Introduction
Primary or, more frequently, secondary oversecretion of cortisol results in Cushing's syndrome. The leading cause of morbidity and mortality in Cushing's syndrome is cardiovascular disease, and increased risk persists even in patients receiving excellent treatment. Excess cortisol has various adverse effects on the heart, such as increased blood pressure, truncal obesity, hyperinsulinemia, hyperglycemia, insulin resistance, and dyslipidemia. The principal human glucocorticoid is required to maintain normal blood pressure and, when present in excess, either globally or locally, results in hypertension.
What Are the Metabolic Risk Factors for Atrial Fibrillation In Patients with Cushing Syndrome (High Level Of Plasma Cortisol)?
A characteristic of Cushing's syndrome is increased cardiovascular morbidity and death. Only 50% of people with untreated Cushing's syndrome survive for five years. Morbidity is still high in people with Cushing's syndrome even after treatment, and cardiovascular disease is a significant contributor. Due to an accidental adrenal adenoma with minor autonomous cortisol hyperproduction, subclinical Cushing's syndrome patients had considerably higher systolic and diastolic blood pressures than controls. The risk of cardiovascular and cerebrovascular illness is also markedly raised in glucocorticoid-treated patients.
1. Hypertension
There is concrete evidence that increased cortisol secretion caused by the adrenocorticotropic hormone (ACTH) causes the raised blood pressure associated with Cushing's syndrome. It has been demonstrated that ACTH elevates blood pressure in healthy normotensive and hypertensive participants in a reproducible manner, but not in Addison's disease patients receiving steroid therapy.
This shows that ACTH hypertension is dependent on the adrenal glands. Although human aortic endothelial cells have been found to contain ACTH receptors, it seems improbable that ACTH directly causes ACTH hypertension in humans. In a case study, excess cortisol was linked to hypertension associated with Cushing's syndrome.
Several pathophysiological pathways that control plasma volume, peripheral vascular resistance, and cardiac output, all of which are elevated in CS, interact to produce hypertension in people with CS. Additionally, glucocorticoids may have some hypertensive effects on the central nervous system's control of the circulatory system through glucocorticoid and mineralocorticoid receptors (MR). These glucocorticoid alterations result in chronic hypertension through rising cardiac output, total peripheral resistance, and renovascular resistance. CS's hypertension also appears to be influenced by insulin resistance and sleep apnea.
Following are the pathophysiological pathways that control plasma volume, peripheral vascular resistance, and cardiac output:
1. Cortisol's mineralocorticoid action.
2. Renin-angiotensin system activation.
3. Heart rate increases when given vasoconstrictor drugs like angiotensin and vasopressin. Enhanced catecholamine sensitivity of beta-adrenergic receptors suppresses the vasodilatory system, Total peripheral resistance, and enhanced cardiac output.
2. Obesity
Many metabolic problems brought on by central obesity lead to early death. In excess, glucocorticoids lead to central obesity because they control how adipose tissue differentiates, functions, and is distributed. Two isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which converts hormonally active cortisol to inactive cortisone, play a role in regulating glucocorticoid hormone action.
A defining feature of Cushing's syndrome is truncal obesity. Compared to controls of the same age and sex, patients with Cushing's illness (n = 25) exhibited greater body mass index and waist-to-hip ratios (Faggiano et al. 2003). In 15 patients who had been treated more than five years prior, these symptoms lingered (Colao et al. 1999). Weight increase is a feature in the investigations of short-term cortisol treatment (200 mg/day) in healthy normotensive males, and it most likely results from salt and water retention over five days. (Connell et al. 1987)
Bujalska et al. 1997 discovered that omental, but not subcutaneous fat, adipose stromal cells might produce active cortisol from inactive cortisone by expressing 11-HSDI. That enzyme expression was increased after exposure to cortisol and insulin. They found that such a method would guarantee continuous glucocorticoid exposure, primarily to omental fat, resulting in central obesity (Bujalska et al. 1997). The lab has since demonstrated that 11-HSDI predominantly functions as a dehydrogenase in intact, undifferentiated omental adipose stromal cells, but in mature cells, oxidoreductase activity predominates. They proposed that since glucocorticoids restrict cell proliferation, 11-HSDI activity in uncommitted cells may promote proliferation; nevertheless, once early differentiation is initiated, a switch to oxidoreductase activity generates cortisol, which promotes adipogenesis (Bujalska et al. 2002).
According to Whorwood and colleagues (2001, 2002), insulin resistance may be significantly influenced by the modulation of glucocorticoid receptor isoforms and 11-HSDI expression in skeletal muscle, and elevated receptor expression may aid in the etiology of the metabolic syndrome.
3. Dyslipidemia
Dyslipidemia appears less common in human Cushing's syndrome than other metabolic comorbidities. However, overt and subclinical Cushing's syndrome is crucial in establishing the overall cardiovascular risk. Though HDL levels can fluctuate, triglyceride and total cholesterol levels rise in Cushing's syndrome. Both overt and subclinical Cushing's syndrome share numerous characteristics of the metabolic syndrome, such as insulin resistance, elevated fasting glucose levels, hypertension, obesity, and dyslipidemia. The pathogenetic mechanisms are multifaceted and involve both direct and indirect effects of cortisol on lipolysis, the formation and metabolism of free fatty acids, the synthesis of very low-density lipoproteins, and the accumulation of fat in the liver. Many of the metabolic alterations brought on by glucocorticoids are mediated by AMP-activated protein kinase. Lipid abnormalities are largely determined by insulin resistance. Other hormonal adjustments include Growth hormones, estrogen, testosterone, catecholamines, and cytokines, among the additional hormonal changes involved.
4. Hypokalemia
Instead of the impact of adrenal steroid biosynthetic intermediaries with mineralocorticoid activity or the regulation of the 11betaHSD2 enzyme by ACTH, excessive cortisol levels (Cushing syndrome) may be the primary cause of hypokalemic alkalosis in Cushing's syndrome.
To be considered hypokalemic, serum K+ levels must be below 3.5 mM. The use of diuretics and activation of the renin-angiotensin-aldosterone pathway, which results in K+ loss in the urine, are the main causes of hypokalemia in heart failure. By relocating K+ into the intracellular compartment, increased catecholamine levels contribute, although volume overload in more advanced HF may result in a diluting effect (Leier et al., 1994). It has long been known that people taking digitalis are more likely to develop hypokalemia and cardiac arrhythmias when taking diuretics, including Thiazides and Loop diuretics.
Mineralocorticoid receptor antagonists decrease the renal excretion of K+, raise serum-[K+], and reduce the risk for cardiac arrhythmias brought on by hypokalemia, in contrast to thiazides and loop diuretics. ACE inhibitors, aldosterone receptor blockers, and beta blockers may prevent hypokalemia by preventing the neurohumoral activation brought on by HF, which decreases serum-[K+].
Conclusion
There is growing evidence that cortisol increases cardiovascular risk generally as well as in Cushing's syndrome. Dyslipidemia, hypertension, truncal obesity, hyperglycemia, and insulin resistance are all significant in this context. Mineralocorticoid-induced sodium retention and volume expansion cannot account for glucocorticoid hypertension. Treatments for Cushing's syndrome patients should focus on reducing cardiovascular risk, and they will likely need to address several metabolic and hemodynamic problems.
