Obesity as a risk factor for heart failure: overview of systematic reviews

The overweight and population with obesity has an increased risk of mortality from HF. However, some studies point to the existence of an "obesity paradox" where there could be a protective effect on the relative risk of death by HF in these populations with high BMI. In this way, the present study aimed to investigate obesity as a risk factor for heart failure. For this, an overview of systematic reviews was performed by selecting articles from the following databases: "Pubmed", "Scopus" and "SciElo”. A total of 615 articles were found from this initial search, leaving 59 articles for full-text reading, of which 22 articles were included for data extraction using the predefined inclusion criteria. From these 22 studies 73% were meta-analysis and 64% of the studies are of high methodological quality according to AMSTAR-2. Overweight and obesity have demonstrated a close relationship with the onset and increase of mortality by HF, studies have even been found that point to a gene interference in this relationship. In studies reporting on the obesity paradox, the results pointed to a momentary protection from mortality risk.


Introduction
HF is an important public health problem and, despite significant improvements in its therapeutic management, it is still considered a serious syndrome associated with substantial rate of death and hospitalizations, affecting more than 23 million patients worldwide (Mozaffarian et al., 2016). After five years of diagnosis, survival rate is estimated at 35%, with prevalence increasing with age. There is an increase of 0.9% in individuals aged 55-64 years, reaching 17.4% in those aged ≥85 years. Besides the poor prognosis, HF is one of the most costly syndromes in the United States and Europe, where it accounts for about 1% to 2% of the overall healthcare budget (Bleumink et al., 2004).
The effectiveness of clinical practice in health care depends on higher quality evidence-based and practices to be implemented should be discussed between health care professionals and their patients for decision making. To accomplish this process, healthcare professionals need to keep up to date. However, this is a complex challenge, due to the globalized world and the speed in which information is disseminated (Silva et al., 2012).
An alternative way to reduce the complexity of tracking, dating, and facilitating clinical decision making is to use systematic reviews (SR). One of the main functions of these studies is to summarize clinical information from multiple studies to answer a question related to diagnosis, prevention, or treatment in areas where the results may or may not agree, by critically evaluating the evidence (Green et al., 2011).
Professional updating remains a challenge, even when using SR. A possible solution to the problem has been put forward by methodologists specializing in SR: a new type of study called the systematic reviews overview, or Overview, considered to be a user-friendly "front end" to health care decision making. By definition, Overview is a study developed to integrate and produce a synthesis of existing SR information in a specific clinic, considering all available interventions to treat or prevent this condition (Silva et al., 2012;Thomson et al., 2010). In this context, the present study aimed to evaluate obesity as a risk factor for heart failure through an Overview of systematic reviews.

Methodology
The following oveview was performed according to the PRISMA and Cochrane Collaboration recommendations (Higgins et al., 2019;Moher et al., 2009).

Eligibility Criteria
Systematic review studies were included, with or without meta-analyses, published until March 3, 2020, in English, Portuguese and Spanish, analyzing the association of obesity with HF. Studies on the effects of drugs on these pathologies and studies with non-Roman characters were excluded. The search was performed in Pubmed / Medline; Scielo and Scopus databases. This study was updated in the same databases on November 21, 2021. 197 articles were found, but none met the eligibility criteria.

Study Screening and Selection
All titles and abstracts of the studies identified by the literature search were independently reviewed by two reviewers (RF and CB). If a reviewer considered the article potentially relevant, a full-text review was conducted. Disagreements about the inclusion of the full article were resolved by a consensus discussion between the two reviewers. In case of remaining discrepancies, a third reviewer (WR) made the final decision.
Data from each included study were extracted using a pre-designed template that included variables corresponding to the study characteristics (study design, outcome assessed, data search period and number of studies included).

Evaluation of Methodological Quality and Risk of Bias
AMSTAR-2 is a popular tool for the critical appraisal of systematic reviews of randomized controlled trials, providing a broad assessment of quality, including flaws that may have impacted on poor conduct of the review. This instrument has 16 questions, 7 of which are considered critical to the validity of the systematic review and the relevance of its conclusions. Based on this, general confidence ratings can be assigned to the review results ranging from critically low, when several points of critical failure are found independent of the non-critical weaknesses, low, when one critical failure is found, moderate, when more than one non-critical weakness is observed, or high, which is when none or only one non-critical weakness is identified.

Study selection procedure
The article selection process is shown in figure 3. A literature search in the Pubmed, Scopus and SciElo databases yielded 615 articles published up to March 3, 2020. After excluding duplicates, 555 articles remained and were then displayed with based on the evaluation of abstracts and titles. After excluding articles that did not meet the eligibility criteria, 59 full-text articles were evaluated. Of these articles, 37 articles were considered irrelevant. Finally, the remaining 22 articles were included in this Overview.

Characteristics of the included studies and synthesis of results
Figure 1 and table 1 shows that of the 22 articles that met the eligibility criteria, 73% contained meta-analyses, which shows a greater robustness of the analyzed data. The number of studies included in systematic reviews ranged from 6 to 85, with an average of 24 studies per systematic review. It also presents the outcomes found in 22 articles included and Research, Society andDevelopment, v. 11, n. 1, e0811124380, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i1.24380 4 demonstrates the global effects found in the relationship between obesity and HF. It also shows that 41% of 22 articles reported a positive, that is, a beneficial effect of the concomitant presence of obesity and HF, and 36% negative effect of obesity on HF, 18% reported positive and negative effects, and only 1 study reported no harm or benefit.
The systematic reviews ranged in quality from low to high quality according to the AMSTAR-2 quality assessment tool. However, approximately 64% of the studies are of high-quality, 27% are of moderate quality, and only 9% are considered to be of low quality.

2019)
75 Systematic review He presented obesity, especially severe, long-lasting, and abdominal obesity as an increased risk factor for HF by 15 to 70%. However, he reported that overweight and obesity are associated with reduced mortality by 24 to 59% and 15 to 65%, respectively, while malnutrition is an aggravating factor for mortality and hospitalization.

Discussion
Overweight is related to hemodynamic and anatomic alterations of the cardiovascular system. Recent evidence suggests that the relationship of overweight with changes in metabolism, inflammatory profile, and hormonal changes (such as insulin resistance), may help to understand the relationship between obesity and HF (Comitê, 2018). In the systematic review and meta-analysis of prospective studies by Aune et al., (2016), it was found that for every 5 unit increment in BMI there was a significant increase of 1.41 (95% CI: 1.34 -1.47; I2 = 83%) for incidence and increase of 1.26 (95% CI: 0.85 -1.87; I2 = 95%) for mortality by CI. It was also observed that the risk was maintained with the increase of 10 cm in waist circumference, being 1.29 (95% CI: 1.21 -1.37; I2 = 89%) and through the increase of 0.1 unit in waist-to-hip ratio the risk was also 1.29 (95% CI, 1.13 to 1.47; I2 = 82%). Demonstrating, then, that both overweight and obesity can increase the risk of HF incidence and mortality.
Corroborating with the findings of the previous study, the systematic review and meta-analysis conducted by Krittanawong et al., (2018), noted that being overweight increased the incidence of HF by 1. Childhood obesity is an important factor for the development of risk factors for cardiovascular morbidity and mortality in adulthood. In general, excessive BMI in childhood is believed to be associated with an increased risk of coronary artery disease in adulthood. On the other hand, high BMI in adolescence was independently associated with angiographyconfirmed coronary heart disease, and the risk of atherosclerosis in adulthood is affected by the cumulative exposure time of overweight or obesity (Sommer;Twig, 2018).
The systematic review by Sommer and Twig (2018), concluded that childhood obesity leads to considerable consequences in adulthood, being associated with adult hypertension and dyslipidemia, resulting in high cardiometabolic risk.
Additionally, it appears to induce changes in myocardial geometry and function, demonstrating a worrying and early onset of potentially adverse changes in the myocardium. This way, childhood and adolescent obesity has been associated with increased risk of cardiovascular morbidity, mainly from ischemic heart disease or stroke. Therefore, as the prevalence of overweight and children and adolescents with obesity continues to grow, the risk of weight-related cardiovascular disease and death in adults may increase. From this, it is pointed out that a successful reduction in the incidence and prevalence of obesity in children and adolescents will lead to a reduction in cardiometabolic sequelae in adulthood.
In the largest Mendelian randomization study to date by Fall et al., (2013) corroborated the studies already mentioned in this study, where obesity is pointed out as a causal factor for the development of HF. The meta-analysis also revealed a relationship in the locus portion of the fat mass and obesity-associated gene (FTO), responsible for increased BMI, with increased incidence of HF and adiposity, and increased concentrations of the liver enzymes ALT and Gamma GT. The study further estimates that a 1-unit increase in BMI will increase the incidence of heart failure by 17%. In another Mendelian randomization study carried later by the same research group, the association between BMI and genetic score was confirmed.
Another systematic review and meta-analysis of prospective cohort studies was performed and observed a significant positive association between all metabolic phenotypes of overweight 1.10 (95% CI, 0.60 to 2.00, p = 0.76) and obesity (RR = 0.96, 95% CI: 0.25-3.77, p = 0.95) metabolically healthy and the risk of developing HF, it was further observed that for patients with obesity of weakened metabolic phenotype, a risk of infarction 1.82 (95% CI, 1.50 to 2.22, p <0.001), when compared to normal weight and metabolically healthy phenotype patients. Demonstrating, thereby, that a genetic relationship exists, where obesity exerts an influence on the incidence of HF, the article further highlights that the profile of metabolically healthy patients is not completely protected from cardiovascular events (Mirzababaei et al., 2019).
The phenomenon of the obesity paradox, characterized by the protective effect on survival of patients with overweight or obesity who concomitantly have HF and having lower BMI as a marker of poor prognosis 29, was evidenced in 13 of 22 systematic review studies, 8 of these with meta-analysis, the U-shaped graphical association with all-cause mortality according to all BMI categories, confirming the increased risk in patients with low BMI, and attenuated risk for patients with BMI category compatible with overweight or obesity, some studies also highlighted the importance of the protective effect of overweight in mortality from cardiovascular events (Chang Et Al., 2015;Chrysant;Chrysant, 2013;Ma Et Al., 2018;Mahajan Et Al., 2020;Milajerdi Et Al., 2019;Oga;Eseyin, 2016;Oreopoulos Et Al., 2008;Padwal Et Al., 2014;Qin;Wan, 2017;Sharma Et Al., 2015;Shirley;Davis;Carlson, 2008;Wawrzeńczyk Et Al., 2019;Zhang Et Al., 2019). Shirley;Davis;Carlson, (2008) found a temporal relationship in the protective effect promoted by the paradox, where the higher level of BMI was not associated with improved survival in the first 12 months and in 5 years, showing beneficial effect only in the second year, when the calculation of ideal weight percentage was used instead of BMI the same relationships held to be true. However, it also demonstrated several reports of improved survival for patients with increased BMI, with adjusted hazard ratios of 0.88 (95% CI: 0.80 to 0.96) and 0.81 (95% CI: 0.72 to 0.92) for overweight and patients with obesity, respectively, and increased risk of death for patients with underweight BMI 1.21 (95% CI: 0.95-1.53) compared to normal BMI patients. He also observed the highest percentage of major clinical events such as cardiovascular death or urgent transplant were related to patients with low body surface area percentage (2.0 m2), BMI (27.7 kg/m2), body fat (22.5%), total fat (19.7 kg) and lean body weight (65.5 kg), whereas patients with higher body fat percentage was the strongest predictor of survival reported in the study.
In order to prove the existence of the obesity paradox and clarify the questions regarding the gaps left by BMI, Oga and Eseyin (2016) verified articles that measured, in addition to BMI, the thickness of the triceps skinfold (TSF), waist-to-hip ratio (WHR), and waist circumference (WC), and after the analyses pointed out that patients with the highest BMI, TSF and WC parameters had a better prognosis when compared to normal weight categories, added to this the study found that the paradox existed even for survival after 2 years.
In the systematic review and meta-analysis conducted by Lin et al., (2016) in order to investigate the association between BMI and HF mortality the East Asian region found that all-cause mortality, cardiovascular and noncardiovascular mortality increased with decreasing BMI categories compared to normal weight, underweight showed higher risk of all-cause mortality and cardiovascular mortality, and obesity showed lower risk of noncardiovascular mortality, compatible with the obesity paradox also for eastern populations, however an ethnic difference of the paradox was observed, where at each increment of 5 kg/m2 the risk of noncardiovascular mortality was shown to increase in European and American patients than in Japanese.
The systematic review and meta-analysis conducted by Cuspidi et al., (2014) argues that obesity is a powerful risk factor for systolic and diastolic dysfunction, since their findings were consistent with a much higher incidence of HF in patients with obesity when compared to non-obese patients, therefore the authors argue that prevention and/or treatment may have an important favorable impact on HF.
Corroborating these data, in the systematic review conducted by McDowell et al., (2018), the authors argued that although the obesity paradox was present in the sample studied, with greater survival and lower mortality risk for the population with obesity, intentional weight loss in patients who coexisted with obesity and HF demonstrated improvement in exercise capacity, NYHA classification, and quality of life. Similarly, the meta-analysis conducted by Mahajan et al., (2020) also argues that intentional weight reduction, since it showed a reduction in left ventricular mass index, improvement in diastolic function, and reduction in left atrial size, resulting in improvement of structural and functional cardiac indexes in individuals with obesity affected with HF. Reddy et al., (2019) conducted a systematic review and meta-analysis, noted that weight loss is associated with significant reductions in biventricular filling pressures, pulmonary arterial pressure, heart rate, cardiac output, systemic arterial pressure, and whole-body oxygen consumption. That is, the authors hypothesize that weight reduction interventions could then be effective in mitigating the hemodynamic derangements that contribute to morbidity and mortality in people with the obese phenotype and with HF. However, they warn that weight loss alone without aerobic exercise training may result in a loss of lean body mass, which can be detrimental in older patients with PFEI.

Conclusion
Given the results obtained, it can be inferred that overweight, as well as obesity, represents an important risk factor contributing to the increase in mortality. Mendelian randomization studies have also been found that point to this close relationship across gene loci associating increased BMI with increased HF. However, studies have reported the phenomenon known as the "obesity paradox", where obesity, despite aiding in the development of HF, for some patients would serve as a protective effect against mortality. It was also observed that the intentional weight reduction,when associated with aerobic physical activity, it is an important management to be performed with patients, as studies point to an improvement in the clinical picture. Based on the results obtained from this overview, further evidence-based health research can be carried out on the influence of other comorbidities, such as coronary artery disease, kidney disease and dyslipidemia, as well as their implications for the development and morbidity and mortality of HF.