Obesity is becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Health service use and medical costs associated with obesity and related diseases have risen dramatically and are expected to continue to rise. Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, in addition to as-yet-unrecognized mechanisms. On the whole, overweight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death because of their impact on the cardiovascular system. The pathophysiology of these entities that are linked to obesity will be discussed. However, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. In this statement, we review the available evidence of the impact of obesity on CVD with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system.

/pdf/obesity-and-cardiovascular-disease-pathophysiology-3oufiofv6y.pdf

Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss

1.

Antidromic vasodilation and neurogenic plasma extravasation were induced by antidromic stimulation of the saphenous nerve in guanethidine-treated rats. Vasodilation was measured by the change of outflow from the femoral vein and plasma extravasation was determined by Evans blue exudation.




2.

Antidromic vasodilation was reduced by 85% in adult rats which were pretreated with capsaicin on the second day of life.




3.

Antidromic vasodilation was inhibited by 46% after pretreatment with cimetidine plus mepyramine and by 64% after pretreatment with compound 48/80, but was not affected by pretreatment with cimetidine, atropine, methysergide, or indomethacin. Similarly, neurogenic plasma extravasation was reduced by 50% after pretreatment with cimetidine plus mepyramine, and by 88% after pretreatment with compound 48/80, but was not altered after pretreatment with indomethacin.




4.

Infusion of substance P into the femoral artery dose-dependently produced vasodilation (threshold: 0.1 pmol min−1) and plasma extravasation (threshold: 0.5 pmol·min−1). Vasodilation induced by substance P was inhibited by 47% after pretreatment with cimetidine plus mepyramine and by 58% after pretreatment with compound 48/80. Plasma extravasation induced by substance P was reduced by 61% after pretreatment with cimetidine plus mepyramine and by 81% after pretreatment with compound 48/80. Pretreatment with indomethacin had no influence on substance P-induced vasodilation and plasma extravasation.




5.

It is concluded that vasodilation and plasma extravasation following antidromic stimulation of sensory nerves are initiated by peripheral release of substance P from chemosensitive pain fibres. The actions of substance P include, besides direct effects, release of histamine from mast cells.

Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation

The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H]glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) and the sum of truncal and peripheral skinfold thicknesses. 39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role.

/pdf/relationships-of-generalized-and-regional-adiposity-to-3oim76ntgf.pdf

Relationships of generalized and regional adiposity to insulin sensitivity in men.

Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome.

https://www.soard.org/article/S1550-7289(08)00630-8/pdf

American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery Medical Guidelines for Clinical Practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient.

The kinetics of the elimination from the blood stream of intravenously injected fat emulsion (Intralipid®) and of chylo-micrones have been studied in the fasting dog. The elimination was estimated by determination of the arterial whole blood glyceride concentration and subtraction of the basal glyceride concentration. The same type of elimination was found in all dogs studied. The elimination consisted of two phases operating above and below a glyceride concentration of around 1.1 mM (increase above basal level) respectively. Above the concentration 1.1 mM the elimination was linear, i.e. a constant amount of glycerides was eliminated per unit time. The mean value for the elimination in this phase was 0.05 mmole/l blood per minute. Below this concentration the elimination was single exponential, i.e. a constant fraction was removed per unit time. The mean value found for this elimination was 5 per cent per minute. No greater difference was observed between the synthetic emulsion and chylomicrones. The physiological significance of the maximal elimination rate above 1.1 mM and the concentration dependent elimination below is briefly discussed.

Studies on the elimination of exogenous lipids from the blood stream. the kinetics of the elimination of a fat emulsion and of chylomicrones in the dog after single injection.

Using the electromagnetic flowmeter technique, the blood flow in the aorta, carotid, hepatic, superior mesenteric, renal and femoral arteries and portal vein was recorded during continuous i.v. infusion of synthetic Substance P (SP) in 8 dogs. Systemic and portal blood pressures were recorded. A significant decrease in mean arterial blood pressure was recorded at infusion of SP in the femoral vein at a rate of 2.5 ng x min-1 x kg b.w.-1 or higher. Portal venous blood pressure increased. A rapid increase in the carotid, hepatic, mesenteric and portal blood flow was obtained at infusion rates of 1.2 ng x min-1 x kg b.w.-1 or higher. The femoral artery responded with a late, transient increase in flow, with a return to the base level while the infusion was still in progress. The renal artery 0lood flow decreased slightly at low infusion rates and increased at higher. At SP infusions in the portal vein the infusion rate had to be increased to 20 ng x min-1 x kg b.w.-1 or higher before any general vascular reactions lere recorded, indicating that the liver has a high capacity for inactivating SP.

Effect of substance P on various vascular beds in the dog.

Cardiovascular function in 19 patients with obesity has been studied by electrocardiography (ECG), exercise test, determination of heart and blood volumes, and right heart catheterization. Pathological ECG findings appeared in one patient at rest and during exercise, and in another only during exercise. Blood volume was low in relation to body weight, but hemoglobin concentration was normal. Heart volume and stroke volume were normally related to the total amount of hemoglobin (THb), while the working capacity (W170) in eight cases was low in relation to THb. The cardiac output was found to be normal when related to the oxygen intake both at rest and during exercise. There was a statistically significant linear relationship between intravascular pressures and cardiac output. Brachial artery pressures and left ventricle filling pressure were significantly elevated at rest and during exercise, while pulmonary artery pressures and end-diastolic pressure of the right ventricle showed a statistically significant steeper rise with increase in cardiac output than normally found. It is concluded that the circulatory dimensions and the cardiac output reflect an adequate adaptation to the metabolic demands laid upon the circulation in obesity. The elevated filling pressures of the ventricles and the high systemic and pulmonary vascular resistance, however, suggest that obesity is not without deleterious effect on cardiovascular function.

Cardiovascular function in extreme obesity.

Hallberg, D. Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion studied by single injection technique in man. Acta physiol. scand. 1965. 64, 306–313. – The kinetics of the elimination of a fat emulsion (Intralipid®) from the blood stream was studied after single injections to 10 fasting individuals. Plasma triglycerides (TG) were fractionated by means of polyvinylpyrrolidone density gradients into three fractions. The emulsion TG was found in the top fraction of the gradient and endogenous plasma TG separated into two fractions which were found in the lower part of the density gradient. The kinetics of the emulsion TG fraction were composed of a zero order elimination rate at high TG concentrations and a first order elimination rate at low TG concentrations. Intra-individual variations were only observed in the zero order part of the kinetics; the possible causes of these variations are discussed. Changes in concentration of the lipids found in the lower part of the density gradient were observed during the elimination of the emulsion TG from the circulation. The possibility that the kinetic principle for one of these fractions (middle fraction) is the same as that for the fat emulsion is discussed.

Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion studied by single injection technique in man.

. The effects of marked weight reduction on cardiovascular function in extreme obesity were studied before and on average 2 years after jejunoileostomy. In 17 female and 5 male patients, mean age 36 years, with obesity as the sole diagnosis, circulatory data were obtained at rest and during exercise through right heart catheterization. Blood volume and heart volume were measured and ECG was recorded at rest and during exercise. A mean weight loss of 58.1 kg reduced percentage overweight from 104 to 39%. Resting oxygen consumption and cardiac output fell in proportion to weight loss. A slightly hyperkinetic central circulation was observed during exercise. Stroke volume fell parallel to the decrease in blood volume and heart volume. Systemic arterial pressure declined, while systemic arterial resistance did not change. Left ventricular stroke work diminished. Although lower than preoperatively, the filling pressures of the right and left side of the heart were high in relation to cardiac output compared with healthy subjects. ECG at rest and during exercise remained normal. Thus, despite reductions in heart size and left ventricular stroke work, evidence of left ventricular dysfunction persisted. The observations indicate that the circulatory effects of gross obesity are largely reversible over weight loss periods of up to 3.5 years, apart from signs of a reduced myocardial wall compliance. The clinical implication seems to be that therapeutic weight-reducing intervention should be made at a younger age.

Dag Hallberg

Papers

Studies on the elimination of exogenous lipids from the blood stream. the kinetics of the elimination of a fat emulsion and of chylomicrones in the dog after single injection.

Effect of substance P on various vascular beds in the dog.

Cardiovascular function in extreme obesity.

Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion studied by single injection technique in man.

Reversibility of cardiovascular changes in extreme obesity. Effects of weight reduction through jejunoileostomy.