Impact of Endocrine Disorders on the Heart
The endocrine system has many hidden interactions with the cardiovascular system. Cardiovascular medical specialists, therefore, may not directly recognize hormonal involvement on the cardiovascular system. The role of the pituitary and thyroid gland in cardiac conditions is well known. However, the recently discovered pathophysiological relation between prolactin and peripartum cardiomyopathy enables novel treatment options. The predominant prevalence in women of emerging pathologies such as broken heart syndrome and spontaneous coronary artery dissection suggests involvement of the female hormonal system. Carcinoid and pheochromocytoma may have serious implications on right and left sided heart failure, respectively.
KeywordsEndocrine and heart Endocrine and cardiovascular Hormones and heart
List of Abbreviations
Acute coronary syndrome (with or without ST-elevation)
Broken heart syndrome
Coronary artery bypass grafting
Coronary artery disease
Carcinoid heart disease
Insulin like growth hormone
Major adverse cardiovascular events
Percutaneous coronary interventio
Renin angiotensin aldosterone system
Spontaneous coronary artery dissection
This chapter handles the cross-links between endocrine disorders and cardiac involvement, which is an excellent example where a general medical specialist is warranted. The etiology and diagnosis of cardiac disease in endocrine disorders is extremely challenging. The symptoms are often not specific and therefore not directly recognized by highly specialized medical doctors. First we had one big specialty of internal medicine covering all contemplative medicine. Among many others, cardiology emerged as one of the distinct specialties with super specialties such as coronary interventionalists and electrophysiologists. The consequence of the ongoing super specialization is that the overall view of the patient has been lost completely. Therefore, nowadays there is a call for a general medical specialist who may keep the overview of all medical concerns of the patient. Recently, we were involved with a patient with end-stage heart failure referred to our tertiary center for left ventricular assist device implantation and/or heart transplantation. In the end, this patient was diagnosed with a pheochromocytoma. It is conceivable that a timely diagnosis may have prevented the deleterious complication of this endocrine disorder. In this chapter, a broad spectrum of colleagues collaborated to highlight the most common endocrine disorders involving the heart.
The Pituitary Gland and Cardiovascular Disease
The pituitary gland is a dominant structure in the regulation of distinctive hormones. Afferent signals from the hypothalamic regions influence the pituitary gland in its hormone secretion capacity, in absolute levels and in diurnal pattern. The latter is of importance, because recent observation show that perturbations in pituitary derived hormones affect the cardiovascular system. Cardiovascular physiology is influenced by hormone levels and hormone patterns. In extreme conditions, in case of hormone excess or hormone deficiency, the cardiovascular system will respond. In general, adaptive properties from the heart muscle and its associated vasculature will be affected when hormone derangements are present. Hormones with mineralocorticoid properties will increase intravascular volume. In the next paragraph, individual pituitary-derived hormones and their effect on cardiovascular function will be highlighted. Patients with a hypopituitarism, a defect in hormone release from distinctive pituitary hormones, has an increased cardiovascular mortality. Especially female patients with hypopituitarism display more cerebrovascular disease. Other specific conditions, such as in acromegaly (GH excess) and Cushing disease (steroid excess), displayed typical cardiomyopathies. These observations triggered a considerable research to explain the mechanisms behind these hormones and the cardiovascular system.
Prolactin is one of the ancient hormones and is found among all species. In humans, prolactin is especially known as a principal factor in initiation of birth and lactation. Prolactin is also abundantly present in males. It is obvious that prolactin have various biological effects beyond lactation, for instance, on the water-salt balance. Recent observations suggest a close relationship between prolactin and the cardiovascular system. Patients with a prolactinoma may often develop left ventricular dysfunction. However, no increased cardiovascular mortality could be found in patients with hyperprolactinemia (Soto-Pedre et al. 2017). Prolactin receptors are found in the human atherosclerotic plaque, especially on CD-68 positive macrophages in the surroundings of the high inflammatory shoulder (Reuwer et al. 2011). In the Norfolk study comprising apparently healthy male subject, prolactin levels were not associated with occurrence of cardiovascular events. Incubation studies showed a dose response effect on angiogenesis that could be inhibited by a specific prolactin receptor blocker (Reuwer et al. 2012a). In an atherogenic rodent model, dissociation was found between a pro-atherogenic dyslipidemic profile and atherogenesis (van der Sluis et al. 2014). In atherosclerotic rodent models, contribution of inflammation is not prominent. No prolactin receptors were found on human platelets or effects platelet aggregation. Clot formation will therefore be not directly stimulated by prolactin. On the other hand, in prolactinoma patients (with highly elevated prolactin levels), microcirculation is disturbed with higher endogenous thrombin potential and prothrombin levels (Reuwer et al. 2012b). In summary, prolactin is a hormone that acts locally but also generally by modulating immune responses with subsequent effects on atherogenesis and the cardiovascular system.
Peripartum Cardiomyopathy (PPCM)
The etiology of PPCM is unknown. Several predisposing factors have been recognized such as, pre-eclampsia, African ethnicity, age, inflammation, multiple pregnancies, and malnutrition. An important role for prolactin is been considered in women with PPCM. The mechanism behind PPCM is local expression of cathepsin-D that is able to cleave prolactin in prolactin fragments (so called vasoinhibins). Fig. 1. Its 16 kD fragments is acknowledged being an anti-angiogenic factor, and in presence of high levels, this vasoinhibin impairs microcirculation in the heart. Prolactin fragments, as vasoinhibins, have been found in several studies as influencers of physiologic cardiovascular function and cardiovascular morbidities. The distinct geographical incidences and familial clustering suggest a genetic predisposition. PPCM has been associated with significant variations in the gene encoding for sarcomeric protein titin. Also a post-viral myocarditis has been considered as endomyocardial biopsies were positive for parvo B19 and coxsackie virus. PPCM is an infrequent cause of heart failure and ventricular arrhythmias manifesting between the third trimester of pregnancy and the first 6 months after delivery. The incidence of PPCM varies from 1 in 1000 to 1 in 10,000 live births and is more prevalent in African and Asian women (Arany and Elkayam 2016).
The clinical presentation in the beginning is difficult because early heart failure symptoms may mimic symptoms associated with the peripartum stage. Symptoms of dyspnea, generalized malaise, tachycardia, body weight increase, and peripheral edema are common. However, (supra) ventricular tachycardia and atrial fibrillation are prevalent in almost 20% of patients. PPCM is associated with a mortality rate of approximately 5% per year (and is lower than other types of cardiomyopathies). Cardiac thromboembolic events may be the first manifestation of PPCM. Intra-cardiac thrombosis is prevalent because of a high coagulation state in pregnancy, dilatation of the failing heart, and atrial fibrillation. Both physical signs and blood investigations regarding heart failure are difficult to interpret. Echocardiography as an imaging tool without use of radiation is crucial in the diagnosis and follow-up of PPCM. Given the consequences of PPCM for the mother and fetus, minor suggestions towards PPCM is enough to consult a cardiologist and to perform an echocardiography.
This scheme depicts the cascade of processes involved in the pathophysiology of peripartum cardiomyopathy. Oxidative stress (ROS) promotes the cleavage of prolactin 23 kDa into the anti-angiogenic form prolactin 16 kDa. This process is mediated by matrix metallopeptidases (MMPs) and cathepsin D (CD). Both prolactin 16 kDa and placental soluble fms-like tyrosine kinase 1 (sFlt1) are enhancers of endothelial cell dysfunction, which plays a key role in cardiomyocyte damage. Bromocriptine blocks the production of prolactin 23 kDa and may reduce further deterioration of peripartum cardiomyopathy.
Growth hormone (GH) levels will influence the hepatic secretion of insulin-like growth hormone (IGF-1) and other paracrine derived IGF-1. From twin studies, we learned that almost 60% of circulating IGF-1 levels are genetically determined. Therefore, diurnal GH pulses, secreted by somatotropic pituitary cells, just only modulate IGF-1 profile. Most physiologic effects of GH and IGF-1 (such as increase in height) are dominantly processed by local tissue IGF-1. Growth hormone receptors are found on cardiovascular structures, such as the heart and the endothelium. Stimulation of these GH receptors will have a trophic effect on the heart muscle and more nitric oxide is synthesized in the endothelium (resulting in arterial vasodilation). In heart failure, the concept of GH resistance is acknowledged partly explaining peripheral muscle cachexia and loss of tropic stimulation at the heart. Due to local inflammation, metalloproteinases split the extracellular part of the GH receptor with loss of intracellular signaling. This mechanism explains no effect of GH substitution in patients with late-stage heart failure. In patients with a growth hormone deficiency, as part of hypopituitarism or congenital syndrome, GH substitution improves the left ventricular function. There is also an improvement in arterial function, in studies using flow-mediated dilation and pulse wave velocity. A less flow mediated dilation and pulse wave velocity is associated with future cardiovascular morbidity and mortality. Intima media thickness of the carotid artery, an intermediate endpoint in atherosclerosis studies, decreases after GH substitution. In addition to a direct effect on heart and vessels, GH deficiency is characterized by a pro-atherogenic profile. GH is known to influence the hepatic expression of the LDL-receptor and key enzymes in the cholesterol bile acid pathway. However, discussion exists whether GH substitution specifically affects the lipid profile. Metabolic syndrome like features could also be explained by other associated hormonal derangement (supra-physiologic dosage of hydrocortisone, conversion of T4 to T3).
In patients with a GH excess (acromegaly, a relatively rare endocrine disorder mostly originating from a benign adenoma) a hyper dynamic circulation exists leading to biventricular hypertrophic cardiomyopathy in 60% of patients, with diastolic dysfunction and in a later stage systolic dysfunction, valvular insufficiency, aortic root dilatation, and arrhythmias (Colao et al. 2004). Excess of GH facilitates vasodilation (nitric oxide synthesis stimulation) and a trophic effect on the heart muscle. GH also increases sodium retention by the kidney. Mortality is increased in patients with acromegaly due to premature cardiovascular disease. This increased mortality is more pronounced with coexistent glucose disturbances and hypertension. Normalization of excess GH, and adequate treatment of hyperglycemia and hypertension, improve cardiovascular outcomes. Several reports exist describing occurrence of overt heart failure that could be totally reversed after GH normalization in patients with de-novo acromegaly.
Follicle-Stimulating Hormone- Luteinizing Hormone (FSH-LH) and Testosterone
Testosterone and dihydrotestosterone have both a high affinity for the cytoplasmic androgene receptor (genomic action) that is present in cardiomyocytes, endothelium, and smooth muscle cells. Stimulation of this receptor results in vasodilation and expression of the angiotensin-II receptor in the heart. Testosterone could also affect these cardiovascular tissues by nongenomic action. Intracellular calcium fluxes and nitric oxide synthesis in the endothelium are influenced as part of the nongenomic action of testosterone. The improved muscle mass from skeletal muscle is directly associated with left ventricular function. Thus part of the influence of testosterone on the heart may be explained as a secondary effect. Effects of testosterone has recently been studied extensively. In hypogonadotropic hypogonadism, most studies present the presence of the metabolic syndrome, possibly related to low total plasma testosterone levels. Few studies present an impaired effect on cardiovascular performance. The total testosterone levels in circulation decrease in aging males. Lower total testosterone levels were associated in cross-sectional studies with a lower quality of life, sexual dysfunction, and pro-atherogenic profile. However, the benefits of testosterone substitution in aging male are under discussion, especially in them who already suffer from cardiovascular disease with an age above 65 years. One small randomized control trial showed an increased risk in cardiovascular events after testosterone substitution in older men (Basaria et al. 2010). The most comprehensive RCT, however, showed beneficial effects without any increase of cardiovascular risk (Snyder et al. 2016). In patients with heart failure, total testosterone levels are within the lower range. Another randomized control trial showed improved symptoms and exercise capacity in male patients with heart failure after substitution of testosterone during 12 weeks (Pugh et al. 2004).
Adrenocorticotropic Hormone (ACTH)-Cortisol
Addison himself was probably the first who recognized the effects of cortisol on heart performance. As he stated in 1855: “that in patients with adrenal failure the remarkable weakness of the heart’s action” (Addison 1855). Glucocorticoid receptors are being expressed in both heart and vasculature. Cortisol can affect, for instance, nitric oxide (NO) synthesis in a “genome directed way” (by binding to glucorticoid receptors) and a “non-genome directed way” (by a direct effect on intracellular NF-kappa beta expression). The first one gives expression to various intracellular enzymes (like eNOS that is able to generate (NO), while the second one change local oxidative stress capacity that in its cascade also include (NO) generation. Subjects who carry a polymorphism (A3669G) in exon 9 of the glucorticoid receptor gene (with a subsequent insufficient receptor signaling) displayed an increased risk of coronary artery disease and a less cardiovascular performance (generation R study) (Geelhoed et al. 2011; van den Akker et al. 2008). Glucocorticoids have an important impact on the heart and vessels. Improvement of heart function have been observed in patients with absolute cortisol deficiency (either due to adrenal or pituitary damage) after suppletion with hydrocortisone. However, blood pressure could acutely drop after starting with (intravenous) hydrocortisone therapy in the acute phase. Glucocorticoids are acknowledged to generate endothelial (NO) with a subsequent (arterial) vasodilation. In order to keep up with optimal hemodynamics, aggressive fluid replacement could be necessary. However, at chronic terms, supraphysiological substitution with oral hydrocortisone therapy (>20 mg total daily dose) was associated with more cardiovascular morbidity (increase in waist girth, nonbeneficial lipid profile, and increase in blood pressure). The increased cerebrovascular mortality in patients with hypopituitarism, under supraphysiologic hydrocortisone treatment, is probably due to this steroid overtreatment.
Thyroid Hormone-Mediated Cardiac Disease
The thyroid gland and its derived hormones has a critical regulatory role in both development and maintenance of the cardiovascular system. Secondary cardiovascular effects are cardinal symptoms in the presence of thyroid disturbances including a marked perturbation in cardiovascular risk factors (such as lipids), rhythm disturbances, and occurrence of heart failure (in the elderly). Cardiovascular manifestations typically observed in hypothyroidism are mostly the opposite of those observed in hyperthyroidism. This chapter aims to summarize the interplay between thyroid dysfunction and cardiovascular conditions. Thyroid hormone levels are regulated by the hypothalamus-pituitary-thyroid axis, which has a unique set point for each individual. Regulation of biological effects of thyroid hormone is maintained by the equilibrium between T3 (the active metabolite) and T4 (the T3 precursor), which occurs in a paracrine matter in each distinctive tissue by a specific set of deiodinases. The synthesis of thyroid hormones from the thyroid gland (predominantly T4) is regulated by the pituitary trophic factor thyrotropin. T4 is released in the blood pool and undergoes a paracrine conversion to T3 in cardiovascular tissue, such as heart muscle or vascular endothelium. T3 binds to the nuclear T3 receptor with a subsequent response in an increased work capacity and energy consumption. This includes an augmented basal rate of oxygen consumption and heat production, generated via stimulation of ATP-requiring cellular processes. In the heart, this promotes evolution of heart rate and contractile force delivered by cardiomyocytes. On the molecular level, within the cardiomyocytes, T3 exerts regulatory actions affecting the distribution of myosin heavy chain isoforms. In addition, other intracellular processes occur that are closely related to tightening (during systole) and relaxation (during diastole) of heart muscle fibers, by affecting calcium influx between cytosol and sarcoplasmic reticulum by its specific calcium pump, SERCA-2, and phospholamban pathways. In the downstream vascular bed, T3 acts locally on endothelium (that is able to convert T4 to T3) through upregulation of the enzyme endothelium-derived NO synthase (eNOS). Generation of nitric oxide (NO) by eNOS causes vasodilatation and reduces systemic vascular resistance and subsequently diastolic blood pressure, largely due to its effects on thermogenesis. There is a significant cross talk between the sympathetic nervous system and beta-adrenergic stimulation in particular, but stimulatory action may also be exerted independent of this catecholamine response. Taken together, an excess of thyroid hormone effects the hemodynamics by creating a hyperdynamic state which includes: (1) sinus tachycardia by increased sinus node sensitivity for adrenergic action with a decreased heart rate variability; (2) increased atrial ectopy; (3) pro-arrhythmia, particularly in the setting of vulnerable substrates for ventricular arrhythmias; (4) increased cardiac work and pulmonary vascular resistance; (5) systemic hypertension with large pulse pressure; (6) left ventricular hypertrophy; (7) angina pectoris with or without ischemic changes on electrocardiogram, due to supply/demand mismatch in coronary flow, microvascular dysfunction, or vasospasm; and (8) pulmonary hypertension. On the other hand, hypothyroidism results in a slow cardiac function resulting in a low heart frequency and cardiac output.
Thyroid Hormone-Related Coronary Artery Disease
A disturbance in circulating T4 levels negatively affect the cardiovascular system primarily by stimulating local processes involved in atherogenesis and, secondarily, by modification of cardiovascular risk factors, such as hypertension and dyslipidemia. Of interest, not only overt thyroid dysfunction exerts in manifested cardiovascular disease but also subclinical thyroid disease is associated with an increased cardiovascular mortality (so called J-curve), especially in the elderly. Hypertension is more prevalent in patients with either a hyper- or a hypothyroidism that could be explained by changes in renin angiotensin aldosterone system (RAAS), systemic vascular resistance, and cardiac stimulation. Both overt and subclinical hypothyroidism are associated with a dyslipidemia and a higher risk of coronary heart disease. The effect of thyroid hormones (T3) on local atherothrombosis is still not well established but appears to be ambivalent: a slow-down effect in atherogenesis and a more promoting effect in thrombosis/coagulation. This is due to the fact that T3 stimulates both lipogenesis and lipolysis in the liver. In addition, T3 increases expression of hepatic LDL cholesterol receptors and enhances hepatic removal of lipids from the circulation, with less generation of oxidized LDL particles. On the other hand, factor VIII and von Willebrand are upregulated by T3, leading to a pro-thrombotic environment. Knowledge about T3 interaction on atherothrombotic processes might be helpful in understanding the occurrence of cardiovascular disease in patients with T3 excess. So screening and eventual treatment of T3 excess may be beneficial. Indeed, clinical studies targeting T3 with specific T3 antagonist are underway.
Excess of thyroid hormone (T4 and T3), as seen in subclinical and overt hyperthyroidism, increases the risk of atrial fibrillation (AF) and other atrial arrhythmias. There is still little knowledge about its pathophysiology. However, thyroid hormone (T3) is known to alter cardiac excitability. More in detail, atrial cardiomyocytes are more sensitive to the action of thyroid hormones than ventricular cardiomyocytes, probably due to a different distribution of beta-adrenoceptor expression. Typical arrhythmias found in hyperthyroidism consist therefore more frequently in atrial premature contractions. In the sinus node, T3 decreases the duration of the repolarization phase with a subsequent effect on membrane action potential. This increases the rate of diastolic depolarization, probably due to a shift in sodium pump density and Na+ and K+ permeability. These different effects of T3 on the conductive system leads to a reduced heart rate variability and a depressed parasympathetic tone. It is estimated that 10–20% of all patients with a new onset atrial fibrillation express a hyperthyroidism. Epidemiological studies showed that the combination of hyperthyroidism and supraventricular rhythm disturbances is mostly present in males at increasing age and preexistent ischemic and valvular heart disease. The prevalence of AF being present in 15% of patients at the age 70 (Auer et al. 2001). In young subjects with hyperthyroidism, an uncomplicated sinus tachycardia is mostly found. However, such a tachycardia can sometimes provoke hemodynamic instability in case of aortic stenosis. It can also result in a tachycardia-induced cardiomyopathy in case of atrial fibrillation with long-term uncontrolled high ventricular frequencies. By treating the hyperthyroidism as its primary cause in combination with antagonizing, the beta adrenoceptors by beta blockers may reverse the cardiomyopathy completely. Dependent on age, in young patients it concerns predominantly a thyroiditis (viral or auto-immune thyroiditis, such as in Graves’ disease) and in the elderly, a toxic adenoma. In case of a thyrotoxic storm, an urgent endocrine condition with a high mortality rate, intravenous administration of beta-blockers is indicated to prevent complete hemodynamic collapse. Acute interventions that control the acute release of T4 and T3 by the diseased thyroid gland should directly be applied. A fast recognition of this clinical picture in disguise is one of the major challenges. The overall incidence of arterial embolism that is associated with atrial fibrillation and hyperthyroidism ranges from 8% to 40%. Actually, there is no consensus whether these patients need anti-coagulation therapy. The American Heart Association recommends to start anticoagulant therapy until the euthyroid state is re-established. Without any doubt, the treating physician should consider the “pros and cons” of anticoagulant therapy in each specific patient (prevention of stroke versus the risk of major bleedings), especially in the elderly. No randomized clinical study on this topic actually exist. Ventricular arrhythmias as a complication of hyperthyroidism are exceptional and may occur in patients with preexisting substrates such as scar-tissue or cardiomyopathy.
Hyperthyroidism could be complicated by congestive heart failure. During overt hyperthyroidism, there is a “high-output” state of the heart (caused by upregulation of contractility and heart frequency, rate of ventricular pressure development, and speed of relaxation) that results in a 2.5 fold higher cardiac output (compared to physiologic condition). This is accompanied by salt and volume retention in the kidney. This increase in vascular volume is associated with a drop in systemic vascular resistance. At the same time, the pulmonary vascular bed is not affected in parallel with a subsequent increase in volume influx in pulmonary circulation; (non-fixed) pulmonary hypertension is present in 35% of hyperthyroid patients. Although the ejection fraction (EF) is essentially preserved in this initial stage, a number of signs and symptoms do resembles heart failure, such as exercise intolerance, orthopnea, peripheral edema and elevated jugular pressure, and hepatic congestion. Accordingly, NT-proBNP levels will be elevated in patients with hyperthyroidism. A particularly vulnerable group of patients are those with suspected ischemic, valvular, or hypertensive comorbidities. It is therefore critical to recognize hyperthyroidism in those specific group of patients with a higher risk of cardio-cerebro-vascular ischemic events, before or during treatment. If untreated, and long-standing, this condition may develop into a “hyperthyroid cardiomyopathy” or tachycardia induced heart failure with a reduced left ventricle ejection fraction (HFREF) below 40%. The prevalence of congestive heart failure is estimated being approximately 6%, particularly in patients with a long-standing untreated hyperthyroidism and coexistent atrial fibrillation. Mitral and tricuspid valvular insufficiency have been described. Sometimes, electrophysiological treatment is indicated to control the arrhythmia. There are no characteristic histopathological changes in these disease states. Again, primary objective in these patients is to treat the cause of the disease, hyperthyroidism. Multidisciplinary approach by endocrinologist and cardiologist are therefore mandatory.
Hypothyroidism rarely leads to clinically significant arrhythmias but does affect fibrillatory thresholds in the cell and conduction times, as a result of changes in ion channel composition. The ECG in hypothyroidism is therefore characterized by sinus bradycardia, low voltage, prolonged action potential duration, and QTc interval see Fig. 3. Rarely AV block or torsade des pointes ventricular tachycardia has been described.
These arrhythmias are rare and do not lead to severe clinical consequences in daily clinical practice (Klein and Ojamaa 2001).
Amiodarone-Induced Thyroid Disease
Amiodarone is a “class III,” highly effective, anti-arrhythmic drug. On the other hand, it could display serious toxicity, and a disruption of thyroid function is a relatively common one. An estimated 60% of all patients using amiodarone have a change in thyroid function with a 15–30% developing a hypothyroidism. There is delay in both the recognition and management of amiodarone-induced thyroid disease due to its long half-life time (a highly lipophilic compound that accumulates in body fat). Amiodarone has the potency to inhibit de-iodination of T4 in the liver and pituitary, which in the short term frequently causes subclinical hypothyroidism, and chronically, it leads to overt hypothyroidism, especially in patients with underlying thyroid conditions. Currently, management after the start of Amiodarone therapy is to measure TSH, T4, and T3 levels every 3–6 months and to treat hypothyroidism promptly. Amiodarone-induced thyrotoxicosis is less common but may have even more clinical impact given the fact that this is associated with a threefold increase of major adverse cardiovascular events. A prompt treatment is therefore mandatory, mostly using high-dose corticosteroids (with possibility of severe side effects) given the mostly occurring ineffectiveness of other antithyroid medication. The underlying mechanisms are a type I variant based on autoimmune phenomena or a more destructive type II thyroiditis evolving in a thyroid storm. Eventually, this could lead to a total thyroidectomy. Whether or not to continue amiodarone therapy in patients developing an uncontrollable thyroid state and a secondary deteriorating cardiac function is a genuine challenge for both the patient and his supporting medical team (cardiologist, endocrinologist, and endocrine surgeon).
Parathyroid Hormone-Related Cardiovascular Disease
Parathyroid disease, and in particular hyperparathyroidism is frequent to occur in concert with cardiac disease. As of yet, solid clinical implications have not been established; however, data on this topic are still emerging.
Hyperparathyroidism, Vitamin D, and Calcium Homeostasis
Hyperparathyroidism as a whole is frequently present being the third most prevalent endocrine disorder with a general prevalence of around 1%. Prevalence numbers vary largely in literature, depending whether patients with symptomatic (initial symptoms present, such as kidney stones) or asymptomatic hyperparathyroidism (no symptoms present, diagnosis as a result of a screening analysis) have been included. It comprises a very heterogeneous population and its prevalence increases with age and in females most commonly after the menopause. This group of subjects is characterized by an elevated parathyroid hormone. It imposes a large burden of morbidity with less quality of life due to its secondary complications such as vertebral fractures with osteoporosis, nephrolithiasis, and decrease in mental health. In its origin, this condition could be due to either autonomous parathyroid secretion by the parathyroid gland. This could give rise to an increase in calcium levels (and by definition, physiological vitamin D levels). However, calcium levels could also be in the high normal range with significantly elevated parathyroid hormone. A condition named as “inappropriate parathyroid” or normocalcemic hyperparathyroidism. In most cases, phosphate is in the low-normal range. This is of interest, as “a high calcium-high phosphate balance” as clinically observed in renal insufficiency, with a higher risk of calcium phosphate deposits in, for instance, the arterial media layer, is in its origin another phenomenon.
However, in the presence of low vitamin D levels, parathyroid will always be secondary elevated. In patients with a creatinine clearance, less than 60 ml/min, parathyroid levels starts to rise. First in the physiologic range, but along the decrease in kidney function, parathyroid can achieve significantly high levels. A distinction between distinctive subtypes, known as primary (autonomous parathyroid secretion), secondary (consequence of low vitamin D condition whatever its cause), and tertiary hyperparathyroidism is therefore a necessity, regarding the therapeutic strategy. The etiology of cardiovascular involvement, as a direct consequence of parathyroid disease, is currently not settled. However, several lines of evidence suggest an association between calcium and vitamin D homeostasis and cardiovascular disease. In particular, hyperparathyroidism appears to be associated with risk factors, and increased cardiovascular morbidity and mortality (Pepe et al. 2017). Lower levels vitamin D occur in chronic renal disease and heart failure and associate with increased all-cause and cardiovascular morbidity, although it is too soon to draw conclusions regarding vitamin D supplementation to prevent cardiac disease.
Incubation of parathyroid hormone with cardiomyocytes, vascular smooth muscle cells, or endothelial cells (as an early marker of atherosclerosis) exhibit diverse effect through stimulation of the parathyroid-related peptide receptor, with increase of c-AMP/adenylate cyclase and subsequently intracellular calcium homeostasis (L-type calcium channels). In animal models, parathyroid exert chronotropic effects (probably due to an increased conduction in sinoatrial node cells) (Pepe et al. 2017). To keep in mind, the systolic phase in the cardiac cycle gives rise to an intracellular flux of ionized calcium (Ca++) by use of L-type Ca++ channels following each action potential, triggering Ca++ release from the sarcoplasmatic reticulum through type 2 ryanodine receptor channels. In human observations, patients with clinically overt hypercalcemia display a prolongation of both QRS and PR intervals, as well as a shortened QTc; these features are acknowledged being part of a arrhythmogenic phenotype. In addition, during exercise tests, more ventricular ectopies have been found in patients with hyperparathyroidism.
Despite these observations, current evidence is still limited, whether parathyroidectomy is beneficial when taking cardiac arrhythmias into account. If parathyroid or calcium levels trigger these conditions and therefore be considered as causal, one would expect that these specific rhythm disturbances will be reversible. Therefore, we cannot conclude a causal relationship between hyperparathyroidism and conduction perturbations in the heart. In line with this conclusion, it is established that in patients with hyperthyroidism, the cardiovascular mortality is higher. However, most of these patients are elderly patients with underlying cardiovascular disease. Experimentally, increase of intracellular calcium in the endothelium results in vasodilatation, and parathyroid has been shown to act as a vasorelaxant due to increase of production of endothelial nitric oxide synthase. However, parathyroid infusion in humans could give contradictory observations considering arterial pressure. Interestingly, parathyroid has been recognized to coincide with hypertension in 40–65% of cases, and this relation has been confirmed in large-scale epidemiological studies (Kalla et al. 2017), and several mechanisms including RAAS system activation have been postulated. Calcium homeostasis has direct effects on beta-cell function, glucose-level abnormalities, and insulin resistance, and insulin sensitivity is experimentally determined by parathyroid. Clinical evidence at present suggest hyperthyroidism patients share an elevated risk to develop diabetes, and this risk might partly be reversible after parathyroidectomy. Echocardiographic data has shown that left ventricular hypertrophy is common in parathyroid patients, and a reduction in left ventricular mass may often takes place after parathyroidectomy. Whereas left ventricular systolic function is generally maintained in primary hyperparathyroidism, severe or chronic disease may impair diastolic function. A recent meta-analysis could not confirm the reversibility of these changes in left ventricular structure and function after successful parathyroid surgery (Best et al. 2017). Calcification of heart valves are mostly found in patients with primary hyperparathyroidism. The aortic valve is mostly affected, but also calcification of the mitral valve is often described. Remarkably, no regression in valve calcification is found after parathyroidectomy with normalization of parathyroid hormone levels. These observations always questions whether PTH or elevated calcium levels are the causes of calcification.
Hypoparathyroidism often results after the parathyroid gland is removed due to surgery. This condition could be characterized by low calcium levels, if not optimally substituted with exogenous calcium and active (1.25 OH) vitamin D. Low calcium levels gives rise to bradycardia, conduction disturbance (prolonged QTc), and a decreased cardiac output (rare). Chronic low calcium levels is often without symptoms.
Carcinoid Heart Disease (Hart et al. 2017)
Neuroendocrine Tumors (NETs)
NETs are malignancies that arise from neuroendocrine cells throughout the whole body but mainly in the GI or respiratory tract. They are a heterogeneous group of malignancies with unpredictable and diverse biological behavior (Modlin et al. 2008). The majority of individuals (40–60%) exhibit advanced local disease or distant metastases at diagnosis (Korse et al. 2013; Yao et al. 2008). Over the last decades, there is an increase in incidence and prevalence rates for NETs, possibly due to improved diagnostic techniques and awareness of the disease. The majority of patients do not present with typical symptoms (nonfunctional) others have well-defined symptoms associated with the overproduction of active hormones such as serotonin. The overproduction of serotonin mainly due to metastatic small intestine NETs causes the so-called carcinoid syndrome, characterized by flushing, diarrhea, and/or wheezing. Patients with a carcinoid syndrome have a 5-year survival rate around 50–80% (Niederle et al. 2016). First-line systemic treatment is usually a somatostatin analogue for the management of the hormonal secretion and decrease of carcinoid syndrome. Radiolabelled somatostatin analogues, targeting therapy for tumors with a high expression of the somatostatin receptor, resulted in markedly longer progression-free survival in patients with metastatic small intestine tumors, as compared to higher doses of somatostatin analogue, as shown in the NETTER-1 trial. This therapy is now the best second-line systemic treatment option up to now, although not available in all Western countries.
Carcinoid Heart Disease
Patients with carcinoid syndrome are at risk of developing carcinoid heart disease (CaHD), also known as Hedinger syndrome. Since the introduction of somatostatin analogues, the incidence of CaHD has dropped from over 50% to approximately 20% in patients with carcinoid syndrome (Bhattacharyya et al. 2011). CaHD is most likely caused by the paraneoplastic effects of vasoactive substances excreted by the tumor, particularly serotonin (Zuetenhorst et al. 2003). Although patients with CaHD are often asymptomatic in the early stages of the disease, signs of right heart failure are associated with disease progression. The disease is characterized by plaque-like deposits of fibrous tissue involving the endocardium of the valve leaflets, cardiac chambers, and less frequently, the intima of the pulmonary arteries and aorta. Primarily, the right side of the heart is affected, due to thickening and retraction of the tricuspid and pulmonary valve leaflets, with subsequent regurgitation and/or stenosis. Left-sided valve involvement occurs in less than 10% of patients with CaHD and is commonly observed in patients with a right-to-left shunt (e.g., patent foramen ovale) and elevated right-sided heart pressures, bronchial NETs, or severe carcinoid syndrome with high amounts of vasoactive substances. Sporadically, left-sided valvular disease is present in the absence of right-sided valve involvement. There is no clear explanation for the predominant right-sided valve involvement. Vasoactive substances excreted by the tumor are thought to be largely inactivated within the pulmonary circulation (Moller et al. 2003).
Several biochemical markers are useful in the diagnosis of CaHD and are related to disease progression and prognosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are significantly elevated in patients with CaHD compared with those without. Due to its high sensitivity and specificity for the detection of CaHD in NET patients (92% and 91%, respectively), NT-proBNP may be useful as a screening test. High levels of chromogranin-A, a neuroendocrine secretory protein, are associated with the development of CaHD in NET patients (Pape et al. 2012) and with worse survival, especially when NT-proBNP levels are elevated. 5-Hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin, and its urinary excretion directly correlates with serotonin production. Urinary 5-HIAA levels are significantly higher in NET patients with CaHD than in those without, and higher levels are associated with progression of cardiac involvement (Moller et al. 2003). Although specificity is low, suggesting the development and progression of CaHD is codependent on other factors, aggressive treatment to decrease 5-HIAA levels is advisable.
Typical characteristics of carcinoid heart disease
Significant tricuspid regurgitation
Mixed pulmonary regurgitation and stenosis
Concomitant left-sided valve involvement (<10%), primarily in patients with persistent foramen ovale, bronchial carcinoid, or severe carcinoid syndrome
Pathognomonic fibrous plaques on echocardiography involving the endocardium of valve leaflets and cardiac chambers
Diabetes and Heart Disease
The prevalence of diabetes mellitus (DM) in the world’s population is approximately 8% (Whiting et al. 2011). This corresponds to over 350 million adults worldwide, of whom approximately 90–95% have type II DM. Within patients with DM, cardiovascular disease (e.g., myocardial infection, heart failure, and stroke) is the primary cause of death. DM-related functional and structural myocardial alterations may also occur, which may cause significant myocardial morbidity (e.g., diabetic cardiomyopathy) in addition to noncardiac morbidity (e.g., retinopathy and neuropathy). One should note that DM often coexists with factors such as hypertension, hypercholesterolemia, and obesity (i.e., metabolic syndrome), which are independent predictors of major adverse cardiac events and act as therapeutic targets in the pursuit of myocardial preservation. In this article, we will provide an overview of the effect of DM on the cardiovascular system and briefly discuss management and screening.
Classification of DM
Diagnostics for impaired glucose tolerance versus DM rely on a fasting plasma glucose level >6.1 versus >7.0 mmol/L, and a 2-hour post-load plasma (i.e., glucose level measured 2 h after ingestion of 75 g of glucose) of 7.8 versus 11.1 mmol/L, respectively. Glycated hemoglobin (Hb1Ac) >6.5 mmol/L is often used as an additive diagnostic measurement of DM. A number of DM types can be recognized, of which type I DM, type II DM, and gestational/pregnancy DM are most prevalent (i.e., others include drug-induced, pre-DM, and maturity-onset DM). Type I DM is characterized by an absolute insulin deficiency due to pancreatic beta cells destruction as a result of circulating auto-antibodies. Onset of disease typically occurs at a young age and in nonobese patients, yet later presentation may also occur (i.e., particularly in latent auto-immune DM (LADA). Type II DM is characterized by a relative insulin deficiency as a result of insulin resistance, impaired insulin release, and consecutive hyperglycemia. This type commonly occurs in obese, middle-aged patients. Finally, gestational DM is characterized by hyperglycemia during pregnancy. Although most of these patients return to euglycemic state after delivery, their risk of progression to DM has significantly increased.
DM and Cardiovascular Disease
DM is an independent risk factor for adverse cardiovascular events. For instance, the risk of fatal coronary artery disease (CAD) is 5.4% versus 1.6% in patients with and without DM, respectively. In patients without a history of vascular disease, DM is associated with a twofold increased risk of cardiac death (hazard ratio 2.3, 95%CI 2.1–2.6) and nonfatal myocardial infarction (hazard ratio 1.8, 95%CI 1.6–2.0). Interestingly, the lifetime risk of death due to CAD in patients with DM appears to be approximately 50% higher in women (7.7% vs. 1.2%, adjusted relative risk 3.12) than in men (4.5% vs. 2.0%, adjusted relative risk 1.99) (Huxley et al. 2006). Many theories have sprung to explain this finding, which are currently being investigated.
Functional and Structural Alterations
DM type 2, as stated earlier, is characterized by hyperglycemia, insulin resistance, and a predominance in obese patients. Of note, high circulating levels of fatty acids from adipose tissue in obese patients directly facilitate impairment of glucose sensitivity of pancreatic beta cells. Furthermore, the free fatty acids cause excessive lipid deposition in coronary arteries and myocardium, which – in turn – increases lipid use and decreases glucose oxidation. Also, lipotoxicity, glucotoxicity, oxidative stress, cardiac dysautonomia, and activation of the renin-angiotensin-aldosterone system are initiated, which increases blood pressure and macrophage activation. This process gives rise to collagen depositions and stiffening of the cardiomyocyte, in addition to left ventricular concentric remodeling, diastolic dysfunction, and atrial dilatation (Fig. 1). Overall, this increases the risk of both CAD and heart failure, including diabetic cardiomyopathy.
The term diabetic cardiomyopathy was introduced in 1972 by Rubler and colleagues as “ventricular dysfunction in patients with DM in the absence of obstructive CAD, hypertrophy or valvular heart disease” (Rubler et al. 1972). Over the years, recognition of a uniform pathophysiologic mechanism has proven difficult due to heterogeneity of study populations (i.e., heart failure with reduced ejection fraction versus preserved ejection fraction, chronic versus acute heart failure, symptomatic versus asymptomatic, and DM type I versus type II). The most relevant factors appear to be ventricular stiffness due to deposition of glycated products and increased collagen formation, a reduced myocardial capacity due to anaerobic metabolism, and consecutive elevated intracellular glucose requirement, microvascular dysfunction, and autonomic neuropathy. Interestingly, the level of hyperglycemia is associated with the risk of heart failure: each percent increase in glycated hemoglobin (HbA1c) correlates to an increased relative risk of heart failure of 8% after a median of 2.2 years, and each 1 mmol/L increase correlates to an increased relative risk of 5%.
Cardiovascular Risk Assessment
Screening for DM in the general population has not proven beneficial. Therefore, clinical guidelines only advocate assessment of glucose levels in high-risk populations (i.e., based on risk-assessment forms that incorporate age, body mass index, and family history of DM). Once DM has been established, physicians should be aware of blunting of signs and symptoms consistent with ischemic heart disease due to autonomic cardiac denervation (i.e., up to 60% of myocardial infarctions are asymptomatic (Valensi et al. 2011). This often hampers recognition of CAD and may delay treatment. Consequently, cardiovascular risk assessment should be assessed using risk scores such as ADVANCE and UKPDS, which have better predictive value for patients with DM than well-known risk scores such as the European Systematic Coronary Risk Evaluation (SCORE) and the Framingham Study. (Coleman et al. 2007). Screening for CAD in patients with DM may be performed using biomarkers such as albuminuria and NT-proBNP, which are independent predictors of (cardiovascular) mortality. Furthermore, noninvasive imaging techniques such as stress-echocardiography and cardiac computed tomography (cardiac CT) may be considered as screening tools, despite being hampered by limited interventional options in case of adequate use of primary prevention for cardiovascular disease (i.e., most patients with DM are already being treated with statin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors). On the other hand, the presence of non-obstructive CAD on cardiac CT does yield important prognostic value for 5-year mortality in patients with DM, which may imply a potential benefit for individualized treatment.
Prevention and Management of Cardiovascular Disease
Prevention of cardiovascular disease in patients with DM requires a multifactorial approach and appears to be of particular importance in women because of the strong increase in relative risk of cardiovascular events after onset of diabetes. First, nonmedicinal interventions such as diet and lifestyle adjustments – including cessation of smoking and starting physical exercise – should be pursued in order to lower the cardiovascular risk. Second, improved glucose management (target HbA1c <7%) is recommended because of a decrease in long-term risk of diastolic dysfunction, myocardial infarction, and mortality in both DM type I and II. Such improved glucose management is achieved by increasing insulin sensitivity (e.g., metformin), insulin levels (e.g., sulphonylureas and insulin injections), and glucose excretion (e.g., sodium glucose co-transporter-2 (SGLT2) inhibitors). One needs to be aware of the risk of lactate acidosis during metformin use in patients with moderate to severe renal insufficiency (glomerular filtration rate <50%). In such patients, the use of insulin rather than metformin is advocated. Of note, SLGT2 inhibitors are of high potential because recent trials have shown a significant reduction of cardiovascular events, i.e., a relative risk reduction of 38% for cardiovascular mortality (3.7% vs. 5.9%), 32% for all-cause death (5.7% vs. 8.3%) and 35% for heart failure (2.6% vs. 4.1%). No differences were observed for myocardial infarction and stroke. Additional studies are currently being performed to assess its efficacy in subpopulations and to further examine a potentially higher risk of peripheral artery disease. The third pillar for cardiovascular prevention in patients with DM is a target blood pressure of <140/85 mmHg and <150/90 for patients >80 years old is recommended in patients with DM, and 130/80 mmHg in case of diabetic nephropathy. Reduction of blood pressure can be achieved using weight loss, beta-blockers, and ACE inhibitors, of which the latter has also shown to improve the risk of nephropathy. ACE inhibitors are the preferred initial therapy and are also recommended in patients with stable CAD (i.e., because of a 25% reduction in a myocardial infarction, stroke, or cardiovascular death). Forth, initiation of statins is recommend as the relative risk reduction in myocardial infarction, and cardiovascular death is 16–21% per 1.0 mmol/L reduction in LDL cholesterol, with even better numbers for high-dose statins (Baigent et al. 2010). The benefit of statin therapy, however, is slightly hampered by a minor risk increase of developing type II DM (i.e., the significance of this finding is currently under investigation). The current low-density lipoprotein target is <1.8 mmol/L or >50% reduction if this goal cannot be achieved. In case of the latter, one could consider ezetimibe or even a proprotein convertase subtilisin/kexin type 9 inhibitor (Sabatine et al. 2017). Finally, antiplatelet use is recommended for secondary prevention in patients with DM. Management of patients with acute coronary syndrome (ACS) is quite similar in patients with and without DM, although patients with DM generally have a poorer prognosis. Of note, hyperglycemia often occurs in the setting of an ACS because of catecholamine release, elevated levels of free fatty acids, and increased glucose resistance (which may further impair myocardial function). More aggressive glucose monitoring or lower target glucose levels has been conflicting and only yielded results in specific populations, e.g., hyperglycemia levels >10 mmol/L.
Because of the diffuse inflammatory response in the coronary arteries, the risk of multivessel CAD is significantly higher in patients with DM versus those without (i.e., 66% vs. 46% in an ACS population using coronary angiography (Granger et al. 1993). In patients with stable CAD, no significant improvement in major adverse cardiovascular events was observed when coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) were compared to optimal medical therapy. In patients with ACS or complex coronary lesions, CABG appears to be superior to PCI in regard to long-term mortality; i.e., a 5-years mortality of 20% in PCI versus 12% in CABG (odds ratio 0.7, 95% CI 0.6–0.9) (Hlatky et al. 2009). It has to be noted that bare metal stents were used in that analysis, and increased use of modern drug-eluting stent are expected to lower the gap in PCI’s and CABG’s efficacy.
DM is a risk factor for atrial fibrillation (AF), yet its prognostic value appears to be inferior to factors such as CAD, hypertension, and obesity. Similar to nonpatients with DM, anticoagulation is recommended based on thrombotic and bleeding risk scores such as CHADSVASc and HAS-BLED, respectively (Kirchhof et al. 2016). Furthermore, sudden cardiac death occurs more frequently in patients with DM. Most of these events are attributed to CAD and more generally atherosclerosis, yet some are primarily related to DM (i.e., in case of autonomic dysregulation and microvessel disease). One should be wary of conduction delays and arrhythmia, yet therapy should primarily be focused on prevention of cardiovascular disease (see section “Prevention and Management of Cardiovascular Disease”).
The structural and functional adaptations that occur in DM constitute an approximately doubled relative risk of heart failure in men and even higher for women. For instance, in patients with DM without known heart failure, the incidence of heart failure is 8% after 30 months versus 3% in non-patients with DM. In patients with known heart failure, DM also constitutes for a higher risk of 12-month and 3-year mortality (Gerstein et al. 2006). Notably, subanalyses have indicated that patients with an ischemic cardiomyopathy have the highest risk of 12-month mortality. Treatment of heart failure is essentially the same in patients with DM as in non-patients with DM, and relies on ACE inhibitors, beta-blockers, and mineralocorticoid receptor blockade. Of note, minimal variations in drug efficacy have been reported such as a slightly lower efficacy of beta-blockade in reducing mortality rates in patients with DM versus non-patients with DM; relative risk 0.77 versus 0.65, respectively ( p >0.05). Mortality rate reduction for angiotensin-converting enzyme (ACE) inhibitors – in contrast – is similar; 0.84 versus 0.85, respectively. Finally, a recent SLGT2 inhibitor trial in patients with DM (10% heart failure) has suggested a 39% relative risk reduction for hospitalization and death due to heart failure (2.8 vs. 4.5% HR: 0.61 (0.47–0.79), p <0.001), which may have important implications for patient management. Studies regarding its efficacy in heart failure patients are currently being performed.
Pheochromocytoma-Related Cardiovascular Disease
Pheochromocytoma (PCC) is a rare neuroendocrine tumor that is often located in the adrenal gland (80%). When located in the paraganglia, it is called paraganglioma. Paroxysmal or sustained hypertension is the hallmark of presentation in 90% of patients, though its prevalence is low as estimated at less than 1 in 2000 cases of diastolic hypertension. Around 10–25% of the tumors are malignant and metastasizes often to the liver. The neuroendocrine tumors secrete several types of catecholamines (norepinephrine, epinephrine, and dopamine) which are known to have a direct effect on the cardiovascular system. The cardiovascular system expresses an abundant amount of dopamine and adrenergic receptors that are intensively stimulated by burst-wise release of the catecholamines. In clinic, the catecholamine outbursts may provoke serious complications, such as acute heart failure in the absence of coronary disease in young subjects. A notorious first presentation may appear during pregnancy and in the perioperative period. Inflammation may also play a role as suggested from histopathological analyses (Ferreira et al. 2016). Genetic factors may also be involved in PCC as one third have a familial history and about 20 known susceptibility genes have been discovered (Gupta and Pacak 2017; Pillai et al. 2016). Patients with dilated cardiomyopathy more frequently carry a gene mutation (MEN-2A, neurofibromatosis and von Hippel Lindau disease). In patients with a PCC succinate dehydrogenase, mutations such as SDH-B should be considered. Sometimes PCC is a part of other endocrine disorders such as in the MEN syndrome. The clinical presentation of PCC is highly heterogeneous. Hypertension, palpitations, and headache are the most common signs and may be paroxysmal. Postural hypotension or alternating episodes of high or low blood pressures may also present. The classical triad of pain (headache), palpitations, and perspiration is present in only a minority of patients but should lead to immediate suspicion of PCC. Other common nonspecific complaints are anxiety, panic attacks, trembling, nausea, fatigue, dyspnea, weight loss, visual problems, and polyuria. Paroxysms of symptoms may occur monthly, weekly, or several times daily, lasting from an hour to several days. A severe complication of PCC is heart failure. The desensitization of locally expressed cardiovascular receptors by the chronic exposure of catecholamines may provoke specific wall motion abnormalities leading to Takotsubo cardiomyopathy (Gravina et al. 2017; Zhang et al. 2017). Around a quarter of patients suffering from PCC may develop dilated or hypertrophic cardiomyopathy (Zhang et al. 2017). Arrhythmias are present in around 20% of patients which include sinus tachycardia, supraventricular, and ventricular tachycardia and sick sinus syndrome. A marked QTc prolongation and inverted T-waves are frequently observed and can cause malignant ventricular arrhythmias.
Diagnosing a PCC starts with determination of metanephrines in early morning fasting plasma (supine position) or in a 24 h urine collection (most sensitive screen). A MIBG scan (a functional scan) or a CT scan from thorax, abdomen, and pelvic will be a next step, but only in those patients with a positive biochemical test. Functional scanning, by Ga-DOTATATE is only practiced in presence of metastatic disease.
The treatment of choice of PCC is surgical excision of the tumor. Exposure to high levels of circulating catecholamines during surgery may cause hypertensive crises and arrhythmias. All patients with PCC should receive appropriate preoperative medical therapy to block the effects of the circulating catecholamines. Of interest, beta-blockers without concomitant alpha blockade is absolutely contraindicated in patients with PCC because of the risk of paradoxical deterioration of the hypertension. In case of persisting tachycardia, treatment with a beta1-selective agent such as atenolol is mandatory. A calcium channel blocker should be considered if the hypertension persists without signs of heart failure. In contrast, if heart failure occurs, renin angiotensin aldosterone inhibitors should be preferred. Invasive treatment for advanced heart failure should be considered as a bridge to recovery from surgical excision of the tumor. Actually, chemotherapy in PCC is limited, and under research. Radiotherapy could be considered as additional treatment option, especially in metastasized disease.
In pregnancy, PCC could mimic the hypertensive condition like preeclampsia. If the diagnosis of PCC is clear before 23rd week of pregnancy, postponing laparoscopic surgery from second to the third trimester (or after giving birth) was found not being beneficial in pregnancy outcomes. The unborn child is protected from maternal catecholamine outbursts, as the placenta contains enzymes breaking those down. However, the uteroplacental circulation is at risk. Of interest, preoperative preparations (that could take 5–10 days) could be a special point of consideration, although alpha blockade (by either phenoxybenzamine or doxazosine) is proposed as a good and a safe treatment option in pregnancy practice. If case of an unstable cardiac situation and surgery is not feasible, local embolization of the PCC mass may be an alternative.
Spontaneous Coronary Artery Dissection
Spontaneous coronary artery dissection (SCAD) is a nontraumatic dissection of the coronary arterial wall. The dissection originates either by a tear in the intima growing further by the inflow of coronary blood or by rupture of the vasa vasorum in the tunica media creating intramural hematoma. Subsequently, a false lumen develops with compression of the true lumen leading to myocardial ischemia. Historically, SCAD is associated with the most frequent cause of acute myocardial infarction (MI) in the peripartum period (Bush et al. 2013; Elkayam et al. 2014). More recent data clearly shows that SCAD more often occurs outside the peripartum period. The incidence of SCAD in all patients undergoing coronary angiography for an acute coronary syndrome (ACS) is around 3% (Saw et al. 2014; Vanzetto et al. 2009). In women below the age of 50 years, the incidence of MI due to SCAD differs from 24% to 35% (Saw et al. 2016). Around 10% of patients with SCAD were in a peripartum status. On the other hand, one third of MIs during pregnancy and 50% postpartum is because of SCAD. Predisposing factors are young-/middle-aged women (90%), peripartum status, multiparity, hormonal therapy, systemic inflammation, and systemic artheriopathies (FMD: fibromuscular dysplasia and connective tissue disease such as Marfan’s syndrome or Ehlers-Danlos type IV) (Al-Hussaini and Adlam 2017). Several triggers has been identified that could be categorized in emotional and physical stress. The latter is predominantly associated in males with SCAD. Often there is a diffuse arteriopathy reflecting the coexistence of SCAD in multiple arteries both in the coronary and extra-coronary system. SCAD is most prevalent in the left descending coronary artery, frequently involving the mid and distal segments. The pathophysiology is not elucidated yet. The high incidence of SCAD in females in the reproductive period underscores a potential relationship with female sex hormones. In particular, estrogens is known to have a softening effect on tissue and may weaken the coronary arterial wall as well. Autopsy studies suggest that inflammation with eosinophilic infiltration in the adventitia is involved in the process of periarteritis and dissection.
The clinical picture of SCAD mimics that of an acute coronary syndrome (ACS). ST-elevation MI (STEMI) may be present in up to 50% of patients. The first presentation may also be more disastrous with life-threatening ventricular arrhythmias (around 5%). The first line diagnostic as common in daily practice ACS is a coronary angiogram with or without intracoronary imaging (intravascular ultrasound/optical coherence tomography) (Rogers and Lasala 2004). Three distinct angiographic types has been described (Tweet et al. 2016; Yeo et al. 2018). Most often the middle/distal part of the left anterior descending coronary artery is affected. In contrast in peripartum SCAD, more proximal part of the coronary artery is involved, with higher STEMI rates resulting in a more disastrous clinical picture. SCAD is highly suspected in case of significant tortuosity of the coronary arteries in the absence of atherosclerotic disease and hypertension. When SCAD is assumed, the operator should decide whether the benefit of an invasive procedure outweighs the potential risk of iatrogenic lesions of the vulnerable arterial wall. Coronary CT angiography is a novel noninvasive technique that may be considered, but its Spatial resolution is often too low to detect dissection in small arteries beyond 1 mm in diameter.
Broken Heart Syndrome
In 1990, Sato and Dote introduced the Japanese term takotsubo syndrome describing the systolic left ventricular apical ballooning that mimics the typical silhouette of the octopus trap (Sato and Taiteishi 1990). This syndrome is also named broken heart syndrome (BHS), takotsubo cardiomyopathy, stress cardiomyopathy, or apical ballooning. Typically, the mid- and apical segments of the left ventricle (LV) are depressed, but three other types has been described (Akashi et al. 2015), see Fig. 8. The left ventricle wall motion abnormalities are not consistent with the anatomical coronary artery blood supply and often recover completely within hours, days, or weeks. (1) BHS is highly prevalent in women (90%) than in men and in particular in the postmenopausal phase, suggesting involvement of the change in female hormone profiles. The pathophysiology is not fully elucidated but catecholamine excess, coronary artery spasm, and microvascular dysfunction may play a key role (Akashi et al. 2015). Most of the time, a physical (36%) or emotional (28%) trigger is preceding BHS such as death of a close relative but also intracranial hemorrhage. It is believed that the over-activation of sympathetic nervous system is playing a crucial role. In some series, catecholamine levels (epinephrine and norepinephrine) were significantly higher in patients with BHS as compared with patients with myocardial infarction (Wittstein et al. 2005). In addition, similar reversible cardiomyopathy with global or focal dysfunction in patients with pheochromocytoma and in the setting of acute brain injury has been described. Endomyocardial biopsy data are consistent with histologic signs of catecholamine toxicity with in particular contraction band necrosis (Karch and Billingham 1986).
Patients with a BHS have clinical features of an acute coronary syndrome (ACS) presenting with acute chest pain, dyspnea, or arrhythmias. BHS is present in 1–2% of the patients with suspicion of ACS. Troponin is raised without ST-segment elevation but often with ST-segment abnormalities on the electrocardiogram. Around 10% of patients are in cardiogenic shock. The prevalence of life-threatening arrhythmias is higher in men than in women, 33% versus 11%, and is often associated with QTC-interval prolongation (Stiermaier et al. 2015). The in-hospital MACE rate is around 20% and comparable with patients with ACS. Regardless of the low prevalence of BHS, MACE occurs more often in men than in women. On the coronary, in angiogram or intra-coronary imaging, there are no signs of plaque rupture or obstructive coronary artery disease. The typical LV wall motion abnormalities can be detected with left ventricle angiography, echocardiography, or MRI see Fig. 9. During long-term follow-up, the MACE rate was 9.9% per patient-year and death rate was 5.6% per patient-year. In more than 20% of patients, BHS may relapse.
It is magnificent to acknowledge that today there is much more awareness and insight in infrequent occurring cardiac diseases originating from endocrine disorders. Unravelling the role of prolactin in peripartum cardiomyopathy is an excellent example. International and multidisciplinary collaboration is prerequisite for the management of these diseases. The challenge is to disseminate the obtained knowledge between all involved specialties in order to timely recognize and to manage the underlying endocrine-associated cardiac disease.
The interaction between the thyroid and the heart has profound implications for contemporary management of patients with cardiovascular disease. Thyroid physiology plays a central role in modulating risk of cardiovascular disease in the area of arrhythmia, heart failure, and accelerating atherothrombosis.
Carcinoid heart disease refers to the cardiac manifestations of neuroendocrine tumors. The clinical course is frequently characterized by right-sided valvular disease provoking cardiac decompensation with significant mortality and morbidity. Although medical therapy may relieve symptoms, surgical intervention is the only curative option for carcinoid heart disease. The prognosis of carcinoid heart disease has significantly been improved over the last years with novel medical and surgical interventions.
Diabetes triggers a cascade of mechanisms that leads to a significantly higher risk of cardiovascular morbidity and mortality. In order to prevent such events, a multifactorial approach is required that includes lifestyle and glucose-level improvements, as well as antihypertensive, lipid-lowering, antiplatelet drugs and timely coronary revascularization. Efficacy of individualized therapy based on factors such as gender and atherosclerotic burden is currently under investigation and may yield important improvements.
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