Medicine is Not an Exact Science
Ramon F. Abarquez, Jr., MD, EFACC, FAsCC, FPCP, FPCC, CSPSH
IS “reverse epidemiology” or “risk-factor paradox” merely an elderly issue?
In the absence of propensity matching format, randomized trials’ baseline data characteristic presumption of similar risk for both control and treatment groups may be a calculated assumption, for hard clinical endpoints of adverse events or mortality, since the most number of risk factors clustering to each individual trial participants, the worse is the prognosis compared to a subject with the least attributable risk factor. The propensity matching addresses this loophole in the baseline characteristic “similarity”. Risk-factor paradoxes are bound to emerge, since medicine is not an exact science.
Clinical studies have indicated the existence of an “obesity paradox” in patients with chronic heart failure (HF), that is, reduced mortality in patients who have elevated body mass index (BMI) scores compared with normal- weight reference groups.
Obesity definition paradox
The health consequences of being overweight have been discussed controversially since from a metabolic point of view, overweight and obese people are quite heterogenous groups.
The body mass index (BMI) is not suitable to predict health oriented outcomes on an individual level without taking into account waist circumference, blood pressure, serum glucose, serum lipids, and physical fitness. The BMI does not distinguish between metabolically healthy and metabolically unhealthy without considering body fat distribution (abdominal and gluteofemoral fat). Waist circumference and hip circumference can distinguish between those two types.
Body fat in the abdominal region has a markedly higher risk of developing type 2 diabetes and cardiovascular disease with increased total mortality. On the other hand, instead of waist circumference, the amount of visceral fat is believed to be the primary risk factor related to increased lipolysis, diabetogenic, and atherogenic adipokine profile, being an indicator of the parallel accumulation of fat deposits in organs placed in the abdomen.
The accumulation of lipids in tissues not primary intended for fat storage is called, “ectopic fat”, located in muscle, liver, pancreas, and kidneys that has a key role in the pathogenesis of type 2 diabetes. The pathophysiological effects of ectopic fat and the associated metabolic derangements may solve the conflicting health and therapeutic consequences of BMI. (Strohle, Med Monatsschr Pharm. 2014 Feb;37(2):54-64)
Obesity paradox overview
The prevalence of obesity has increased worldwide and is a source of concern since the negative consequences of obesity start as early as in childhood. The most commonly used anthropometric tool to assess relative weight and classify obesity is the body mass index (BMI) that shows a U- or a J-shaped association with clinical outcomes and mortality leading to the “obesity paradox”, which associates better survival and fewer cardiovascular (CV) events in patients with elevated BMI afflicted with chronic diseases compared to non-obese patients.
However, BMI cannot make the distinction between an elevated body weight due to high levels of lean versus fat body mass. Generally, an excess of body fat (BF) is more frequently associated with metabolic abnormalities than a high level of lean body mass.
Another explanation for the paradox is the absence of control for major individual differences in regional BF distribution. Adipose tissue is now considered as a key organ regarding the fate of excess dietary lipids, which may determine whether or not body homeostasis will be maintained (metabolically healthy obesity) or a state of inflammation/insulin resistance will be produced, with deleterious CV consequences.
Obesity, particularly visceral obesity, also induces a variety of structural adaptations/alterations in CV structure/function. Adipose tissue can now be considered as an endocrine organ orchestrating crucial interactions with vital organs and tissues such as the brain, the liver, the skeletal muscle, the heart and blood vessels themselves.
Thus, adipose tissue quality/function is as important, if not more so, than body fat amount in determining the overall health and CV risks of overweight/obesity. (Bastien, Prog Cardiovasc Dis. 2014 Jan-Feb;56(4):369-81) Is the issue of obesity paradox “ectopic fat” and/or adipose tissue quality/function more than amount interacting or competing with targeted vital organs?
Oxidative stress may originate from various sources, wherein the mitochondrion is proposed to play a major role. Extra-mitochondrial sources such as NADPH oxidases can also generate reactive oxygen species (ROS) in cardiomyoblasts, simulated by hyperglycemic conditions, as well as from excessive ROS production from glucose autoxidation and/or non-enzymatic, covalent attachment of glucose molecules to circulating proteins that results in the formation of glycated proteins and advanced glycation endproducts (AGEs).
Greater AGE availability can in turn lead to downstream consequences, that is, binding to the receptor for AGE (RAGE) on target cells. Enhanced AGEs formation and the subsequent tissue and cellular oxidative damage, together with inflammation, are established in pathophysiologic disorder progression in adipose tissue that may contribute to obesity-associated insulin resistance.
However, the precise nature and mechanisms of AGEs impact on the adipocyte’s function remain poorly understood and more complex in focusing only on the role of circulating AGEs versus intracellular AGEs in adipocytes. Moreover, the human body’s defense mechanisms to counter the overproduction of AGEs is a “hot topic” and dysregulation of the glyoxylase system, constituted by glyoxylase-1 (GLO1) and glyoxylase II (GLO2), is emerging as important contributors to higher AGEs levels wherein GLO1 over-expression attenuates AGEs to diminish oxidative stress. (Boyer, Oxid Med Cell Longev. 2015;2015:534873)
Vital Signs Issue 85 Vol. 4, March 1-31 2016