The association between metabolic syndrome and its components and heart failure in patients referred to a primary care facility

Abstracts

FUNDAMENTO: A síndrome metabólica (SM) caracteriza-se por um conjunto de fatores de risco que, quando presentes, se associam a elevadas taxas de eventos cardiovasculares, como também a risco de insuficiência cardíaca (IC). Em nosso meio, não está estabelecida a associação da SM nos pacientes portadores de IC crônica estável. OBJETIVO: Determinar, em pacientes encaminhados da Atenção Primária, a prevalência de SM, segundo o sexo e o tipo de IC. MÉTODOS: De janeiro de 2005 a agosto de 2006, 144 pacientes foram incluídos em um estudo transversal. A ecocardiografia, por meio de critérios modificados no estudo EPICA, foi utilizada para definir o tipo de IC, como também sua presença ou ausência. A análise estatística foi processada pelo software SAS® System, versão 6.04, sendo adotado o nível de significância de 5%. RESULTADOS: SM foi observada em 111 pacientes (77%), dos quais 73 (66%) eram do sexo feminino (razão de chance [RC] de 0,195; intervalo de confiança = 0,08-0,46; p < 0,0001). IC foi identificada em 102 pacientes (71%), com o sexo feminino apresentando grande correlação com a presença de SM: 51 pacientes (65%) (RC de 0,116; intervalo de confiança = 0,36-0,37; p < 0,0001). Entre os portadores de IC, 61 pacientes (42%) apresentavam IC com função sistólica preservada e 41 (29%), IC com disfunção sistólica (p = ns). IC com função sistólica preservada foi associada à presença de SM em 53 (87%) dos 61 pacientes (p = 0,022). CONCLUSÃO: A SM está fortemente associada à presença de IC com função sistólica preservada e ao sexo feminino em nossa comunidade.

Síndrome metabólica; insuficiência cardíaca; baixo débito cardíaco; atenção primária à saúde; mulheres

ORIGINAL ARTICLE

The association between metabolic syndrome and its components and heart failure in patients referred to a primary care facility

Flávio Augusto Colucci Coelho; Marco Aurélio Espósito Moutinho; Verônica Alcooforado de Miranda; Leandro Reis Tavares; Maurício Rachid; Maria Luiza Garcia Rosa; Evandro Tinoco Mesquita

Hospital Universitário Antônio Pedro (HUAP), Departamento de Pós-Graduação em Ciências Cardiovasculares da Universidade Federal Fluminense (UFF) - Niterói, RJ - Brazil

^{Mailing address}

SUMMARY

BACKGROUND: Metabolic syndrome (MS) is characterized by a collection of risk factors that are associated with elevated rates of cardiovascular events and the risk of developing heart failure (HF). In our field, the association of MS in stable chronic HF patients has not been established.

OBJECTIVE: To determine the prevalence of MS in relation to gender and HF type in patients treated at a Primary Care Facility.

METHODS: Between January 2005 and August 2006, 144 patients were included in a cross sectional study. An echocardiogram, using the modified criteria of the EPICA study, was performed to determine whether or not the patient had HF, and of which type. Statistical analysis was conducted using the software SAS™ System, version 6.04, and statistical significance was established as 5%.

RESULTS: MS was observed in 111 patients (77%), of which 73 (66%) were females: odds ratio (OR) 0.195 – (confidence interval - CI = 0.08 – 0.46) and p< 0.0001. HF was identified in 102 patients (71%) with a great correlation between females and the presence of MS: 51 patients (65%); OR 0.116 (CI = 0.36 – 0.37) and p < 0.0001. Among the HF patients, 61 (42%) presented HF with preserved systolic function and 41 (29%) with systolic dysfunction; p= ns. HF with preserved systolic function was associated with the presence of MS in 53 (87%) of the 61 patients, p = 0.022.

CONCLUSION: In our community, MS is closely related to HF with preserved systolic function and to the female gender.

Key words: Metabolic syndrome; heart failure; cardiac output, low; primary health care; women.

Introduction

Metabolic Syndrome (MS) is characterized by a cluster of risk factors such as, elevated waist circumference, systemic hypertension (SH), hyperglycemia, insulin resistance and dyslipidemia (reduced HDL and elevated triglyceride levels). The presence of this cluster of factors is associated with elevated rates of cardiovascular events: sudden death, acute myocardial infarction (AMI) and encephalic stroke as well as a higher risk to develop diabetes mellitus (DM)^1-4.

In different adult populations, an elevated prevalence of MS is observed that ranges from 25 to 35%^5,6, and it is more common in women. Different criteria have been used to diagnose MS including those of WHO (World Health Organization)⁷, NCEP-ATP III (National Cholesterol Education Program Panel III)⁸ and more recently the criteria of IDF (International Diabetes Federation)^7-9.

Ever increasing amounts of solid epidemiological proof indicate an association between MS and the presence of cardiovascular alterations. Recently, a greater risk of the onset of heart failure (HF) was identified, particularly in middle aged and elderly men^1-4.

In our community, the prevalence of MS and its components in HF patients and differences in relation to gender have not yet been established.

Methods

Between January 2005 and August 2006, 150 patients were included in a cross sectional study involving patients with clinical suspicion of HF treated by the Family Medical Program (FMP). The patients were referred to a specialized HF outpatient clinic for diagnostic confirmation of HF by means of clinical criteria and echocardiography (ECHO). The population sample of HF patients was estimated at 100 patients based on the population of 100,000 patients treated by FMP and a HF prevalence of 1% to 2% for the overall population in accordance with data from the Framingham study¹⁰.

Inclusion criteria - Patients with suspected HF – presence of dyspnea, fatigue or edema in the lower limbs or asymptomatic patients using digitalis and/or ACE inhibitors and/or diuretics. All patients had to be over the age of 18 and referred by the FMP.

Exclusion criteria - Lack of required data for analysis of the presence of MS (Laboratory tests) or HF (echocardiography) and other types of HF that did not include: HF with preserved systolic function or HF with systolic dysfunction. The M-mode or two dimensional transthoracic echocardiogram, in accordance with the modified criteria of the EPICA study for community HF patients¹¹, was used to determine whether or not the patient had HF and its type. The HF patients were identified according to the functional and structural alterations evaluated on the ECHO.

Structural alterations evaluated on the echocardiogram - 1) LV fractional shortening < 28%; 2) significant segment alterations associated with LV dilation; 3) LV mass index > 134 g/m² in males and > 110 g/m² in females; 4) hypertrophy of the interventricular septum and LV posterior wall according to the parameters for age and gender; 5) increased LA (left atrium) diameter according to the parameters for age and gender; 6) moderate to severe valve lesions of rheumatic origin; 7) moderate to severe pericardial hemorrhage; 8) RV dilation.

Structural alterations that determined HF type - 1) fractional shortening < 28% or the presence of significant segment alterations associated with LV dilation; - classified as HF with systolic dysfunction; 2) fractional shortening > 28% with no segment alteration, however with the presence of increased LA, or LV mass index (differentiated by gender), or hypertrophy of the interventricular septum or LV posterior wall; - classified as HF with preserved systolic function.

Upon admission to the study, the patients were clinically assessed and underwent PA and left lateral view chest x-rays, 12 lead ECG and the following biochemical tests: 1) fasting glucose; 2) triglycerides; 3) HDL cholesterol for composition of the MS criteria.

Determination of the MS components in accordance with the NCEP-ATP III criterium was performed using the following values: 1) Waist circumference > 102cm for males and 88cm for females; 2) Triglycerides >150mg/dl; 3) HDL-c < 40mg/dl for males and < 50mg/dl for females; 4) SBP >130X85mmHg and 5) blood glucose level >110mg/dl; and in accordance with the IDF criterium: 1) Waist circumference >94cm for males and 80cm for females; 2) Triglycerides >150mg/dl, 3) HDL-c < 40mg/dl for males and < 50mg/dl for females; 4) SBP >130X80mmHg and 5) blood glucose level >100mg/dl.

The use of hypoglycemic or antihypertensive medication was designated as a positive criterium. MS was confirmed by the NCEP ATP III criterium when three of the five possible components were present⁷. MS confirmation using the IDF components required an alteration in waist circumference along with two other alterations^8,9. DM was determined by glucose levels >126 mg% and insulin resistance by glucose values between 100 and 125 mg%.

The variables evaluated in this model were: age, gender, blood pressure, waist circumference, blood glucose level, HDL, TG, BMI as well as the ECHO data to determine whether or not the patient had HF and of which type. The study was approved by the Research Ethics Committee at the Medical School of the Federal Fluminense University. All patients signed a free and informed consent form to participate in the study.

Statistical analysis - Mean value difference was calculated using the Student's t-test to estimate the association between the presence of HF with MS. Proportion differences and the prevalence odds ratio were calculated using the chi-square test (c2). Statistical significance was established as 5%. Statistical analysis was performed using the software program SAS® System, version 6.04.

Results

The clinical and metabolic characteristics of the patients included in the study that were referred to the Primary Care Clinic with suspected HF are shown in table 1. From the sample of 150 patients, six were excluded due to moderate to severe valve disease. The study involved 144 patients of which 82 (57%) were females. No statistical differences were observed in relation to mean age or gender for this group.

A higher incidence of MS was observed using the IDF diagnostic criterium, and was diagnosed in 103 patients (72%), of which 69 (67%) were females; p < 0.0001. Using the NCEP-ATP III criterium, 65 patients (70%) were females; p < 0.0001.

HF was confirmed by the echocardigraphic criteria in 102 patients (71%) and there was a higher incidence of HF with preserved systolic functionin 61 patients (42%); p = ns.

No significant differences were found between the MS components and gender when the mean value of the measurements that determined the presence of MS was used. The only exception was BMI that was higher in the female group; p = 0.032; (Table 1).

No statistical significance was found in relation to age, gender, or incidence of MS components when analyzing whether or not the patients had HF. However, the HF patients had a greater incidence of insulin resistance syndrome; p = 0.07 and DM; p = 0.09; (Table 2).

Characterization of MS in relation to HF type revealed a greater incidence of HF with preserved systolic function; odds ratio (OR) 3.82 – confidence interval (CI) 1.4 to 10 and p = 0.005. The most prevalent MS components associated with HF with preserved systolic function were: SBP, DBP, waist circumference (IDF and NCEP ATP III criterium), triglycerides and BMI.

The presence of MS was determined using the mean values of the MS components. In relation to HF type, the greatest component association was found in the HF group with preserved systolic function with the presence of 3.6 ± 1.0 components (IDF criterium), p = 0.009 and 3.2 ± 1.1 components (NCEP-ATP III criterium), p = 0.017; (Table 3).

Evaluation of the prevalence of MS, using both criteria (NCEP and IDF), the presence of MS associated with HF was found in 79 patients (78%). A significant correlation was found in both groups between HF type, IDF and NCEP criteria, of which HF with preserved systolic function had greater prevalence with both the NCEP (p = 0.020) and IDF criteria (p = 0.010). The MS prevalence was 49 patients (80%) for HF with preserved systolic function and 22 patients (54%) for HF with systolic dysfunction in accordance with the IDF criterium. Using the NCEP-ATP III criterium, MS prevalence was 47 patients (77%) for HF with preserved systolic function and 21 patients (51%) for HF with systolic dysfunction; (Graphics 1, 2 and 3).

Evaluation of the association between HF and MS by gender indicated that women with HF are 8 times more likely to present MS than men in accordance with both the NCEP and/or IDF criteria; OR 0.116 - CI 0.36 – 0.37 and p< 0.0001, (Table 4).

Discussion

This study, the first to evaluate the presence of MS in stable chronic HF patients treated in Primary Care facilities in Brazil, identified an elevated prevalence of MS and HF in these patients. The presence of MS in this scenario was identified using the NCEP-ATP III criteria and the new determinations of IDF. We found a greater frequency of MS in females (70% and 67%, respectively), using the NCEP-ATP III and IDF criteria. HF with preserved systolic function had a greater association with MS and was also more prevalent in females.

The significant association between the presence of MS and the female gender, as demonstrated in earlier studies^12,13, could be indirectly correlated to the alterations presented, such as elevated triglycerides (53%), abdominal adiposity, SH (94%) and elevation of BMI (46%), that are inherent characteristics of females like hormonal alterations. Therefore, these factors could represent the decisive alterations in our case study to justify the presence of HF with preserved systolic function in females, determining the possible structural alterations presented on the ECHO; this was the link in the correlation found in our study between the presence of HF with preserved systolic function and the female gender.

Recently, MS has been identified as an independent risk factor for the onset of HF^1-4,14. The possible mechanisms associated with MS that cause HF are still speculative. Nevertheless, evidence suggests that the damage to cardiac cellular integrity caused by MS can favor the development of HF. Just as the stimulating effect of insulin on the myocardium of mice leads to increased cardiac mass and consequent reduction of cardiac output¹⁵, hyper stimulation of the sympathetic nervous system, caused by hyperinsulinemia, as well as its ability to promote fibroblast activation in hypertensive patients, causing LV hypertrophy, increases the production of collagen and fibrosis¹⁶. This collection of actions causes disease progression and greater mortality.

HF is regarded as an emerging cardiovascular epidemic whose increase is directly related to population growth as well as the alarming increase in conditions that favor its onset, in particular the MS components - DM, SH, Dyslipidemia and Obesity¹⁷. Therefore, it is of utmost importance to identify HF risk factors that can be modified in order to enable adequate intervention.

Visceral obesity, another factor correlated to MS, develops its aggressive role on the myocardium through the production of substances with cardiovascular and systemic actions,such as leptin, inflammatory cytokines (interleukins and tumor necrosis factor), plasminogen activator inhibitor-1 (PAI-1) and free fatty acids in addition to promoting a reduction of adiponectin¹⁸. Therefore, the loss of the protective vascular action generated by the reduction of the adiponectin levels^19,20, in conjunction with the inflammatory and prothrombotic action determines the substrate that will jeopardize the cardiovascular system.

Current concepts confirm that the physiopathlogy of HF is distinct in relation to gender and HF type^12,13. In these studies, it is confirmed that HF with preserved systolic function is predominately associated with females, advanced age and a lower incidence of ischemic heart disease²¹. This fact correlates with data throughout the world as demonstrated by Rodrigues-Artalejo et al²² where the number of female deaths increased between 1980-2000. This is an important fact that demonstrates nonconformity in relation to HF treatment for females.

Data from the EPICA study¹¹, that evaluated HF patients in a community, confirmed that HF in females occurs at a more advanced age and heart failure with preserved systolic function is more predominant.

Kenchaiah et al²³ demonstrated that the HF risk when related to an increase of one BMI unit is 5% for men and 7% for women and that when comparing the incidence of HF between obese and non-obese individuals this same increase doubles the risk which is higher for women – 2.12 (females) / 1.90 (males). Other studies²⁴ suggest that the female hormones affect heart function by means of estrogen-induced vasodilatation that in conjunction with SH could reduce rennin action and consequently reduce myocardial fibrosis.

A sub-study of Framingham²⁵, conducted between 1950 and 1999, determined that in a population of white individuals, there is a greater prevalence of HF in males, which can be explained by the higher incidence of atherosclerosis in males when compared to females. Barker et al²⁶ demonstrated that the HF epidemic increase occurred in the elderly male population (> 65 years), where the increased prevalence was directly associated to the increased incidence and therefore directly related to its greater survival rate. Other relevant data were demonstrated by Levy et al²⁷ where the association between HF and hypertension was more common in females; also, the risk to develop HF for individuals with SH was two-fold for males and three-fold for females.

In our study, a substantial under usage of hypoglycemia-inducing medication was confirmed, where in a population of 78 patients (54%) with blood glucose levels > 100mg/dl, only 37 patients (47%) used some type of oral hypoglycemia-inducing medication. Another significant correlation was the strong trend of the presence of HF in DM and insulin resistance syndrome patients, with respective p values of 0.07 and 0.09, odds ratio of 2.22 for the insulin resistant patients and 2.77 for the diabetic group (Table 3).

The US Health Maintenance Organization Study, demonstrated that a 1% increase in the level of glycosylated hemoglobin correlated to an increased risk of 15% to develop HF, demonstrating the important relationship between dysglycemia and HF. Another significant correlation is that MS patients are two times more likely to develop atherosclerotic cardiovascular disease and five times more likely to develop DM²⁸. It has also been demonstrated that LV wall thickness and mass are directly altered in relation to glucose intolerance; this is higher for the female gender²⁹.

A small observational and prospective study³⁰ demonstrated that patients treated with glitazones, had higher survival rates and lower HF risk, whereas another study³¹ demonstrated that glitazones worsen survival rates and increase HF prevalence. These variances are probably related to the different study populations analyzed, where the first group could be a population with a better controlled heart disease. The PROACTIVE study demonstrated a greater number of hospital admissions but a stable mortality rate³².

The under usage of medications related to MS and HF treatment was also confirmed in the dyslipidemia patients. The use of oral hypolipemia-inducing medication was only confirmed in 18 (12.5%) of the 111 (77.1%) MS patients in the study. For chronic HF patients, large studies involving the use of statins have systematically excluded HF patients. Therefore, the use of statins in chronic HF patients remains a topic for further discussion³³.

Prospective studies, such as the one by Node et al³⁴, demonstrated a functional capacity improvement in HF patients that received statins in comparison to those that received placebo, where a reduction in the levels of TNF-a, IL-6 and BNP were significantly greater in the sinvastatin group. Another prospective, double blind, randomized study used cerivastatin in patients with nonischemic dilated cardiomyopathy, confirming an improvement in quality of live, physical capacity and endothelial function³⁵. Recently, the study called the TNT-study (Treating to New Targets) involved 10,001 patients with CAD and ejection fractions > 30% to evaluate the incidence of hospital admissions as a primary HF event. The study concluded that patients taking 80mg of artorvastatin, presented a reduction of 26% in hospital admission rates for HF³⁶. Therefore, the study concluded that statins could reduce the incidence of new HF cases. The answers to these questions will probably come to light when two large placebo-controlled studies, that are currently in progress, called CORONA, (The Controlled Rosuvastatin Multinational Trial) involving HF patients with chronic systolic dysfunction and GISSI (GISSI heart failure trial) involving ischemic and nonischemic patients are concluded³³.

Conclusion

There is a high incidence of MS in our community; this condition has a significant association with HF with preserved systolic function and also with females.

References

Manuscript received October 7, 2006; revised received January 23, 2007; accepted March 1, 2007.

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Publication Dates

• Publication in this collection
  28 Aug 2007
• Date of issue
  July 2007

History

• Received
  07 Oct 2006
• Accepted
  01 Mar 2007