [PubMed] [Google Scholar]
- 2.Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–2038. doi: 10.1001/jama.241.19.2035. [DOI] [PubMed] [Google Scholar]
- 3.MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, Aguilar D, Krum H, McMurray JJ. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J. 2008;29:1224–1240. doi: 10.1093/eurheartj/ehn156. [DOI] [PubMed] [Google Scholar]
- 4.Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:209–216. doi: 10.1016/j.ahj.2004.08.005. [DOI] [PubMed] [Google Scholar]
- 5.Cubbon RM, Adams B, Rajwani A, Mercer BN, Patel PA, Gherardi G, Gale CP, Batin PD, Ajjan R, Kearney L, Wheatcroft SB, Sapsford RJ, Witte KK, Kearney MT. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res. 2013;10:330–336. doi: 10.1177/1479164112471064. [DOI] [PubMed] [Google Scholar]
- 6.Shindler DM, Kostis JB, Yusuf S, Quinones MA, Pitt B, Stewart D, Pinkett T, Ghali JK, Wilson AC. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol. 1996;77:1017–1020. doi: 10.1016/s0002-9149(97)89163-1. [DOI] [PubMed] [Google Scholar]
- 7.MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, Solomon SD, Granger CB, Swedberg K, Yusuf S, Pfeffer MA, McMurray JJ CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29:1377–1385. doi: 10.1093/eurheartj/ehn153. [DOI] [PubMed] [Google Scholar]
- 8.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P Authors/Task Force Members; Document Reviewers. 2016. 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. Eur Heart J. 2016;37:2129–2200. doi: 10.1093/eurheartj/ehw128. [DOI] [PubMed] [Google Scholar]
- 9.Retnakaran R. Novel Biomarkers for Predicting Cardiovascular Disease in Patients With Diabetes. Can J Cardiol. 2018;34(5):624–631. doi: 10.1016/j.cjca.2017.10.017. [DOI] [PubMed] [Google Scholar]
- 10.Bhalla MA, Chiang A, Epshteyn VA, Kazanegra R, Bhalla V, Clopton P, Krishnaswamy P, Morrison LK, Chiu A, Gardetto N, Mudaliar S, Edelman SV, Henry RR, Maisel AS. Prognostic role of B-type natriuretic peptide levels in patients with type 2 diabetes mellitus. J Am Coll Cardiol. 2004;44:1047–105. doi: 10.1016/j.jacc.2004.05.071. [DOI] [PubMed] [Google Scholar]
- 11.Tarnow L, Gall MA, Hansen BV, Hovind P, Parving HH. Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes. Diabetologia. 2006;49:2256–2262. doi: 10.1007/s00125-006-0359-4. [DOI] [PubMed] [Google Scholar]
- 12.Marathe PH, Gao HX, Close KL. American Diabetes Association Standards of Medical Care in Diabetes 2017. J Diabetes. 2017;9(4):320–324. doi: 10.1111/1753-0407.12524. [DOI] [PubMed] [Google Scholar]
- 13.Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Failure Reviews. 2013;18(2):149–166. doi: 10.1007/s10741-012-9313-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Seferović P, Milinković I, Ristić A, Mitrović JS, Lalić K, Jotić A. Diabetic cardiomyopathy: Ongoing controversies in 2012. Herz. 2013;8:880–886. doi: 10.1007/s00059-012-3720-z. [DOI] [PubMed] [Google Scholar]
- 15.Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes. Care. 2004;27:699–703. doi: 10.2337/diacare.27.3.699. [DOI] [PubMed] [Google Scholar]
- 16.Sitar Taut AV, Pop D, Zdrenghea DT. NT-proBNP values in elderly heart failure patients with atrial fibrillation and diabetes. J Diabetes Complications. 2015;29(8):1119–1123. doi: 10.1016/j.jdiacomp.2015.08.013. [DOI] [PubMed] [Google Scholar]
- 17.Bozkurt B, Aguilar D, Deswal A, Dunbar S, Francis G. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134(23):e535–e578. doi: 10.1161/CIR.0000000000000450. [DOI] [PubMed] [Google Scholar]
- 18.National Diabetes Statistics Report 2017 [cited 30 November 2017]. Available from: http://www.cdc.gov/diabetes/data/statistics/2014StatisticsReport.html.
- 19.Moţa M, Popa SG, Mota E, Mitrea A, Catrinoiu D, Cheta DM, Guja C, Hancu N, Ionescu-Tirgoviste C, Lichiardopol R, Mihai BM, Popa AR, Zetu C, Bala CG, Roman G, Serafinceanu C, Serban V, Timar R, Veresiu IA, Vlad AR. Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study. J Diabetes. 2016;8(3):336–344. doi: 10.1111/1753-0407.12297. [DOI] [PubMed] [Google Scholar]
- 20.Darabonţ R, Tautu OF, Pop D, Fruntelată A, Deaconu A, Onciul S, Salaru D, Micoara A, Dorobantu M. Visit-to-Visit Blood Pressure Variability and Arterial Stiffness Independently Predict Cardiovascular Risk Category in a General Population: Results from the SEPHAR II Study. Hellenic J Cardiol. 2015;56(3):208–216. [PubMed] [Google Scholar]
- 21.Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L, Look AHEAD Research Group Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes.. Diabetes Care. 2011;34:1481–1486. doi: 10.2337/dc10-2415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lavie CJ, De Schutter A, Parto P, Jahangir E, Kokkinos P, Ortega FB, Arena R, Milani RV. Obesity and Prevalence of Cardiovascular Diseases and Prognosis-The Obesity Paradox Updated. Prog Cardiovasc Dis. 2016;58(5):537–547. doi: 10.1016/j.pcad.2016.01.008. [DOI] [PubMed] [Google Scholar]
- 23.Lee KS, Moser DK, Lennie TA, Pelter MM, Nesbitt T, Southard JA, Dracup K. Obesity Paradox: Comparison of Heart Failure Patients With and Without Comorbid Diabetes. Am J Crit Care. 2017;26(2):140–148. doi: 10.4037/ajcc2017634. [DOI] [PubMed] [Google Scholar]
- 24.Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol. 2014;2(8):634–647. doi: 10.1016/S2213-8587(14)70102-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Greene SJ, Vaduganathan M, Lupi L, Ambrosy AP, Mentz RJ, Konstam MA, Nodari S, Subacius HP, Fonarow GC, Bonow RO, Gheorghiade M. Prognostic significance of serum total cholesterol and triglyceride levels in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial). Am J Cardiol. 2013;111(4):574–581. doi: 10.1016/j.amjcard.2012.10.042. [DOI] [PubMed] [Google Scholar]
- 26.Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Medicine. 2017;15(1):123. doi: 10.1186/s12916-017-0890-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Rho YH, Lu N, Peloquin CE, Man A, Zhu Y, Zhang Y, Choi HK. Independent impact of gout on the risk of diabetes mellitus among women and men: a population-based, BMI-matched cohort study. Ann Rheum Dis. 2016;75(1):91–95. doi: 10.1136/annrheumdis-2014-205827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Saeed A, Ballantyne CM. Assessing Cardiovascular Risk and Testing in Type 2 Diabetes. Curr Cardiol Rep. 2017;3:19. doi: 10.1007/s11886-017-0831-4. [DOI] [PubMed] [Google Scholar]
- 29.Clodi M, Resl M, Neuhold S, Hülsmann M, Vila G, Elhenicky M, Strunk G, Abrahamian H, Prager R, Luger A, Pacher R. A comparison of NT-proBNP and albuminuria for predicting cardiac events in patients with diabetes mellitus. Eur J Prev Cardiol. 2012;19(5):944–951. doi: 10.1177/1741826711420015. [DOI] [PubMed] [Google Scholar]
- 30.Huelsmann M, Neuhold S, Resl M, Strunk G, Brath H, Francesconi C, Adlbrecht C, Prager R, Luger A, Pacher R, Clodi M. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol. 2013;62(15):1365–1372. doi: 10.1016/j.jacc.2013.05.069. [DOI] [PubMed] [Google Scholar]
- 31.Yoon CH, Youn TJ, Ahn S, Choi DJ, Cho GY, Chae IH, Cho H, Han S, Cho MC, Jeon ES, Chae SC, Kim JJ, Ryu KH, Oh BH, Korean Heart Failure Registry Low serum total cholesterol level is a surrogate marker, but not a risk factor, for poor outcome in patients hospitalized with acute heart failure: a report from the Korean Heart Failure Registry. J Card Fail. 2012;18(3):194–201. doi: 10.1016/j.cardfail.2011.12.006. [DOI] [PubMed] [Google Scholar]
- 32.Ribeiro A, Lourenço P, Silva S, Cunha F, Vilaça J, Gomes F, Araújo JP, Bettencourt P. Predictors of natriuretic peptide non-response in patients hospitalized with acute heart failure. Am J Cardiol. 2015;115(1):69–74. doi: 10.1016/j.amjcard.2014.09.053. [DOI] [PubMed] [Google Scholar]
- 33.Sandek A, Bjarnason I, Volk HD, Crane R, Meddings JB, Niebauer J, Kalra PR, Buhner S, Herrmann R. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int J Cardiol. 2012;157(1):80–85. doi: 10.1016/j.ijcard.2010.12.016. [DOI] [PubMed] [Google Scholar]
- 34.Anand IS, Gupta P. Anemia and Iron Deficiency in Heart Failure. Circulation. 2018;138(1):80–98. doi: 10.1161/CIRCULATIONAHA.118.030099. [DOI] [PubMed] [Google Scholar]
- 35.Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790:682–693. doi: 10.1016/j.bbagen.2008.08.006. [DOI] [PubMed] [Google Scholar]
- 36.Peng Q, Hu W, Su H, Yang Q, Cheng X. Levels of B-type natriuretic peptide in chronic heart failure patients with and without diabetes mellitus. Exp Ther Med. 2013;1:229–232. doi: 10.3892/etm.2012.760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Zdrenghea DT, Ilea M, Zdrenghea M, Sitar-Tăut AV, Pop D. The Effect of Maximal and Submaximal Exercise Testing on NT-pro-BNP Levels in Patients with Systolic Heart Failure. Revista Română de Medicină de Laborator. 2014;22:25–33. [Google Scholar]
- 38.Lund LH, Donal E, Oger E, Hage C, Persson H, Haugen-Lofman I, Ennezat PV, Sportouch-Dukhan C, Drouet E, Daubert JC, Linde C KaRen Investigators. Association between cardiovascular vs. non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014;16:992–1001. doi: 10.1002/ejhf.137. [DOI] [PubMed] [Google Scholar]
- 39.MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS, Petrie M.C., McMurray J, Petrie JR, McAlister F. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database. Diabetes Care. 2010;33:1213–1218. doi: 10.2337/dc09-2227. [DOI] [PMC free article] [PubMed] [Google Scholar]