Metabolic Corruption

We are beautifully created with perfectly designed incredibly complex metabolic systems. In the foetus, helpless, entirely at the mercy of our Mother’s habits and well-being our myocardial mitochondria gene expression code for processes that utilize glucose as the sole fuel for our energetics. After birth profound changes in the program gene expression in the myocardial mitochondria occurs, leading to an increase in expression of genes involved in fatty acid metabolism with down regulation of the genes for glucose metabolism.

Intrinsic cardiac cell metabolism in the adult depends primarily on the utilization of fatty acids in beta-oxidation in the mitochondria to produce our ATP (energy). As we corrupt and damage this beautifully delicately balanced process from obesity; metabolic syndrome; myocardial hypertrophy (in hypertension); myocardial ischaemia (from coronary atherosclerosis); cytokine damage (systemic inflammation); oxidative damage & cellular glucotoxicity & lipotoxicity there is a switch back to foetal transcription genes coding for glucose as a fuel rather than fatty acids.

This is associated with altered substrate usage and reduction in mitochondrial ATP generation from glucose metabolism (glycolysis) compared to beta-oxidation of fatty acids thus depleting our important cellular energy. The secondary effect on our cells is triglyceride and free fatty acid (fat) accumulation exacerbating the lipotoxicity with progressive cellular and ultimately myocardial dysfunction.

In the heart this dysfunction gives rise to the well documented heart muscle failure or cardiomyopathy seen particularly in obese subjects with metabolic syndrome and Type 2 Diabetes Mellitus.

 Individual Risk Factors for Metabolic Syndrome:

Poor lifestyle choices lead to progressive metabolic chaos and metabolic corruption with the risk of Type 2 Diabetes increasing exponentially as BMI increases above 25 kg/m2.  As the metabolic corruption perpetuates in obese subjects specifically with visceral adiposity, insulin resistance and hyperinsulinaemia develops with disastrous knock-on effects on our cellular physiology.

The excessive adipose tissue contributes to chronic increase in circulating fatty acids which in turn corrupt our Insulin signalling pathways exacerbating the Insulin resistance which impairs the metabolism and cellular uptake of glucose and fatty acids.

Excess fatty acids result in increased deposition of fat in the heart, pancreas, muscle and liver (fatty liver) and increased toxic metabolites such as diacylglycerol and ceremide further corrupt cellular energy pathways with toxicity to the various organ systems.  Progressive beta-cell dysfunction in the pancreas acting in conjunction with insulin resistance aggravates the hyperglycaemia.  The latter contributes to glucotoxicity of metabolic pathways and cellular structures.

Finally the detrimental effects of the adipokines and inflammatory cytokines are additional mechanisms through which obesity potentiates the end organ damage in metabolic syndrome and Type 2 DM.

Thus the high incidence of cardiovascular damage due to obesity; metabolic syndrome and Type 2 Diabetes is multifactorial but chiefly driven at the centre by obesity, metabolic syndrome, insulin resistance, hyperinsulinism and metabolic chaos with lipotoxicity and glucotoxicity.

To reverse and prevent this problem we need to address the central issue of obesity, metabolic syndrome, insulin resistance and Type 2 diabetes mellitus.  As you can imagine with the epidemic increase in obesity and overweight status there is a parallel epidemic of obesity and diabetes with increased cardiovascular disease to follow.

The maps show the trend of obesity     (BMI > 25) in the USA from 1994 to 2010

Diabetes and obesity are thus closely linked diseases with rising prevalence and incidence in developed and developing countries. Westernized eating habits and lifestyle are presumed to be the major reasons for this epidemic. Official guidelines recommend diets with low-fat contents and high amounts of carbohydrates although it has never been proven that these are effective in reducing cardiovascular disease morbidity and mortality, the major health problems connected with diabetes and obesity.

Recently the Women’s Health Initiative study showed no effect of a diet restricted in fat content and enriched in carbohydrates on cardiovascular morbidity and mortality.

This was a massive trial randomizing    >40 000 women to an intervention group eating a low-fat (< 20% of daily calories) and high carbohydrate diet (increased fruit/ vegetables and grains).

Remarkably and surprisingly over 9 years of the study there was no survival benefit in the intervention group taking low-fat high carbohydrate intake.

This study has therefore questioned “conventional wisdom” of the cardiovascular benefits of “low-fat, high carbohydrate” diets.

It seems reducing body weight is considered an important therapeutic intervention to preventing cardiac disease and to treat obese / overweight patients with metabolic syndrome and type 2 diabetes. Most intervention trials have failed to demonstrate a long-lasting diet effect. Putting patients on insulin will often cause an increase in body weight resulting in the need for further insulin to be injected. Although many patients are on high insulin doses, metabolic results are often poor with high HbA1c values (poor diabetic control). The standard low fat-high carbohydrate intervention has been challenged

Historically, there has been a scientific tradition favoring dietary carbohydrate-restriction in obese patients in Europe before the Second World War and in the Fifties in the USA. The recently published A to Z trial showed that the most beneficial effect in weight reduction was in those patients treated with a carbohydrate-restricted diet in comparison with three other dietary interventions, lower in fat and higher in carbohydrates.

There may be individual differences, some patients doing better on a carbohydrate-restricted diet (ATKINS) compared to high carbohydrate diets (Ornish) to reduce weight while others do better on a fat-restricted diet (ZONE and LEARN).   A possible explanation might be a different insulin response after a glucose challenge, i.e. a high response reflecting insulin resistance, in those patients that did better on a carbohydrate-restricted diet.

In addition, diets that are rich in carbohydrates will result in an unfavorable cardiovascular risk profile resulting in raised triglycerides and lowered HDL and increased small dense LDL. Glycemic index of carbohydrates is a strong determinant of HDL-cholesterol concentration in plasma. In context of carbohydrate-restriction, dietary saturated fat has also been shown to exhibit a beneficial effect on plasma lipids.These latter conditions are neglected in official recommendations. A recent review of the scientific evidence of dietary carbohydrate-restriction in type 2 diabetes challenged the official recommendation of low-fat diets. The beneficial effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index caloric restricted diet improved metabolic control in patients with type 2 diabetes and also resulted in greater weight loss and reduction or complete cessation of anti-diabetic medications. A two-year randomized trial comparing low carbohydrate diet versus low fat diet in obese patients did also show a more favorable lipid profile in those patients randomized to the low carbohydrate diet treatment.

This study published this year (2012) on very low carbohydrate intake      (< 20 g/d) had profound benefit on glucose control (measured by HbA1c level) and weight loss in 35 established Type 2 diabetics on conventional therapy.

This ketogenic diet with low carbohydrate; modest protein and high fat intake gives further “food for thought” to fix a corrupt metabolism.

Blessings

Cardiologydoc

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Adiposopathy – “Sick Fat” a Cardiovascular Disease?

Introduction:

There is a fundamental difference between uncomplicated adiposity defined as excessive adipose tissue and adiposopathy (“sick fat”) defined as anatomically and functionally pathological enlargement adipocyte cells leading to adipose tissue dysfunction. The latter results from positive caloric balance in genetically and environmentally susceptible individuals that result in adverse endocrine and immune responses that may directly promote cardiovascular disease and may worsen or potentiate metabolic disorders. As many of these metabolic disorders are themselves major cardiac risks (type 2 diabetes mellitus; hypertension and dyslipidaemia), adiposopathy therefore indirectly increases cardiovascular disease and vascular damage self-perpetuating the metabolic chaos and end organ damage.

Adiopsopathy is promoted by unhealthy lifestyle including calorie overload and sedentary living in genetically and environmentally predisposed individuals. With impaired adipogenesis of peripheral, sub cutaneous and visceral adipose tissue during positive calorie balance, existing fats cells hypertrophy; increase circulating free fatty acid and lipids depositing in non-adipose tissue such as liver; muscle; pancreas and the heart resulting in lipotoxicity. The adiposopathic endocrine and immune dysfunction directly contribute to the pathophysiology of the cardiovascular system disease and of the organ dysfunction.

Adipose Tissue Anatomy, Embryology and Adiopogenesis:

Fat-containing adipocyte constitutes the majority of adipose tissue cellular content. Adipocytes are surrounded by fibrous connective tissue, collagen, nerves and blood vessels termed the supporting stromal network including fibroblasts, preadipocytes, endothelial precursor cells, smooth muscles cells, blood vessels cells and immune cells. Interestingly adipose tissue, the stromal network and surrounding tissues and organs share a common lineage from the mesoderm of the zygote. The mesenchymal stem cells may differentiate into skeletal myoblasts, osteoblasts, chondroblasts, marrow stromal cells, neuron-like cells, cardiomyocytes, angiocytes and adipocytes.

With progressive adiposopathy there appears to be neuro endocrine “cross-talk” from the “sick fat” to the other mesodermal and endodermal derived tissues and accounts for the multisystem organ and tissue disorders in obesity, metabolic syndrome and type 2 diabetes mellitus.

Conversely adipose tissue is a rich, non-embryonic source of mesenchymal cells whose relative ease in accessibility and capacity for differentiating into heart, and blood vessel cells has direct medical applications to cardiovascular disease regenerative medicine, tissue engineering and cell replacement therapies as potential therapeutic modality to repair post ischaemic or other cardiomyopathies.

Previously, adipogenesis was thought to cease early in life, resulting in a fixed number of adipocytes that predestined individuals to be lean or obese. However, fat-cell turnover is now known to be a dynamic process by which mesenchymal stem cells undergo lineage commitment, pre-adipocyte proliferation, growth arrest, and terminal differentiation into mature adipocytes. The number of adipocytes is therefore dependent on the balance between adipogenesis and apoptosis with some suggesting that approximately 10% of fat cells are renewed annually at all adult ages and at all levels of body mass index (BMI). This has clinical implications because during positive caloric balance, adipocytes normally undergo initial hypertrophy, which elicits cellular signaling for the recruitment, proliferation, and differentiation of new fat cells. If adipogenesis proceeds normally in peripheral subcutaneous adipose tissue, then adiposity may not cause demonstrable adipose tissue dysfunction or adverse metabolic consequences. Conversely, if adipogenesis is impaired, then the lack of adipocytes to adequately proliferate (or differentiate) causes existing cells to undergo excessive hypertrophy, causing adipocyte dysfunction and pathogenic adipocyte and adipose tissue endocrine and immune responses.

The concept of adipocyte hypertrophy during positive caloric balance representing a failure of adipocytes to adequately proliferate is supported by findings that T2DM is associated with a decrease in adipogenic gene expression and that T2DM patients have larger adipocyte size but decreased adipocyte cellularity compared with obese patients without T2DM. In short, if during positive caloric balance, any stage of the adipogenic processes is impaired (recruitment, proliferation or differentiation) then this may lead to pathologic adipose tissue endocrine and immune responses that contribute to metabolic disease, particularly in individuals who are genetically or environmentally predisposed.

Fat Depots:

The clinical importance of adiposity is not only how fat is stored (i.e., adipocyte proliferation vs. adipocyte hypertrophy), but also where fat is stored. Visceral adipose tissue (VAT) may be more metabolically active than subcutaneous adipose tissue (SAT), and these depots inherently differ in processes involving lipolysis/lipogenesis, expression of adipocyte receptors, and differ in the secretion of adipokines/cytokines, enzymes, hormones, immune molecules, proteins, and other factors. Derangements in adipose tissue endocrine and immune processes contribute to metabolic disease. Fat depots other than VAT have pathogenic potential. Pericardial, subcutaneous abdominal, perimuscular, perivascular, orbital, and paraosseal fat depots also have lipolytic and inflammatory activities.

Pericardial and perivascular adiposopathy may have direct pathogenic effects on the myocardium, coronary arteries, and peripheral vessels via dysregulated local secretion of vasoactive and inflammatory factors that may contribute to atheroma instability and other cardiovascular pathophysiology. Pericardial adiposity is strongly associated with coronary atherosclerosis in African-Americans with T2DM, which may contribute to ethnic disparities in atherosclerosis susceptibility. Finally, although often assumed that atherosclerosis is exclusively an intraluminal, subendothelial, lipid-mediated process, pathogenic pericardial and perivascular adipose tissue may directly contribute to atherosclerosis through an “outside to inside” inflammatory atherogenic model, which is again supported by the strong association between pericardial adipose tissue and coronary artery calcification.

Extracellular Matrix Remodeling, Angiogenesis, and Hypoxia:

In addition to how fat is stored and where fat is stored, other determinants of the pathogenic potential of expanding adipose tissue include the interdependent physiologic processes of angiogenesis and extracellular matrix (ECM) remodeling. If an increase in fat storage results in excessive adipocyte enlargement, then adipocyte hypertrophy may contribute to intracellular hypoxia. Additionally, when fat accumulation outpaces angiogenesis, then a relative lack of blood flow may result in both cellular and adipose tissue hypoxia. As with other body tissues (heart), cellular and tissue adipose hypoxia contributes to cellular and organ dysfunction, contributes to pro-inflammatory responses, and all may contribute to the onset or worsening of metabolic disease. For example, if periadipose ECM remodeling is impaired due to relative hypoxia or other adipocyte dysfunction, then further fat storage may be physically limited, resulting in increased circulating free fatty acids and lipotoxicity. Furthermore, hypoxia-driven inflammation may promote ECM instability, and excessive synthesis of ECM components may impose long-term interference with cell–cell contact and adipogenic signaling mechanisms, and thus persistent adverse cellular responses even after weight loss.

Free Fatty Acids and Lipotoxicity:

If during positive caloric balance, adipocytes are unable to store excess energy (mostly in the form of triglycerides), then circulating free fatty acids are increased, causing pathologic disruption of nonadipose tissue organs, such as the liver, muscle, pancreas, and blood vessels. Potential adverse metabolic consequences of lipotoxicity include abnormalities of glucose (Insulin resistance) and lipid metabolism, and high blood pressure. Although VAT is most recognized as a contributor to metabolic disease, the majority of circulating free fatty acids actually originates from SAT, mainly because SAT is the largest fat depot, constituting ~80% or more of total body fat. Even within large vessel drainage of VAT (which sometimes constitutes ~20% of body fat), the majority of free fatty acids in the portal system may originate within SAT, which may contribute to lipotoxic effects on the liver, with adverse clinical consequences such as hyperglycemia and dyslipidemia.

So while VAT is generally considered among the most pathogenic fat depots, if SAT fat storage is limited or impaired during positive caloric balance and if SAT net free fatty acid release is increased into the circulation, then this SAT dysfunction may adversely affect nonhepatic organs, resulting in lipotoxicity to muscle (exacerbating insulin resistance) and the pancreas (possibly reducing insulin secretion).

Adipose Tissue as an Active Endocrine and Immune Organ:

Excessive adipocyte hypertrophy disrupts the normal physiological function of fat-cell organelles (causing adipocytes to become “sick”), as evidenced by increased markers of intracellular endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The ER is a network of interconnected tubules, vesicles, and cisternae that, among other functions, produce protein and lipids and transport proteins and carbohydrates necessary for normal cellular function. Increased markers of adipocyte ER stress are associated with inflammation, cellular dysfunction, and metabolic disease. Mitochondria are membrane-enclosed organelles that contain enzymes responsible for transforming nutrients into cellular energy through the production of adenosine triphosphate. Increased markers of adipocyte mitochondrial stress are associated with obesity, insulin resistance, and T2DM. Among the adverse consequences of adiposity-induced “sick fat” is a disruption of physiological endocrine and immune function, which, in turn, contributes to metabolic disease. The mechanisms by which adiposopathic endocrine and immune responses contribute to T2DM, high blood pressure, dyslipidemia, and other metabolic disorders, and mechanisms explaining how nutrition, physical activity, drug therapies, and bariatric surgical interventions improve metabolic disease.

Adiposopathy and Aging:

Irrespective of age, adiposopathy increases the prevalence of metabolic disease and CVD risk factors. However, adiposopathy and aging share analogous pathophysiology. From a cellular standpoint, both adiposopathy and aging can increase markers of intracellular stress and mitochondrial dysfunction, and both are associated with impaired adipogenesis.

From a clinical standpoint, both adiposopathy and aging:

  • are risk factors for CVD, T2DM, high blood pressure, and dyslipidemia
  • promote endocrinopathies, such as increased free fatty acids and reduced testosterone levels in men
  • both may promote immunopathies such as increased C-reactive protein.

When stratified based on age and BMI, the relationship between adiposopathy and aging is complex, as evidenced by the variable association of metabolic syndrome components. Adverse oxidative reactions are also shared by adiposopathy and aging. Oxidation creates unstable oxygen free radicals and other reactive oxygen species that create biomolecular instabilities toxic to cells. If reactive oxygen species production exceeds a biological system’s ability to detoxify them, then this “oxidative stress” may contribute to metabolic disease and atherosclerosis.

Adiposopathy as a Conceptual Resolution of the Obesity Paradox:

Various obesity paradoxes are described when increased body fat mass does not increase morbidity or mortality, when a decrease in excessive body fat does not improve patient health, or when an increase in body fat mass actually reduces morbidity or mortality. Many of these apparent clinical contradictions are mitigated if the pathogenic potential of excess adipose tissue is assessed not solely by adiposity, but also by adiposopathy.

Not all obesity paradoxes are due to adiposopathy. However, many obesity paradoxes are less paradoxical if adipose tissue is accepted as being more than an inert storage organ. For example, not all overweight patients develop metabolic disease and not all patients with metabolic disease are overweight. This paradox is best explained when understanding that fat weight gain most often contributes to the onset or worsening of metabolic disease when accompanied by pathogenic adipocyte and adipose tissue anatomic, endocrine, and immune responses in genetically and environmentally susceptible patients.

This also helps explain paradoxical populations described as “metabolically healthy, but obese”, “metabolically obese, normal weight”.

Cardiovascular Risk Paradox:

The susceptibility to adiposopathy provides an explanation for the high prevalence of T2DM, the metabolic syndrome, and CVD among Asians, particularly those from the South and East Asian subcontinent. Asian Indians have an increased adipocyte size, fewer adipocytes, increased visceral adiposity, increased circulating free fatty acids, increased leptin levels, increased pro-inflammatory factors (e.g., increased C-reactive protein levels), and decreased anti-inflammatory factors (e.g., decreased adiponectin), which lead to increased insulin resistance and increased CVD risk. Genetic susceptibility helps account for the common clinical finding that many patients of Asian descent have metabolic disease, even when not markedly overweight.

This has prompted international organizations to suggest that Asians should have different cutoff points for the determination of overweight and obesity.

Similarly, adiposopathy helps explain why, for the same age and weight, men have higher rate of CVD compared with women. During positive caloric balance, men often expand lower body fat through the more pathogenic process of adipocyte hypertrophy, whereas women typically undergo the less pathogenic process of adipocyte hyperplasia. Furthermore, men often store excessive fat in an “android” or “apple” (i.e., visceral) distribution, whereas women often store fat in a “gynoid” or “pear” (i.e., peripheral subcutaneous) distribution. These differences in adipose tissue expansion and fat depot accumulation may help explain the sex paradox, in which, when corrected for various demographic factors (such as age), men have higher CVD risk than women.

Cardiovascular Event and Cardiac Procedure Paradox:

Modestly overweight individuals may live longer than those who weigh less, possibly because patients with reduced body weight often have illnesses with high mortality (e.g., chronic heart disease, cancer). However, studies have consistently suggested that modestly overweight patients have reduced morbidity and mortality after diagnosis of CVD, after experiencing a CVD event, and/or after undergoing CVD procedures. This CVD paradox may be risk factor dependent.

Regarding the CVD risk factor of sedentary lifestyle, overweight and obese men may have increased longevity only if they are physically fit. Cigarette smoking reduces body weight, but is a major CVD risk factor. CVD patients who smoke have an increase in all-cause mortality compared with those who quit smoking, especially if they have chronic lung disease, which would tend to further decrease body weight. Thus, despite lower body weight in cigarette smokers, their CVD risk is increased.

Patients with chronic heart failure may have no survival benefit with obesity if they have the major CVD risk factor of T2DM. Most CVD patients have “normal” or only modest elevations in cholesterol (another CVD risk factor); yet have a high prevalence of other adiposopathy-associated CVD risk factors. But, although the CVD associated with the adiposopathy-related CVD risk factors may be more frequent, the morbidity and mortality associated with non-adiposopathy-related CVD pathology may be more clinically adverse. In other words, many patients with genetic dyslipidemia (e.g., familial hypercholesterolemia) are not overweight, yet have a disproportionately high rate of premature cardiovascular morbidity and mortality.

Thus, although adiposopathy-induced CVD may be more common, the morbidity and mortality with non-adiposopathy-induced CVD may be much worse. Finally, mortality among those with CVD is directly associated with central obesity and inversely associated with BMI. Given that central or visceral adiposity is an anatomic manifestation of “sick fat,” this supports the concept that adiposopathy may be a more rational treatment target than adiposity alone.

Finally, adiposity may be associated with enhanced cardiovascular autoreparative potential. Overweight individuals may have greater availability of adipose tissue-associated mesenchymal cells that upon release could conceivably reduce CVD morbidity. After an acute CVD event, reparative circulating mesenchymal cells (originating from tissues such as adipose tissue, bone marrow, and blood vessels) migrate to the injured myocardial site. In their naïve state, adult stem cells may have a limited reparative benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification through guided cardiopoiesis may be needed to optimize therapeutic outcomes. Adiposity signaling promotes the recruitment of adipocytes from adipose tissue-associate mesenchymal cells.

Thus, the presence of adiposity may promote an increased number of progenitor cells available for mobilization into the circulation and potentially enhance adipose tissue mesenchymal differentiation into cells more apt to undergo either cardiopoiesis or adipogenesis (i.e., not yet solely committed to adipogenesis). If so, then an increase in the circulatory release of mesenchymal cells during cardiac injury (or possibly cardiac procedures) might have a greater potential for cardiovascular auto repair. Supporting this mechanism is that abnormally expanded fat tissue increases the mobilization of endothelial progenitor cells, which may have a protective effect against vascular atherosclerosis in obese patients.

Cardiovascular Clinical Trial Paradox:

Adiposopathy may also help explain why overweight patients with elevated markers of inflammation and no major cardiovascular risk factors may, paradoxically, not be “healthy.” The JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial was a landmark CVD outcome trial of 17,802 “apparently healthy men and women” with low-density lipoprotein cholesterol levels < 3.3mmol/l and high-sensitivity C-reactive protein levels ≥2.0 mg/l who were randomized to rosuvastatin (Crestor) 20 mg/day or placebo. The conclusion was that rosuvastatin significantly reduced CVD in “apparently healthy persons without hyperlipidemia but with elevated high sensitivity C-reactive protein levels”.

However, baseline median BMI was ~28 kg/m2 (a BMI ≥25 kg/m2 is considered overweight; a BMI ≥27 mg/m2 with co morbidity is a cutoff point to consider weight-loss drug therapy). Also at baseline, metabolic syndrome was present in 41% of study participants.

One interpretation of the study results was that elevated C-reactive protein is not only a marker of vascular inflammation, but also plays a direct role in the pathogenesis of atherosclerosis and thrombosis. An alternative interpretation is that adiposopathy (a “disease”) was present at baseline in many study participants, as supported by the high mean BMI, the high percentage of study participants with metabolic syndrome, and the elevated C-reactive protein. The latter is supported by the findings that C-reactive protein may be directly released from adipose tissue. Perhaps more importantly, excessive body fat increases adipose tissue release of interleukin-6, which stimulates increased C-reactive protein production from the liver.

It seems plausible that the increased C-reactive protein level found among many JUPITER study participants was significantly due to pathogenic adipose tissue immune responses. Thus, within the adiposopathic paradigm, many of the study participants were not “healthy persons.” Many study participants had evidence of adiposopathy, which may directly and indirectly promote CVD. Finally, it is of interest that a reduction in inflammatory markers (e.g., interleukin-6, C-reactive protein) with statins may, in part, be due to statin-induced reductions in adipose tissue inflammation.

Conclusions:

Adiposopathy or “sick fat” is a cardiovascular disease and requires novel solutions to reverse the pathology.

I believe ‘keto-adaptation” with low carbohydrate diets coupled with exercise is possibly the solution. A study has recently been published on the efficacy of carbohydrate restricted diets < 20 g/d in T2DM patients poorly controlled despite combination therapy with Metformin; Insulin and Liraglutide therapy, on metabolic control.

Nearly all participating patients experienced a significant drop in HbA1c at 6 months with 71% reaching the ideal goal of 7.0% . The average mass reduction after 6 months was 10% with most patients satisfied with this form of therapy.

Cheers and Blessings

Cardiologydoc