Challenges in the treatment of cardiometabolic syndrome.

Cardiometabolic syndrome is a constellation of metabolic dysfunction characterized by insulin resistance and impaired glucose tolerance, atherogenic dyslipidemia, hypertension and intra-abdominal adiposity (IAA). Other names used for cardiometabolic syndrome are insulin resistance syndrome, syndrome X, Reavan's syndrome, Beer belly syndrome, etc. Cardiometabolic syndrome is now recognized as a disease entity by the American Society of Endocrinology, National Cholesterol Education Program (NCEP), and World Health Organization.[1] Around 25% of the world's adults are suffering from cardiometabolic syndrome.[2]

The components of this syndrome individually and interdependently are strong risk factors for high cardiovascular morbidity and mortality. People with cardiometabolic syndrome are two times more likely to die from coronary heart disease[3] and three times more likely to have heart attack and stroke.[4] IAA is a major contributor to increased cardiometabolic risk. Visceral fat is metabolically active tissue that produces various pro-inflammatory and prothrombotic cytokines. Further, the association of fatty liver and abdominal visceral adipose tissue (VAT) with cardiometabolic syndrome has been studied in Jackson heart study.[5] Both fatty liver and abdominal visceral adipose tissue are independent correlates of cardiometabolic risk, but the association is stronger for VAT than fatty liver.

In a case-control study by Yusuf et al.[6] various cardiometabolic factors had been identified that were associated with the risk of myocardial infarction. This study also demonstrated that waist circumference is more sensitive parameter than body mass index for prediction of cardiac risk. Recently in one of the first statistical evidence from studies involving more than 300,000 adults, the superiority of waist-to height ratio as a cardiometabolic risk factor over waist circumference and BMI has been shown.[7]

At the cellular level, visceral obesity is the result of imbalance between energy intake and expenditure. Various pathophysiological events are responsible for different clinical manifestations of cardiometabolic syndrome. In particular defective oxidative metabolism seems to be involved in visceral fat gain and the development of insulin resistance. This indicates that the mitochondrial function may be impaired in metabolic syndrome and related cardiovascular diseases. Various studies have shown that the alterations in number or density of mitochondria and its oxidative mechanism are associated with development and progression of metabolic syndrome. A study was conducted to demonstrate the mitochondrial dysfunction in skeletal muscles obtained from the patients with type 2 diabetes, obese and lean subjects. It was observed that skeletal muscle mitochondria from obese and diabetic patients was smaller in size as compared to the lean subjects. It indicated impaired bioenergetics in obese and diabetic patients. Further, mitochondria-based model for insulin sensitivity has been discussed that addresses several hypotheses including thrifty genotype and phenotype.[89] Similarly, insulin resistance seems to be associated with a decrease in the mitochondria to nuclear DNA ratio in adolescents. Furthermore, it was also found that small (body weight less than 10th percentile) and large (body weight higher than 90th percentile) for gestational age newborns, conditions associated with metabolic syndrome in adult life, also have a decreased mitochondria to nuclear DNA ratio.[10]

Adipose tissue, now considered as an endocrine organ secretes various proteins (adipokines) that are involved in derangement and progression of metabolic functions by local and systemic actions.[11] Adiponectin, a fat protein from adipose tissue has shown to possess cardioprotective effects. Its anti-inflammatory and anti-atherogenic properties have been confirmed in various experimental models. Low level of adiponectin has been found in patients with diabetes, dyslipidemia and obesity. Therefore, hypoadiponectinemia has been proposed as an interesting hypothesis to explain the pathophysiology of metabolic syndrome.[12] Excess secretion of free fatty acids from adipose tissue is also associated with insulin resistance by reducing glucose transport into the muscles. An approach toward reduction of free fatty acids in plasma appears to be a potential target in the treatment of cardiometabolic syndrome.

It is evident that visceral adiposity is strongly associated with insulin resistance, dyslipidemia and other metabolic risk factors. Insulin resistance may be influenced by both genetics and environmental factors. The effect of genetics on insulin sensitivity as assessed by the minimal model technique is about 30-40%.[13] Several genes that regulate insulin action at target organ levels include those regulating insulin receptor function (PC-1), intracellular insulin signaling (IRSs), and nuclear receptors peroxisome proliferators activated receptor-γ (PPAR- γ).[14] PPAR- γ receptor is extensively expressed in adipose tissues. It regulates adipocyte differentiation, body weight, and glucose homeostasis. Therapeutic modulation of this receptor by thiozolidinediones has been shown to reverse the problem of insulin resistance. Inflammation has also been incorporated as a component of cardiometabolic syndrome.[15] Inflammation is believed to play a role in the development of atherosclerosis and type 2 diabetes. Serum elevations of proinflammatory markers e.g., IL-6, C-reactive protein, plasminogen activator inhibitor-1 levels, and fibrinogen are associated with the development of impaired glucose tolerance and type 2 diabetes.

Further, recent discoveries on microRNAs (small non-coding RNAs), in the regulation of genes have shown their involvement in diabetes and atherosclerosis. One such microRNA (miRNA-33) is located within the sterol regulatory element binding proteins (SREBP) genes and regulates cholesterol efflux, fatty acid oxidation and insulin signaling. These findings indicate that miRNA could be one novel therapeutic target for the treatment of cardiometabolic syndrome.[16]

The identification of the pathogenesis of the cardiometabolic syndrome will help to develop a successful therapeutic strategy. There is an ongoing research on “master key” that can achieve composite end points by controlling each individual component of this disease and reduce cardiovascular morbidity and mortality. The current approach to the treatment of cardiometabolic syndrome includes aggressive control of the classical risk factors viz., dyslipidemia, hypertension, diabetes and cessation of smoking. However, there are major unmet clinical needs to be addressed for cluster/novel risk factors. These include high plasma insulin, intra-abdominal obesity, pro-thrombotic (PAI-1, fibrinogen) and pro-inflammatory (IL-6, TNF-α, CRP) cytokines. There is significant emphasis on regaining the chronic energy balance between energy intake and expenditure by developing various agents that may act on mitochondrial bioenergetics. Targeting the genes appears to be the ultimate solution.