Impact of Endocrine Disorders on Typical and Atypical Cardiovascular Risk Factors

  • M. PerticoneEmail author
  • F. Perticone
Living reference work entry
Part of the Endocrinology book series (ENDOCR)


Specific factors, both genetic and environmental, modifiable and nonmodifiable, increase the risk of developing cardiovascular diseases. Traditional cardiovascular risk factors are strongly associated with both morbidity and mortality and can be improved through lifestyle modification and/or pharmacologic treatment (e.g., arterial hypertension, dyslipidemia, smoking, obesity, etc.). The so-called “nontraditional” cardiovascular risk factors include chronic inflammation and its markers, such as C-reactive protein, homocysteine, oxidative stress or endothelial dysfunction, lipoprotein (Lp) a, psychosocial factors (i.e., environmental stress and responsiveness to stress), plasma insulin levels and markers of insulin resistance (IR), uric acid, chronic kidney disease (CKD), and activation of the renin-angiotensin-aldosterone system (RAAS).

Normal endocrine function is essential for CV health. Disorders of the endocrine system, both hyper- and hypofunction, exert multiple effects on the CV system.


Cardiovascular risk factors Endocrine disorders Hypertension Insulin resistance Dyslipidemia Endothelial dysfunction 


Population-based studies, such as the Framingham Heart Study, have established that specific factors, both genetic and environmental, modifiable and nonmodifiable, increase the risk of developing cardiovascular (CV) diseases (Dawber et al. 1951). The 27th Bethesda Conference: Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events has classified proposed CV risk factors into four categories based on descending levels of evidence to support the efficacy of direct management in reducing CV morbidity and mortality. Most attention in the literature has focused on the traditional risk factors in categories I and II (Table 1). These risk factors are strongly associated with CV morbidity and mortality and can be improved through lifestyle modification and/or pharmacologic treatment (e.g., arterial hypertension, dyslipidemia, smoking, obesity, etc.).
Table 1

Proposed risk factors categories

I. Risk factors for which interventions have been proved to reduce the incidence of coronary artery disease events

II. Risk factors for which interventions are likely, based on our current pathophysiologic understanding and on epidemiologic and clinical trial evidence, to reduce the incidence of coronary artery disease events

III. Risk factors clearly associated with an increase in coronary artery disease risk, which, if modified, might lower the incidence of coronary artery disease events

IV. Risk factors associated with an increased risk but that cannot be modified or whose modification would be unlikely to change the incidence of coronary disease events

Reprinted from the 27th Bethesda Conference: Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. 1995 Sep 14–15. J Am Coll Cardiol 1996; 27:957–1047. Copyright © 1996 Elsevier Science

The so-called “nontraditional” CV risk factors, such as those in category III (Table 1), have been identified based on more recent studies of the pathogenesis of atherosclerosis and atherothrombotic CV events. These include chronic inflammation and its markers, such as C-reactive protein, homocysteine, oxidative stress or endothelial dysfunction, lipoprotein (Lp) a, psychosocial factors (i.e., environmental stress and responsiveness to stress), plasma insulin levels and markers of insulin resistance (IR), uric acid, chronic kidney disease (CKD), and activation of the renin-angiotensin-aldosterone system (RAAS), which is in part a function of polymorphisms in genes for components of the system, such as angiotensinogen and the angiotensin II, type 1 (AT1) receptor.

Endocrine disorders, involving many organs and systems, have several effects on both traditional and nontraditional CV risk factors. The following paragraphs will analyze all the endocrine disorders impacting on CV risk.

Normal endocrine function is essential for CV health. Disorders of the endocrine system, both hyper- and hypofunction, exert multiple effects on the CV system.

Effects of Glucose Metabolism Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

Diabetes mellitus (DM) is the most common manifestation of glucose metabolism alterations, and it is both a CV risk factor and a CV disease per se. It is associated with long-term micro- and macrovascular complications.

Coronary and peripheral vascular atherosclerotic disease is present in more than 50% of patients with DM, occurring at an earlier age and in a more diffuse pattern than in nondiabetic patients. Vascular disease is the primary cause of death in 80% of individuals with DM. People with DM with no prior history of heart disease have the same risk for myocardial infarction as nondiabetic patients with a known prior history of heart disease. In addition to accelerated atherosclerosis, these patients often demonstrate endothelial dysfunction secondary to early development of coronary artery disease, impaired nitric oxide release, increased serum levels of free fatty acids, and advanced end products of glycosylation. DM leads to impaired regeneration after vascular injury and impaired arteriogenesis.

Dyslipidemia in patients with DM is predominantly characterized by increased triglycerides and low high-density lipoprotein level; classically, the low-density lipoprotein (LDL) level is not elevated, but the LDL particles tend to be smaller, denser, and more susceptible to oxidation, leading to increased atherogenicity. Hypercoagulability secondary to increased levels of fibrinogen and plasminogen activator inhibitor type I and enhanced platelet aggregation is present.

Diabetic cardiomyopathy, which is a distinct entity from ischemic cardiomyopathy, is often seen in patients with DM and may be related to impaired energy utilization and diastolic dysfunction. Autonomic nervous system dysfunction may produce increased sympathetic tone at baseline and may contribute to silent myocardial ischemia, impaired heart rate variability, and poor prognosis (Haffner et al. 1998).

Effects of Prolactin Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

Prolactin (PRL) is synthesized and secreted by lactotroph cells of the anterior pituitary gland and stimulates lactation in the postpartum period. PRL is tonically inhibited by hypothalamic dopamine. PRL levels are physiologically elevated in pregnancy, the postpartum period, and in states of stress. Pathologic hyperprolactinemia may be caused by decreased dopaminergic inhibition or by PRL secretion from benign pituitary adenomas (prolactinomas). The prevalence of hyperprolactinemia ranges from 0.4% in the general adult population to 9% in women with reproductive disorders. Although hyperprolactinemia itself does not have clear effects on the CV system, there is a possible association between long-term treatment with dopamine agonists and cardiac valve abnormalities.

Dopamine agonists, including cabergoline, bromocriptine, and quinagolide, are the primary treatment for prolactinomas. High doses and long duration of therapy with dopamine agonists have been associated (in Parkinson’s disease) with an increased risk of regurgitant valve disease. Although doses used for prolactinoma therapy are much lower than those used for Parkinson’s disease, patients with prolactinoma may be treated for decades. This treatment duration raises concern for increased risk of valvulopathy, including tricuspid regurgitation, mitral regurgitation, and aortic regurgitation (Valassi et al. 2010). Although most reports do not show an association between the use of dopamine agonists and cardiac valve disease, clinicians are advised to use the lowest possible doses of dopamine agonists. Echocardiographic monitoring should be considered, especially in patients requiring long-term and/or higher-dose therapy, and those with underlying heart or valvular disease.

Effects of Sexual Hormone Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

Androgens play a major role in human metabolic health and disease. Female androgen excess (AE) and male androgen deficiency (AD) exhibit overlapping metabolic phenotypes, highlighting the complexity of the role of androgen in metabolism. Effects of androgens on adipose tissue and muscle may largely be governed by circulating serum and tissue-specific concentrations, with a narrow physiological window in both sexes, outside of which disturbances in metabolism and body composition are observed. In healthy women, low androgen concentrations and elevated estrogens lead to predominant gynecoid fat distribution and reduced metabolic risk; at circulating androgen levels observed in severe female AE and male AD, preferential accumulation of central and visceral adiposity is observed, while at higher androgen concentrations seen in healthy men, this effect is dissipated by increasing lean body mass, muscle bulk, and reducing fat mass.

Androgen Excess in Women and Related Metabolic Consequences

Disturbances in androgen metabolism secondary to gonadal, adrenal, or hypothalamic-pituitary disease lead to alterations of circulating androgen concentrations and result in reproductive and metabolic complications. In women, polycystic ovary syndrome (PCOS), a triad of ovulatory dysfunction, polycystic ovarian morphology, and AE, represents the most common endocrine disorder. In men, disturbances of gonadal function most commonly result in hypogonadism and consequent AD, which can be inherited or acquired by disease, obesity, medications, or the aging process. Interestingly, female AE and male AD are associated with a similar adverse metabolic phenotype, including obesity, IR, increased prevalence of type 2 DM, nonalcoholic fatty liver disease (NAFLD), and CV disease (Zarotsky et al. 2014).

Polycystic Ovary Syndrome

PCOS is the most common cause of AE in women, affecting 5–10% of women of reproductive age. According to the 2003 Rotterdam criteria, PCOS is diagnosed when two of the following three features are present: ultrasound appearance of polycystic ovarian morphology (PCOM), anovulation (AO), and AE. PCOS is also a major metabolic disorder, associated with IR, visceral adiposity and obesity, dyslipidemia, NAFLD, and CV disease. PCOS-associated metabolic dysfunctions intimately linked with AE; conventionally, circulating androgen burden has been typically evaluated by measuring serum testosterone (T), but recent work has defined androstenedione (A4) as a more sensitive marker for detecting PCOS-related AE and has demonstrated that integrated assessment of A4 and T is predictive of adverse metabolic risk (O’Reilly et al. 2014).

Women with Monogenic Causes of Androgen Excess

The variants of congenital adrenal hyperplasia (CAH) represent a group of inborn disorders with autosomal recessive inheritance characterized by glucocorticoid deficiency and variable impact on mineralocorticoid and androgen secretion. In affected women, there are three CAH variants AE-associated: 21-hydroxylase deficiency, 11β-hydroxylase deficiency, and 3β-hydroxysteroid dehydrogenase type 2 deficiency. The most common of these defects is 21-hydroxylase deficiency and results in a nonclassic CAH form with only mild glucocorticoid deficiency but relevant AE (Speiser and White 2003). As a consequence of the enzymatic block, precursor steroids are shunted down the pathways of androgen biosynthesis, which is further increased by enhanced hypothalamic-pituitary-adrenal drive due to the loss of the negative feedback by cortisol. While patients with major loss-of-function mutations usually present at birth or in early childhood, patients with mild mutations are often only diagnosed in early adulthood, as their glucocorticoid and mineralocorticoid secretion is sufficiently upheld by continuously increased ACTH stimulation of the adrenals, at the expense of AE. These patients usually do not present with outright virilization but generally with a PCOS phenotype in adolescence or early adulthood, including hirsutism, irregular periods, and PCO appearance of the ovaries. In patients with nonclassic CAH, an increased prevalence of obesity and insulin resistance has been reported, mirroring the adverse metabolic phenotype found in PCOS. As PCOS represents a diagnosis of exclusion and on average 2–3% of women presenting with a PCOS phenotype are identified as suffering from nonclassic CAH, screening for CAH by baseline serum 17-hydroxyprogesterone is recommended in the work-up of PCOS.

Women with Monogenic Insulin Resistance

Severe IR can develop independently of obesity as a consequence of monogenic gene defects impacting on insulin signaling or adipose tissue development. Defects in insulin signaling can be found at the level of the insulin receptor or in post-receptor signal transduction. Monogenic disorders may also cause severe obesity and consequent IR or dysfunctional adipose tissue development resulting in congenital complete or partial lipodystrophy (Semple et al. 2011). Patients with IR due to monogenic lipodystrophy or insulin receptor (INSR) mutations present with AE, ovulatory dysfunction, PCO, and acanthosis nigricans, usually in the absence of obesity. Compensatory hyperinsulinemia may stimulate ovarian androgen biosynthesis by direct effects of insulin on theca and stromal cells, although other peripheral sources of insulin-stimulated androgen generation cannot be discounted.

Androgen Deficiency in Men and Related Metabolic Consequences

Male AD is a clinical syndrome arising from failure of testicular T production, in the context of primary testicular pathology or hypothalamic-pituitary disease. In adult men, it is diagnosed by the presence of physical symptoms of AD with biochemical evidence of low circulating T. Common symptoms are a reduction of libido and erectile strength, fatigue, reduced physical strength and endurance as well as sometimes impaired cognitive function and mood disturbances (Boehm et al. 2015).

Primary Male Hypogonadism

Primary male hypogonadism (HG) is defined by low serum T in combination with increased luteinizing hormone (LH). Normal T and high LH levels characterize compensated hypogonadism, which represents impaired testicular function that is rescued by increased LH stimulation. Compensated hypogonadism is subclinical but increases the likelihood to progress to overt AD when compared to the eugonadal state. Congenital primary HG can be caused by gonadal dysgenesis and cryptorchidism, as well as by autosomal or sex chromosome aneuploidies like in Klinefelter syndrome.

Secondary Male Hypogonadism

Secondary HG, or hypogonadotropic HG, is defined by low T and reduced gonadotrophin secretion due to impaired hypothalamic-pituitary stimulation of testicular androgen synthesis. The overwhelming majority of such cases are caused by tumors of the hypothalamic-pituitary area. Congenital hypogonadotropic hypogonadism may be observed in the context of multiple pituitary hormone deficiencies in conditions such as septo-optic dysplasia but more commonly is associated with isolated gonadotrophin deficiency as observed in Kallmann syndrome, which may be associated with anosmia and craniofacial abnormalities.

Acquired Male Hypogonadism

Acquired HG may be caused by lesions or tumors of the central nervous system or testis, radio- and chemotherapy, pharmacological treatment, chronic illness, poor health, and obesity. Surgical or pharmacological androgen deprivation therapy is an established treatment option for both metastatic hormone-naive and castration-resistant prostate cancer.

Aging affects the hypothalamic-pituitary-gonadal (HPG) axis and can lead to late-onset AD, which is defined as low T levels if any form of classical causes of AD can be excluded. Aging can result in gradual development of testicular failure due to a decreased number and response to LH of Leydig cells and in reduced hypothalamic-pituitary signaling.

Male AD can also be induced by obesity (Kelly and Jones 2015). Obesity significantly increases the age-related T decline and is associated with disordered gonadotrophin release. Conversely, weight loss can reverse obesity-associated hypogonadism. The concept of a hypogonadal-obesity-adipokine cycle is a proposed mechanism behind this association. Obesity has been suggested to lead to enhanced aromatization of androgens to estrogens by aromatase in adipose tissue, thereby reducing the level of active androgens. Estrogens may suppress the HPG axis, which reduces gonadal T synthesis.

The Role of Androgens in Metabolic Target Tissues

In addition to their central role in the development and maintenance of male and female reproduction and sex drive, androgens exert key effects on metabolic target tissues. These include adipose tissue and skeletal muscle, compartments crucially involved in maintaining systemic glucose and lipid homeostasis.

Androgens, Adipose Tissue, and Lipid Metabolism

Patterns of body fat distribution show a clear sexual dimorphism, with women showing a higher percentage of body fat than men and, on the contrary, with men having a greater total lean mass. The typical fat distribution in women is in a gynecoid manner, with less visceral but more subcutaneous fat; men have a predominant android fat distribution, with more visceral and less subcutaneous adipose tissue. Adipose tissue expansion is a consequence of both hyperplasia (adipogenesis), which is driven by proliferation of preadipocytes and their differentiation into adipocytes, and hypertrophy, which is driven by accumulation of lipid in differentiated adipocytes; both processes are major determinants of metabolic dysfunction (Demerath et al. 2007).

Androgens impair adipogenesis by inhibiting proliferation and differentiation of mesenchymal stem cells and preadipocytes. Dihydrotestosterone (DHT) and T have inhibitory effects on multipotent stem cell commitment to the preadipocyte lineage, as well as on adipocyte differentiation in both sexes. In addition, dehydroepiandrosterone (DHEA), but not DHEA-sulfate (DHEAS), inhibits proliferation and differentiation of human subcutaneous preadipocyte cell line and enhances basal glucose uptake. An impairment of adipocyte proliferation and differentiation may lead to adipocyte hypertrophy as a compensatory mechanism to increase adipose tissue mass, which could induce adipocyte dysfunction seen in IR, intracellular stress, and inflammation which, in turn, induces a pro-inflammatory, diabetogenic, and atherogenic serum profile. Androgens also exert direct and indirect effects on adipose insulin sensitivity.

Differential effects of androgens on adipose tissue and skeletal muscle and implications for global metabolism can be summarized as follows: androgens may exert pro-lipogenic effects on adipose tissue, resulting in fat mass expansion; at higher concentrations, as observed in the healthy male range, net anabolic effects on increasing skeletal muscle bulk predominate. However, with circulating androgen levels in the range of female androgen excess and male androgen deficiency, a loss of muscle mass and an increase in abdominal obesity drive the systemic phenotype and give rise to metabolic and CV disease (Fig. 1).
Fig. 1

Differential effects of androgens on adipose tissue and skeletal muscle and implications for global metabolism. T testosterone, DHT dihydrotestosterone, 11KT 11-keto-testosterone, 11KDHT 11-keto-dihydrotestosterone. (Reprinted from: Schiffer L, Kempegowda P, Arlt W, O’Reilly MW. Mechanisms in endocrinology: the sexually dimorphic role of androgens in human metabolic disease. Eur J Endocrinol 2017;177(3):R125-R143)

Insulin Resistance, Type 2 Diabetes Mellitus, and Androgen Status in Men and Women

IR is defined as the impaired systemic metabolic response to insulin, which includes glucose uptake and metabolism, suppression of lipolysis and promotion of lipogenesis, as well as protein and glycogen synthesis. IR is accompanied by compensatory hyperinsulinemia, leading to an exaggerated insulin response in normally less responsive tissues, as well as disturbances in hepatic and adipose lipid metabolism. Frank hyperglycemia occurs after decompensation of the exaggerated pancreatic beta-cell response to systemic IR.

Female Androgen Excess and Insulin Resistance

The presence of AE in PCOS is closely correlated with IR. Women with PCOS show a trend to progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and to type 2 DM, and obesity significantly increases the risk. Both obese and nonobese PCOS women with AE show a high prevalence of IGT and T2DM, but obesity deteriorates the diabetic phenotype. Conversely, T levels are significantly higher in women with T2DM; consequently, AE in women has been suggested as a risk factor for T2DM (Ding et al. 2006).

Male Androgen Deficiency and Insulin Resistance

In men, T levels are positively associated with insulin sensitivity, and even in men with established diagnosis of type 2 DM, low T is independently associated with IR; on the contrary, in women higher T levels predict hyperglycemia.

Body Composition and Impact of Androgen Status in Men and Women

Similar to gender-specific effects observed for androgen activity on systemic IR, there are sexually dimorphic effects of androgens on body composition.

Female Androgen Excess on Body Composition

PCOS women with clinical and/or biochemical evidence of AE show a higher prevalence of obesity and an increased global adiposity than the general female population. Furthermore, studies on PCOS women with AE describe an increased lean mass correlating with serum T and A4, with a shift in fat distribution from a gynecoid to an android pattern (Kirchengast and Huber 2001).

Male Androgen Deficiency and Body Composition

In comparison with women, circulating androgens in men correlate inversely with body mass index (BMI) and visceral adiposity. A large amount of literature supports the association between low T and increased fat mass compared to eugonadal controls. BMI negatively correlates with total and free T, and waist circumference is negatively associated with total T in men. Although age is associated with decreased androgen levels, negative associations between T and total body fat mass, body fat percentage, waist circumference, and visceral adipose tissue are maintained after adjustment for age (Blouin et al. 2005).

Nonalcoholic Fatty Liver Disease (NAFLD) and Male and Female Androgen Status

The term NAFLD covers a spectrum of hepatic injury induced by obesity and IR, in the absence of significant alcohol consumption. The NAFLD spectrum ranges from intrahepatic accumulation of triglycerides or simple steatosis to diffuse tissue inflammation or nonalcoholic steatohepatitis (NASH), with a risk of progression to advanced hepatic fibrosis and cirrhosis (Hazlehurst and Tomlinson 2013). NAFLD is a major metabolic complication and an emerging CV risk factor.

Female Androgen Excess and NAFLD

Prevalence rates of NAFLD in PCOS appear to be higher than those in the general female population; a recent meta-analysis found that patients with PCOS have an almost fourfold higher prevalence of NAFLD compared to controls with simple obesity, even if the putative causative mechanism underlying PCOS-related NAFLD remains to be elucidated.

Male Androgen Deficiency and NAFLD

The role of T in the pathogenesis of NAFLD has been investigated in several studies, all reporting an inverse association between serum T and NFLD. The initial mechanism hypothesized for this association was the increased visceral adiposity in the context of hypogonadism, but recent studies have pointed out a direct role for androgens on liver metabolism, resulting in an increased malonyl-CoA, a substrate for de novo lipogenesis (Schwingel et al. 2011). Moreover, synthetic anabolic steroid use has also been linked hepatic steatosis in men.

Cardiovascular Risk and Male and Female Androgen Status

Female Androgen Excess and Cardiovascular Risk

Several studies demonstrated that AE in PCOS is associated with higher total cholesterol and lower HDL levels, but does not affect triglycerides and LDL levels, as well as with higher values of markers of systemic inflammation, oxidative stress, and coagulation disorders, all contributing to increase the CV risk burden. Women with PCOS and AE also exhibit microvascular dysfunction due to impaired vasodilation. Data on long-term CV events in PCOS are inconsistent: some studies concluded that there is no increased risk for large vessel disease, abdominal aortic plaque, myocardial infarction, or stroke, while others describe increases in the prevalence of myocardial infarction and angina and in the risk of coronary heart disease and stroke.

Male Androgen Deficiency and Cardiovascular Risk

In men, low T levels are associated with a proatherogenic lipid profile, while an inverse relation between T and triglycerides, total cholesterol, and LDL was described (Wu and von Eckardstein 2003). On the other hand, men with coronary artery disease present with lower T levels, and its severity is negatively correlated with T levels. Male AD is associated with a higher risk of all-cause mortality, and an inverse correlation exists between T levels and prospective mortality due to all causes, CV disease, and cancer.

Effects of Thyroid Hormone Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

The thyroid is intricately related to the CV system, sharing a common embryological origin, and thyroid hormones exert effects virtually on every organ system, including the heart and the vasculature (Grais and Sowers 2014).

The thyroid gland secretes two main iodinated hormones, 3,5,3′-triiodothyronine (T3) and 3,5,3′5′-tetraiodothyronine (T4), also known as thyroxine. Both molecules can generate biological activity in target tissues by binding to the thyroid hormone receptors; however, T3 is considered the bioactive form of thyroid hormone that mediates peripheral effects and, therefore, of specific interest with respect to risk for CV events. The affinity of the thyroid hormone receptor is approximately tenfold higher for T3 than for T4; for this reason T4 must be converted to T3 to produce potent thyroid hormone receptor-mediated effects. Anyway, although T4 is a prohormone for T3, it can directly act through thyroid hormone receptors in a variety of tissues, such as blood vessels, exerting a proangiogenic effect. Thyroid hormones have a broad range of effects on the CV system, particularly on the heart. They influence cardiac status in three ways: (1) by direct genomic actions on cardiomyocytes, resulting in the regulation of the expression of target genes; (2) by extranuclear, nongenomic actions on the ion channels in the cardiomyocyte cell membrane; (3) and through the effects of T3 and T4 on the peripheral circulation, which determines CV hemodynamics, cardiac filling, and systolic contractility (Jabbar et al. 2017). Thyroid hormone activity in the cardiomyocyte regulates myocardial contractility and systolic function by the activation of the expression of genes encoding sodium-/potassium-transporting ATPases, myosin heavy chain-α, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and negatively regulates the transcription of myosin heavy chain-β, leading to improved ventricular relaxation. Thyroid hormones also have a direct inotropic effect on the heart by positively regulating the gene expression of the β1-adrenergic receptor. In addition, thyroid hormones influence cardiac chronotropy through both genomic and nongenomic effects on components of the adrenergic receptor complex and on sodium, potassium, and calcium channels. The effect of thyroid hormones on cardiac chronotropy manifests as tachycardia and increased risk of atrial fibrillation in hyperthyroid states and as bradycardia and reduced cardiac contractility in hypothyroidism. Nongenomic effects of thyroid hormones on cardiomyocytes and the systemic vasculature include activation of sodium, potassium, and calcium membrane ion channels, effects on mitochondria, and involvement in signaling pathways of cardiomyocytes and vascular smooth muscle cells. Thyroid hormones activate phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (AKT) signaling pathways, inducing production of endothelial nitric oxide and a subsequent reduction in the systemic vascular resistance. Other nongenomic actions of thyroid hormones include vasodilation, due to a reduction of vascular resistance by both an increased production of nitric oxide (NO) and an increased calcium reuptake within the arterioles, which leads to smooth muscle relaxation. The decrease in systemic vascular resistance induced by thyroid hormones, together with their direct inotropic effects, leads to an increase in cardiac output. The renin-angiotensin-aldosterone system also has an important role in the hemodynamic effects of thyroid hormones. The initial decrease in systemic vascular resistance induced by thyroid hormones leads to decreased perfusion in the kidneys, which increases renin and aldosterone levels. The activation of the renin-angiotensin-aldosterone axis leads to an increase in cardiac preload, which is another explanation for the increase in cardiac output induced by thyroid hormones.

Thyroid dysfunction is very common, and the prevalence of both hypothyroidism and hyperthyroidism increases with age.

Overt and Subclinical Hyperthyroidism

Overt thyrotoxicosis or hyperthyroidism is commonly caused by stimulation of the TSH receptor by autoantibodies (Graves’ disease) or as a result of autonomous production of thyroid hormones by thyroid nodules. The prevalence of overt hyperthyroidism in the general population is 0.5%. This condition is defined by elevated peripheral free thyroid hormone levels (T3 and/or T4) and a decreased or undetectable TSH. Hyperthyroidism may result from autoimmune disease, thyroid nodule autonomy, or exogenous thyroid hormone ingestion.

Tachycardia is a common sign of overt hyperthyroidism, and 5–15% of patients with overt hyperthyroidism present with atrial fibrillation. Normalization of thyroid hormone levels leads to the reversion to normal sinus rhythm in approximately 60% of patients who have atrial fibrillation due to hyperthyroidism. Shortness of breath during minimal exertion is also commonly reported by patients with hyperthyroidism; however, the exact etiology of this symptom has not been clearly defined. Moreover, hyperdynamic circulation – characterized by increased preload and contractility, reduced systemic vascular resistance, and high heart rate, leading to a 50–300% increase in cardiac output – is common in overt hyperthyroidism. If overt hyperthyroidism is left untreated, or in those individuals with severe long-standing hyperthyroidism, this increased cardiac output can lead to symptoms and signs of heart failure as a result of left ventricular hypertrophy, arrhythmias, and an increase in cardiac preload secondary to fluid overload. Patients with hyperthyroidism, unless they received radioiodine therapy to induce overt hypothyroidism, have high long-term CV mortality (Feldman et al. 1986).

Subclinical hyperthyroidism is defined by low circulating TSH levels with serum concentrations of T3 and T4 within the reference range. Subclinical hyperthyroidism can be caused by exogenous (i.e., secondary to excessive thyroid hormone replacement therapy or use of other drugs such as high-dose glucocorticoids) or endogenous (such as an underlying thyroid disease causing thyroid overactivity) factors. The prevalence in the general population of endogenous subclinical hyperthyroidism depends on age, sex, and iodine intake, with a reported prevalence of 0.6–1.8% in iodine-sufficient areas and as high as 9.8% in iodine-deficient areas (Cooper and Biondi 2012). Whether exogenous and endogenous subclinical hyperthyroidism are equivalent in terms of CV effects or the risk of CV disease is currently unclear.

Some evidence shows a higher heart rate, increased frequency of atrial and ventricular premature beats, and a greater left ventricular mass compared with euthyroid individuals, defining a higher CV risk. Carotid intima-media thickness was also shown to be higher in patients with subclinical hyperthyroidism than in euthyroid individuals and patients with hypothyroidism. Moreover, little evidence exists about an increase in fibrinogen plasma levels, which in turn have been associated with an elevated risk of CV events. These risk factors would be expected to lead to an elevated risk of CV disease in patients with subclinical hyperthyroidism; in particular, several studies demonstrated an association between endogenous subclinical hyperthyroidism and incident CV disease, atrial fibrillation, and cardiac dysfunction.

Overt and Subclinical Hypothyroidism

Overt hypothyroidism is diagnosed when serum TSH is elevated (usually>10 mU/L) and circulating free T4 is low (<9–10 pmol/L). The prevalence of overt hypothyroidism in nonpregnant adults is 0.2–2.0%.

Overt hypothyroidism has several cardiac manifestations, including a reduction in cardiac output and cardiac contractility, a decrease in heart rate, and an increase in vascular resistance. Marked changes in modifiable atherosclerotic risk factors also accompany overt hypothyroidism, including hypercholesterolemia, diastolic hypertension, increased carotid intima-media thickness, and reduced production of NO (Biondi and Cooper 2008). All these clinical features are reversible with thyroid hormone replacement therapy.

Subclinical hypothyroidism is diagnosed when serum thyroid hormones are within the reference range, but serum TSH concentrations are elevated. This condition can be defined mild (TSH >4.0–4.5 mU/L, but <10.0 mU/L) or severe (TSH >10.0 mU/mL). The prevalence of subclinical hypothyroidism in the general, adult population is 4–20%.

The most frequent cardiac alteration in individual with subclinical hypothyroidism is diastolic dysfunction owing to impaired ventricular filling and relaxation. Moreover, subclinical hypothyroidism is also responsible of an impaired relaxation of vascular smooth muscle cells, which in turn induces an increase in systemic vascular resistance and arterial stiffness. Also NO bioavailability can be reduced in this clinical condition (Kahaly 2000).

Thyroid Hormones and Cardiovascular Risk Factors


Thyroid hormones are involved in lipid metabolism. Overt and subclinical hyperthyroidism do not adversely influence lipid parameters. By contrast, the association between overt hypothyroidism and hyperlipidemia has been known for many years, with some estimates showing a link in up to 90% of patients with overt hypothyroidism (Duntas 2002). Elevated plasma lipid levels are also evident in some patients with subclinical hypothyroidism, suggesting an increased risk of atherosclerosis in these individuals.

The causes of hyperlipidemia in an underactive thyroid state are the decreased expression of hepatic LDL receptors – which reduces cholesterol clearance from the bloodstream – and the reduced activity of the cholesterol breaking down enzyme monooxygenase-α.

Insulin Resistance

IR is defined as a glucose homeostasis disorder involving a decreased sensitivity of muscles, adipose tissue, liver, and other body tissues to insulin, despite its normal or increased plasma concentration. IR is a recognized CV risk factor, since it leads to prediabetes/overt diabetes, obesity, arterial hypertension, and dyslipidemia. Normal glucose metabolism may be disrupted by either a deficit or an excess of thyroid hormones, leading to carbohydrate disorders (Maratou et al. 2009).

Hyperthyroidism causes a significant increase in the level of tissue metabolism. In order to adapt to the greater energy loss, both baseline and insulin-stimulated rate of cellular glucose depletion increases as a result of the more intense glucose oxidation and lactic acid formation, the latter of which is subsequently used by the liver to accelerate gluconeogenesis and the production of endogenous glucose. Overt hyperthyroidism is often accompanied by abnormal glucose tolerance and IR. One possible explanation is the increased demand of insulin in hyperthyroid conditions, associated with accelerated metabolism, tissue IR, and increased insulin degradation. In thyrotoxicosis, increased glucose absorption occurs in the digestive tract thanks to a higher rate of stomach emptying and increased blood flow in the portal vein, which leads to postprandial hyperglycemia, characteristic of hyperthyroidism. Moreover, the effect of thyroid hormones on hepatocytes is antagonistic to insulin and stimulates glucose production in the liver by an increase in both gluconeogenesis and glycogenolysis. Thus, even if in subjects with hyperthyroidism the glucose uptake rate in peripheral tissues is increased, on the other hand, it has also been observed that anaerobic glucose metabolism stimulated by insulin is inhibited, as glycogenogenesis decreases due to the “redirection” of intracellular glucose to the process of glycolysis and generation of lactic acid. The lactic acid released from peripheral cells returns to the liver, where it becomes a substrate for the increased hepatic glucose production.

On the other hand, overt hypothyroidism is considered a risk factor for IR. In this condition, a decrease in the intestinal glucose absorption rate occurs, along with a decrease in the adrenergic activity leading to a reduction in liver and muscle glycogenolysis, as well as a decrease in gluconeogenesis and baseline insulin secretion. However, a postprandial increase in insulin secretion against the background of generalized peripheral IR has also been observed, associated with a higher concentration of free fatty acids, reduced glucose uptake, and increased glucose oxidation.

On the basis of these evidences, it is possible to affirm that thyroid hormones have a significant effect on glucose metabolism and the development of IR. In hyperthyroidism, impaired glucose tolerance may be the result of mainly hepatic IR, whereas in hypothyroidism it seems to prevail peripheral IR.

Blood Pressure and Vascular Function

The net effect of overt hyperthyroidism on blood pressure is variable depending on the increase in cardiac output versus the reduction in systemic vascular resistance (Danzi and Klein 2003). The relationship between subclinical hyperthyroidism and hypertension is less clear, with most observational studies suggest subclinical hyperthyroidism is not linked to hypertension.

Overt and subclinical hypothyroidism are associated with diastolic hypertension and impaired vascular function. The cause of hypertension in these patients is an increase in systemic vascular resistance, endothelial dysfunction, increased arterial stiffness, and low renin levels, most probably owing the lack of the normal vasodilatory effects of T3.

Central arterial stiffening increases cardiac afterload and is an important predictor of all-cause mortality, as well as a precursor for atherosclerosis. Arterial stiffness can be evaluated by measuring pulse wave velocity that increases in both subclinical and overt hypothyroidism and can be improved with levothyroxine therapy.

Endothelial dysfunction is involved in the early steps of atherosclerosis and is associated with an increased risk of CV events. Endothelial-dependent vasodilation is impaired in patients with hypothyroid states and can be improved by levothyroxine treatment.

Both these conditions – arterial stiffness and endothelial dysfunction – seen in hypothyroid states could be mediated by hyperlipidemia and thyroid autoantibodies. Hyperlipidemia could exert its role on endothelial dysfunction and arterial stiffness in a direct way, being one of the most important causes of atherosclerosis. On the other hand, the presence of an autoimmune process might underlie the endothelial dysfunction in most patients with subclinical hypothyroidism (Taddei et al. 2003). Moreover, both hyperlipidemia and thyroid antibodies are thought to reduce the expression of endothelial nitric oxide synthase and, therefore, impair the capacity of the artery to vasodilate.


Overt and subclinical hyperthyroidism have been associated with alterations in the coagulation pathway, even if this hypothesis needs to be further investigated. In particular, it remains still uncertain if the reported risk of cerebrovascular events is caused by blood thrombogenicity or by alterations in the vascular tree (e.g., an increase in the carotid intima-media thickness or the presence of vascular plaques).

Effects of Growth Hormone Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

Growth hormone (GH) is synthesized and secreted by somatotroph cells in the anterior pituitary gland. It acts directly on peripheral tissues via interaction with the GH receptor and indirectly via stimulation of insulin-like growth factor type 1 (IGF-1) synthesis. IGF-1 promotes glucose uptake and cellular protein synthesis. GH and IGF-1 regulate somatic growth, including cardiac development and function.

Growth Hormone Excess

Acromegaly is characterized by high circulating GH and IGF-1 levels and is caused by a benign pituitary adenoma in more than 98% of cases. Metabolic disturbances in patients suffering from this condition seem to be similar to those in the insulin-resistant state, i.e., hyperglycemia, hyperinsulinemia, and hypertriglyceridemia (Colao et al. 2004). Thus, it is not surprising that CV disease is the leading cause of mortality in these patients. Moreover, in acromegaly there is also an increase of CV risk factors, especially hypertension, impaired glucose tolerance/diabetes mellitus, dyslipidemia (high levels of triglycerides, low or normal levels of HDL cholesterol, presence of small and/or dense low-density lipoprotein cholesterol). Hypertension occurs in 20–50% of patients with acromegaly. Possible mechanisms include increased arterial stiffness due to hypertrophy and fibrosis of the arterial muscular tunica. Both blood pressure values and glycemic control improve with normalization of IGF-1. Acromegalic patients have less visceral and subcutaneous fat mass and increased intermuscular fat mass, which may be related to insulin resistance in this disease. On the other hand, acromegalic patients exhibit an enlargement of organs and soft tissues predisposing to obstructive sleep apnea (OSA), a CV risk factor per se.

Acromegalic patients often exhibit cardiac histological abnormalities, such as myocyte hypertrophy, interstitial fibrosis, inflammatory cell infiltration, reduced capillary density, myofibril derangement, and extracellular collagen deposition. The impact of these changes on the structure and function of myocardial and valvular tissues is determined by the duration and severity of GH/IGF-1 excess. In the early stage of acromegaly, there is enhanced myocardial contractility, decreased systemic vascular resistance, increased cardiac output, and overall increased cardiac performance. In the intermediate stage, after about 5 years of active disease, there is biventricular hypertrophy, diastolic dysfunction, and impaired exertional cardiac performance. Late-stage acromegalic cardiomyopathy is characterized by systolic and diastolic dysfunction, increased myocardial mass, ventricular cavity dilatation, and increased systemic vascular resistance. Acromegalic cardiomyopathy is frequently present at diagnosis. Up to two thirds of patients with acromegaly meet echocardiographic criteria for left ventricular hypertrophy; patients with severe cardiomyopathy may progress to heart failure. Successful treatment of acromegaly halts the progression of cardiac dysfunction and reduces CV mortality.

Several studies have documented cardiac rhythm abnormalities in acromegaly, including atrial and ventricular ectopic beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, bundle branch block, and ventricular tachycardia. Somatostatin analogs have been shown to reduce QT intervals and to improve the arrhythmic profile in acromegalic patients.

Cardiac valve disease (aortic and mitral regurgitation) is frequently observed in acromegaly. GH/IGF-1 excess may lead to abnormal extracellular matrix regulation and thus to pathogenesis of myxomatous valvulopathy. Aortic and mitral valve dysfunction often persists despite treatment of hormonal excess.

In patients with excess of GH, there is also the disruption of coagulation and the fibrinolytic system, in particular consistently high fibrinogen levels and elevated or unchanged levels of plasminogen activator inhibitor-1 (PAI-1).

The biological effects of GH on its target organs are exerted through direct or indirect stimulation of production of insulin-like growth factor 1 (IGF-1). GH directly acts as a strong promoter in lipolytic signaling. In contrast, GH might also promote lipid synthesis and storage by induction of IGF-1, which stimulates the insulin signaling pathway (Saltiel and Kahn 2001). IR is associated with an overactive vascular RAAS and impaired NO production, resulting in impaired vasodilation and, together with the increased reabsorption of sodium and water GH-mediated, in the appearance of arterial hypertension.

In adipose tissue, GH is an important mediator of lipolysis and directly acts on hormone-sensitive lipase and enhances the responsiveness for beta-adrenergic activity, which might explain higher plasma triglycerides concentrations, observed in patients with acromegaly.

Besides these metabolic effects counteracting insulin action and promoting the development of IR, GH and IGF-1 are both reported to increase mitochondrial oxidation capacity in animal models as well as in humans and therefore promote whole-body energy expenditure.

Growth Hormone Deficiency

Both GH and IGF-1 have been suggested to have regulatory role for peripheral resistance, with accumulating evidence supporting the vasodilating effects of IGF-1. This action seems to be mediated through release of NO and/or other vasodilators from the endothelium. Moreover, IGF-1 may cause vasorelaxation through non-endothelium-dependent actions, possibly by increasing the activity of the Na+/K+-ATPase in vascular smooth muscle cells. Nevertheless, conflicting results regarding blood pressure and peripheral resistance have been reported in the literature, with some studies reporting an increased prevalence of hypertension in GH-deficient adults and others demonstrating unchanged blood pressure values in this setting of patients.

Untreated GH deficiency is associated with increased body fat and central adiposity, dyslipidemia (both low values of HDL and high values of LDL), endothelial dysfunction, and IR. Increased carotid intima-media thickness, a marker of early atherosclerotic development, has also been described in GH deficiency. GH replacement therapy can result in increased lean body mass and decreased visceral adipose tissue and may decrease total and LDL cholesterol levels. Endothelial dysfunction improves with GH replacement therapy, with increased flow-mediated dilation and reduced arterial stiffness due to improved NO bioavailability. Anyway, the effects of GH replacement therapy on CV outcomes are uncertain.

Furthermore, echocardiography in patients with childhood- or adolescent-onset GH deficiency has revealed significant reductions in left ventricular posterior wall thickness and interventricular septal thickness, with resultant decrease in LV mass index and LV internal diameter.

Thus, both GH excess and GH deficiency passively promote the development of CV disease. On the other hand, cardiomyocytes directly express receptors for GH and IGF-1.

Stimulation of these receptors induces cardiac hypertrophy and affects cardiac contractility.

Effects of Adrenocorticotropic Hormone and Cortisol Disturbances on Cardiovascular Traditional and Nontraditional Cardiovascular Risk Factors

Adrenocorticotropic hormone (ACTH) is synthesized and secreted by corticotroph cells of the anterior pituitary gland. The primary role of ACTH is to regulate adrenal cortisol secretion. Excess ACTH can be produced by pituitary corticotroph adenoma or, rarely, by an extrapituitary tumor (ectopic ACTH syndrome) such as small cell lung cancer, carcinoid tumor, or medullary thyroid cancer. This excess ACTH secretion results in hypercortisolism, or Cushing’s syndrome. Endogenous Cushing’s syndrome is caused by excessive secretion of ACTH in approximately 80% of cases, and by ACTH-independent causes in approximately 20% of cases that include cortisol secretion by unilateral adrenal adenomas, or by bilateral adrenal hyperplasia or dysplasia.

Hypercortisolism is associated with hypertension, central obesity, insulin resistance, dyslipidemia, and alterations in clotting and platelet function. Hypertension is present in about 80% of adult patients with endogenous Cushing’s syndrome and results from changes in regulation of plasma volume, systemic vascular resistance, and vasodilation. Treatment of Cushing’s syndrome usually results in improvement or resolution of hypertension, although hypertension may persist in patients with long-standing hypercortisolism and/or coexisting essential hypertension. Abnormal glucose metabolism in Cushing’s syndrome results from stimulation of hepatic gluconeogenesis and glycogenolysis. Patients with hypercortisolism may have impaired fasting glucose, impaired glucose tolerance, hyperinsulinemia, insulin resistance, and/or diabetes mellitus. Cushing’s syndrome has been associated with increased lipoprotein (a), decreased HDL cholesterol, and increased triglycerides. The duration of cortisol excess correlates with the degree of dyslipidemia seen. Cortisol also increases the synthesis of several coagulation factors, stimulating endothelial production of von Willebrand factor and concomitantly increasing factor VIII. Hypercortisolism may also enhance platelet aggregation and reduce plasma fibrinolytic capacity (Newell-Price et al. 2006).

Cushing’s syndrome has been also associated with left ventricular hypertrophy, concentric remodeling, diastolic dysfunction, and subclinical left ventricular systolic dysfunction. Echocardiography has revealed increased interventricular septum thickness and posterior wall thickness, increased left ventricular mass index, and increased relative wall thickness in Cushing’s patients. Diastolic dysfunction has been demonstrated, with impaired early left ventricular relaxation, longer isovolumetric relaxation times, and evidence of global myocardial relaxation impairment. The abnormalities of left ventricular structure and function may be reversible with normalization of hypercortisolism.

Effects of Aldosterone Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors

Aldosterone is a mineralocorticoid hormone produced in the adrenal gland. Aldosterone secretion is regulated primarily by the renin-angiotensin system, although other regulatory factors include serum sodium and potassium levels and ACTH. Mineralocorticoid hormones work to maintain normal sodium and potassium concentrations and to maintain normal volume status. Increasing evidence reveals that the renin-angiotensin-aldosterone system (RAAS) is inextricably involved in linking obesity, dyslipidemia, IR, CKD, and hypertension, as well as in the pathogenesis of metabolic syndrome (Sowers et al. 2009). It has been recently demonstrated that elevated plasma aldosterone levels directly contribute to IR, endothelial dysfunction, glomerular hyperfiltration, and excess glomerular and tubular leakage of albumin, leading to maladaptive CV and renal remodeling. Furthermore, it is increasingly recognized that patients with resistant hypertension tend to be overweight and often show elevated plasma and urine levels of aldosterone.

Aldosterone exerts its genomic effects through mineralocorticoid receptors (MRs) binding; on the other hand, aldosterone exerts rapid, nongenomic effects that mediate maladaptive tissue remodeling throughout the CV and central nervous system, further perpetuating the metabolic syndrome, IR, and the hypertensive state.

Aldosterone and Insulin Resistance

Aldosterone secretion from the adrenal gland has been classically considered to be regulated by RAAS activation in response to intravascular volume contraction. When this axis is perturbed, as seen in several clinical conditions, including metabolic syndrome, heart failure, and CKD, inappropriate aldosterone secretion occurs despite high salt and volume retention and contributes to a state of hyperaldosteronism (Whaley-Connell et al. 2010). The increased nongenomic MR signaling, in response to these elevated levels of aldosterone, is involved in the pathophysiology of IR and other components of the metabolic syndrome. In fact, the MR has a high affinity for both aldosterone and 11-beta-hydroxyglucocorticoids, the levels of which are often elevated in clinical states characterized by central obesity, a typical feature of the metabolic syndrome. Since in metabolic syndrome circulating glucocorticoid levels may be several orders of magnitude greater than aldosterone, this clinical condition is plausible that 11-beta-hydroxyglucocorticoids bind to the MR instead of aldosterone, impacting insulin metabolic signaling.

It has been demonstrated that adipose tissue produces a lipid soluble factor that stimulates aldosterone secretion. Moreover, both aldosterone and glucocorticoids can interact via MRs to promote adipogenesis and increases in fat macrophage infiltration. Thus, the interaction of fat, the adrenal cortex, and aldosterone/glucocorticoids promotes further adipogenesis and inflammation in fat tissue. This means that in clinical conditions characterized by increased obesity, MR activation by glucocorticoids, in addition to aldosterone, further potentiates inflammation, oxidative stress, fibrosis, and IR (Fallo et al. 2006).

Primary hyperaldosteronism is a group of conditions in which aldosterone production is inappropriately high, resulting in the suppression of the RAAS. Hypertension is the clinical hallmark of primary hyperaldosteronism, showing a prevalence of 0.5–4.8% in patients with essential hypertension. Potassium depletion is also characteristic of hyperaldosteronism. Common causes of primary hyperaldosteronism include unilateral autonomous adrenal adenoma and unilateral or bilateral adrenal hyperplasia. A rare cause of primary hyperaldosteronism is a heritable condition known as glucocorticoid-remediable aldosteronism (GRA).

Aldosterone and Endothelial Function

Endothelial dysfunction is commonly present in concert with IR and other metabolic alterations. Several vascular metabolic abnormalities have been documented in obese, insulin resistant subjects. These abnormalities include impaired insulin-stimulated glucose uptake and reduced bioavailable NO. In this context, insulin-dependent glucose utilization is partly dependent on insulin-mediated increases in blood flow and substrate delivery to tissues. In IR, there is decreased insulin stimulation of NO bioactivity, diminished vasodilation, and impaired substrate delivery. Increasing evidence demonstrates that elevated plasma levels of aldosterone contribute to this decrease in insulin metabolic signaling in vascular tissue. Insulin-resistant individuals with obesity and elevated plasma levels of aldosterone are more prone to endothelial dysfunction because increases in RAAS generation of ROS activate redox-sensitive serine kinases, which promote serine phosphorylation of insulin receptor-1 (IRS-1) levels which, in turn, reduce engagement with phosphoinositol 3-kinase (PI3-K), with resulting diminution of protein kinase B (Akt) and atypical protein kinase activation of eNOS phosphorylation/activation.

Aldosterone and Hypertension

Elevated plasma aldosterone levels are reported in hypertensive patients and have been correlated with increased left ventricular mass as well as established as a risk factor for developing hypertension. Primary aldosteronism, resulting from bilateral adrenal hyperplasia or an aldosterone-producing adenoma, occurs with prevalence estimated at 0.5% to 4.8% of the population with general hypertension and 4.5% to 22% of those with resistant hypertension.

Elevated levels of aldosterone, in association with obesity and IR, promote nongenomic inflammation and oxidative stress pathways that advance the development of resistant hypertension. Beyond its ability to inhibit endothelium-dependent relaxation by decreasing NO bioavailability, aldosterone-induced perivascular fibrosis reduces vascular compliance and increases vascular stiffness, while increased Na+/H+ exchange promotes vascular smooth muscle cell proliferation. These actions potentiate the elevation of blood pressure that occurs from the classical effects of aldosterone to promote salt retention and volume expansion, causing severe hypertension.

Mechanisms contributing to hyperaldosteronism-mediated hypertension include plasma volume expansion from sodium and fluid retention and vasoconstriction from potassium depletion. Aldosterone has been shown to decrease NO bioavailability, inhibiting endothelium-dependent relaxation. Aldosterone-mediated perivascular fibrosis reduces vascular compliance.

Aldosterone and Cardiac Structure

Hyperaldosteronism causes maladaptive cardiac remodeling and has been associated with left ventricular hypertrophy (LVH), cardiac fibrosis, and diastolic dysfunction. The degree of LVH seen in primary hyperaldosteronism exceeds the effects of hypertension alone. Aldosterone has also been shown to promote collagen deposition, activation of inflammatory cells, and stimulation of fibroblast proliferation.

Aldosterone and Congestive Heart Failure

In conditions such as heart failure and myocardial infarction, aldosterone levels are elevated and contribute to pathologic cardiovascular remodeling via direct effects on collagen deposition and resultant cardiovascular fibrosis. Elevated aldosterone levels also promote endothelial dysfunction and vascular inflammation. The addition of an aldosterone antagonist is recommended in selected patients with moderately severe to severe symptoms of heart failure and reduced LVEF, or with LV dysfunction early after myocardial infarction.


Pheochromocytomas are catecholamine-producing tumors that originate from chromaffin cells of the adrenal medulla and the sympathetic ganglia (catecholamine-secreting paragangliomas, or extra-adrenal pheochromocytomas). Patients may present asymptomatically if diagnosed after detection by adrenal imaging or genetic testing. Symptomatic patients present with hypertension (episodic or sustained) and paroxysmal symptoms such as dizziness, headache, flushing, diaphoresis, and palpitations.

Hypertension is present in over 50% of patients with pheochromocytoma and may be sustained or paroxysmal. Higher variability of blood pressure has been demonstrated in pheochromocytoma compared to patients with essential hypertension and is associated with a higher incidence of target organ damage.

Markers of endothelial dysfunction, such as increased carotid intima-media thickness, have been demonstrated in patients with pheochromocytoma. These changes have been attributed to the effects of excess catecholamines on vascular wall growth and thickening. Normalization of catecholamine levels after surgical removal of pheochromocytoma has been shown to improve carotid intima-media thickness and reduce carotid wall fibrosis.

Excess catecholamine action can also lead to cardiomyopathy, ischemic heart disease, myocardial stunning, and, rarely, cardiogenic shock. Patients with pheochromocytoma-associated cardiomyopathy may present with pulmonary edema or with acute chest pain and myocardial ischemia/infarction. Pulmonary edema results from increased pulmonary capillary permeability, increased peripheral vascular resistance, increased hydrostatic pressure, and overfilling or constriction of efferent pulmonary veins. Myocardial ischemia or infarction may result from coronary vasospasm, with catecholamine action leading to vasoconstriction, decreased coronary blood flow, and increased cardiac oxygen demand.

Catecholamine-induced cardiomyopathy has been shown to improve after surgical treatment of pheochromocytoma. Reversal of cardiomyopathy depends on early identification and treatment (Lenders et al. 2005).

Effects of Parathyroid Hormone Disturbances on Traditional and Nontraditional Cardiovascular Risk Factors


Parathyroid hormone (PTH) plays a critical role in maintaining an adequate calcium-phosphorus homeostasis. PTH affects three principal target organs to maintain calcium balance: bone, intestinal mucosa, and kidney.

Hyperparathyroidism is characterized by inappropriately high levels of PTH in the setting of elevated calcium concentrations. Causes of hyperparathyroidism include an autonomous adenoma or parathyroid gland hyperplasia (primary hyperparathyroidism, PHPT) and secondary hyperparathyroidism due to chronic kidney disease or long-standing vitamin D deficiency. PHPT is a common endocrine disease which is now usually diagnosed at an asymptomatic stage. It is characterized by elevated serum calcium associated with elevated or non-suppressed levels of PTH. Renal stones, osteoporosis, and symptoms related to hypercalcemia are well-known complications, while controversy exists regarding the CV involvement in PHPT. The increased CV risk seen in patients with mild-to-moderate PHPT seems to be mediated by different mechanisms: (1) the effect of PTH on intracellular calcium that, in turn, acts on insulin sensitivity; (2) the direct effect of PTH on vascular and cardiac muscle proliferation; or (3) the dysfunction of the renin-angiotensin-aldosterone system. For these reasons, the CV risk associated with PHPT is attributable in large part to an increased prevalence of hypertension, obesity, glucose intolerance, and IR. Furthermore, vitamin D deficiency secondary to PHP has also been implicated in the increased CV risk of these patients.

Among CV alterations, increased arterial stiffness and carotid intima-media thickness, endothelial dysfunction, hypertension, left ventricular hypertrophy, and diastolic dysfunction have been reported. Among metabolic disorders, impaired insulin sensitivity, high prevalence of T2DM, dyslipidemia, hyperuricemia, increased body weight, and metabolic syndrome have been shown (Procopio et al. 2014).

PTH has been largely recognized as a hormone with vascular and CV properties and paracrine or autocrine roles in the heart. PTH exerts a direct action on cardiac myocytes by activating protein kinase C leading to hypertrophic growth. This hormone is also involved in the expression of endothelial pro-atherosclerotic and pro-inflammatory parameters such as receptor advanced glycation end products and interleukin 6. Furthermore, there are evidences that PTH modulates endothelial function by increasing the production of endothelial nitric oxide synthase and its activity.

Hyperparathyroidism and Hypertension

PHPT has been associated with an increased risk of hypertension, with a prevalence ranging from 40% to 65%. The exact mechanism linking PHPT to hypertension has not yet been completely elucidated. Potential explanations include altered renin-angiotensin-aldosterone axis, dysfunction or structural changes in the resistance of vessels documented by altered vasodilatory response, and/or enhanced vascular constriction in response to pressor hormones.

Hyperparathyroidism Glucose Metabolism

The prevalence of type 2 DM in PHP has been estimated to be approximately 8%, while the prevalence of PHP in patients with type 2 DM is about 1%. The exact mechanism underlying the association between PHP and glucose metabolism disorders is still unclear. In the general population, alteration of serum calcium homeostasis is significantly correlated with the abnormality of glucose level, IR, and beta-cell function; in particular, calcium influences the affinity of insulin receptor and sensitivity to insulin, and PTH concentration is also an independent determinant of insulin sensitivity.

Hyperparathyroidism and Atherosclerosis

High levels of PTH have been related to atherogenesis in the general population possibly via vascular calcification and remodeling, through direct PTH receptor interaction on the vessels as well as indirectly via inflammation and vascular dysfunction. In patients with PHP, flow-mediated vasodilation of brachial artery – a marker of endothelial dysfunction – resulted in impaired compared to controls. Furthermore, patients with PHP show increased aortic stiffness.


Hypoparathyroidism is characterized by inappropriately low or undetectable PTH levels in the setting of hypocalcemia. Hypoparathyroidism may be congenital or acquired, with the surgical removal or damage to the parathyroid glands being the most common acquired cause. The signs and symptoms of this disease derive from hypocalcemia. Mild hypocalcemia may present with neuromuscular irritability such as perioral numbness, muscle cramping, paresthesias, and positive Chvostek’s and Trousseau’s signs. Severe hypocalcemia may present with carpopedal spasm, laryngospasm, tetany, and seizures.

There are case reports of decreased myocardial performance, dilated cardiomyopathy, and congestive heart failure in patients with acute and chronic hypocalcemia. The mechanisms underlying myocardial dysfunction are unclear but may be related to impaired excitation-contraction coupling.

Effects of Intestinal Dysbacteriosis on Traditional and Nontraditional Cardiovascular Risk Factors

Many microbes inhabit the human gastrointestinal tract including viruses and bacteria, fungi and protists, which make up the intestines’ symbiotic microbes. The number of bacteria carried by the human body is approximate to 1014, mostly including anaerobes; the diversity and richness of species are variable between individuals. The intestinal microbiota has many crucial functions in human health and can be considered as a virtual organ with endocrine function. It is directly involved in the body’s nutrient absorption, growth and development, biological barriers, immune regulation, metabolism, and many other aspects (Cani and Delzenne 2007).

Plenty of evidence indicates that the gut microbiota is closely related to the most important CV risk factors.

Gut Microbiota Disturbances and Hyperlipidemia

Recent studies demonstrate that the gut microbiota can explain 6.0% of the variation in triglycerides and 4.0% of that in HDL-c and 4.5% of that in BMI, independent of age, sex, and genetics in the general population. Furthermore, it has been demonstrated that individuals with low microbial richness have increased fasting triglycerides and decreased HDL-c. Reverse cholesterol transport (RCT) is a key pathway involving the return of excess cholesterol from peripheral tissues to the liver to excretion of bile and eventually feces.

Even if the exact mechanisms of action have not been still fully elucidated, it is possible to affirm that intestinal flora metabolites are closely related to lipid metabolism (Fu et al. 2015).

Gut Microbiota Disturbances and Obesity

Recent studies indicate that the increase in the number of Firmicutes and the reduction of Bacteroides in the gut microbiota are associated with obesity. Enterobacter cloacae B29 –internationally recognized as the first “fat bacteria” – has been demonstrated to be a direct cause of obesity.

The gut microbiota may cause obesity by reducing fasting-induced adipokine factor (Fiaf) expression. Intestinal flora can also stimulate the production of various inflammatory factors leading to chronic systemic inflammation and further cause obesity and insulin resistance (Kvit and Kharchenko 2017).

Obesity is often a leading cause for the development of T2DM, so the abovementioned mechanisms of intestinal flora causing obesity can also increase the risk of T2DM (Larsen et al. 2010).

Gut Microbiota Disturbances and Atherosclerosis

Hyperlipidemia is an independent risk factor for atherosclerosis. We have previously discussed the effects of gut microbiota on lipid metabolism, which consequently affect the development of atherosclerosis. Furthermore, some studies also suggest that the GM is directly related to the occurrence of atherosclerosis, even if the core mechanism that causes atherosclerosis remains still unclear (Koren et al. 2011).

Gut Microbiota Disturbances and Cardiovascular Disease

The mechanism of intestinal flora affecting cardiovascular disease mainly includes three aspects: (a) intestinal flora disorder leads to bacterial endotoxin translocation and promotes the release of inflammatory factors leading to an inflammatory response; (b) intestinal flora disorder leads to abnormal metabolism of substances, which causes CVD such as lipid, glucose, and tryptophan metabolism; (c) intestinal flora disorder promotes oxidative stress in the body and aggravates the development of CVD.

Gut microbiota is also involved in the metabolism of purine and uric acid. For example, xanthine dehydrogenase, the key enzyme responsible for the oxidative metabolism of purines, is generated by the secretion of Escherichia coli in intestinal bacteria. Therefore, the decomposing activity of gut microbiota on uric acid is positively related to the content of Escherichia coli. Increased blood uric acid levels can lead to high level nitrite/nitrate in the blood, decreased bioavailability of NO, and oxidative stress.


The risk of cardiovascular diseases, both in terms of morbidity and mortality, can increase in the general population because of a number of factors ranging from gene polymorphisms to modifiable environmental factors. The knowledge of major pathogenic mechanisms influencing cardiovascular anatomy, homeostasis, and function can allow a pharmacologic modulation of traditional risk factors including unbalanced diet, lifestyle, hypertension, dyslipidemia, smoking, obesity, etc.

On the other hand, innovative therapeutic approaches and primary prevention strategies originate from an adequate management of nontraditional risk factors as low-grade chronic inflammation, homocysteine, environment-induced oxidative stress and/or endothelial dysfunction, lipoprotein homeostasis, psychosocial factors, insulin levels, uric acid, chronic kidney disease, and activation of the renin-angiotensin system. Considering the complex picture of cardiovascular effects deriving from disorders of the endocrine system, a normal endocrine function is essential for overall cardiovascular health. Disorders of the endocrine system do have multiple effects on the cardiovascular system, in particular when hyper- or hypofunction develop.



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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Experimental and Clinical MedicineUniversity Magna Graecia of CatanzaroCatanzaroItaly
  2. 2.Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly

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