Endocrinology of heart failure

Clinical Case 8.1

A 45-year-old woman presented to the Emergency Room with acute shortness of breath such that she was barely able to give a history. She was a life-long non-smoker and had a past history of moderately severe asthma requiring on average two courses of oral glucocorticoid steroids per year. In addition, over the previous year she had noted deterioration in her exercise tolerance that was unrelated to her asthma. Non-invasive cardiac investigations (an echocardiogram) 6 months previously had demonstrated impaired left ventricular function. Over the day prior to admission, use of her β₂-adrenergic agonist inhalers had not proved beneficial. When seen, she had a blood pressure of 130/75 mmHg, a tachycardia of 130/min, a respiratory rate of 30/min and widespread wheeze in her chest. No cardiac murmurs were heard. The peak expiratory flow rate was 120 l/min (normal for her age and height 450 l/min). Chest X-ray showed borderline cardiomegaly (Box 8.2).

Box 8.2

Chest X-ray of Clinical Case 8.1. This postero-anterior film shows overexpanded lung fields compatible with asthma and borderline cardiomegaly (the ratio of the radiological width of the cardiac shadow to that of the thorax is 0.5) and with upper lobe (more...)

The dilemma for the medical team in this case was to distinguish the cause of her dyspnea when she clearly had two possible causes; asthma or pulmonary edema due to poor left ventricular (LV) function. In this case, knowledge of the endocrinology of heart failure facilitated the differential diagnosis.

Impaired LV function causes a primary decrease in cardiac output and, as a result, arterial blood pressure falls. Venous pressure rises because of the inability of the heart to match input to output. This can cause edema due to increased pre-load on the venous side of the circulation and this is usually manifest as pulmonary edema. The arterial underfilling, due to failure of the LV, activates the baroreceptor reflex via stretch receptors in the aortic arch and carotid sinuses as well as several neurohumoral reflexes. Increased sympathetic tone in the CVS results in increased myocardial contractility, tachycardia and arterial vasoconstriction thus increasing cardiac afterload.

Increased sympathetic stimulation of the juxtaglomerulosa apparatus of the kidney, as well as decreased perfusion pressure, induces release of renin that activates the angiotensin-aldosterone system (see Box 4.34). This, together with increased sympathetic vasoconstrictor tone, leads to increased renal sodium (and, hence, water) retention. Thus, in heart failure the renin-angiotensin-aldosterone system is activated and the peripheral blood concentration of renin can be used as an indicator of its severity. Furthermore, the effectiveness of aldosterone on salt and water retention in the kidney in such patients is maintained (i.e. there is no mineralocorticoid ‘escape’).

Apart from stimulating aldosterone secretion, angiotensin II has direct vasoconstrictor effects on both afferent and efferent renal arterioles and a constrictor effect on mesangial cells reducing glomerular filtration surface. It also has direct mitogenic effects on cardiac myocytes and may also play a role in increasing thirst in heart failure via a central CNS effect. There is considerable evidence for local tissue renin-angiotensin systems and increasing experimental work indicates that angiotensin II plays an intracrine role in the heart to affect cell proliferation and apoptosis.

Non-osmotic release of AVP also occurs in heart failure as a result of activation of carotid baroreceptors. This (combined with an increase in thirst) leads to a decrease in free water excretion and potentially hyponatremia (see Box 7.42). Hyponatremia in heart failure is an ominous prognostic sign.

LV dysfunction results in increased left atrial pressure and atrial natriuretic peptide (ANP) is secreted from the atria in response to increased distension (Box 8.3). This 28 amino acid peptide increases glomerular filtration, decreases collecting duct sodium reabsorption and inhibits the renal renin-angiotensin-aldosterone system. Brain natriuretic peptide (BNP), belonging to the same family of peptides, is a 32 amino acid hormone (Box 8.3). It is not only synthesized in the brain but also in the ventricles and is released into the circulation in response to ventricular failure. It has the same effects as ANP and can act on the same receptors. Circulating concentrations of BNP are sensitive measures of heart failure and were used in Clinical Case 8.1 to clarify the cause of dyspnea. The serum BNP was markedly elevated (21 pmol/l, NR 0.5–6.1 pmol/l) strongly supporting a diagnosis of pulmonary edema. In clinical studies, measures of BNP have the ability to detect heart failure with a sensitivity of nearly 100% and a specificity of about 85%.

Box 8.3

Structures and sites of synthesis of the natriuretic family of peptides and their receptors. There are three natriuretic peptides: atrial (ANP), brain (BNP) and C-type (CNP). All three hormones have a 17 member amino acid ring formed by a disulfide bridge (more...)

Apart from activation of the renal renin-angiotensin-aldosterone system and the counter-regulatory ANP/BNP peptides, the reduced cardiac output seen in heart failure also activates local hormones involved in the control of vasoconstriction. These include the endothelins (see below) that are very potent hormones working, primarily via paracrine actions, to increase vasoconstrictor tone. High circulating concentrations may be seen in heart failure and again are indicative of a poor prognosis.

The treatment for heart failure is to reduce peripheral resistance (antagonize vasoconstriction) and to reduce total plasma volume so as to decrease preload on the heart. Whilst diuretics remain a therapeutic mainstay, the involvement of the endocrine system means that the vast majority of treatments for heart failure are in fact related to its endocrine control (Box 8.4). Clinical Case 8.1 was treated with inhaled β₂-adrenergic agonist and parenteral glucocorticoid steroid for her asthma; an intravenous diuretic (furosemide) and an oral angiotensin converting enzyme inhibitor was given for her heart failure.

Box 8.4

Endocrine basis of the treatment of heart failure.

Paracrine and autocrine regulation of blood pressure: the endocrinology of sepsis

The vascular endothelium that provides the barrier between the blood and the vascular wall is the site of production of several hormones in the control of blood pressure. These include the endothelins, nitric oxide and prostacyclin. Clinical Case 8.2 introduces the role of these hormones together with that of calcitonin gene-related peptide in vascular homeostasis.

Clinical Case 8.2

A previously fit 54-year-old man has suffered a ‘cold’ for a week before developing a cough, productive of green sputum. He presented to the Emergency Room with increasing shortness of breath such that he was unable to complete sentences. He was an ex-smoker on no medication and with no significant past medical history. He was pyrexial (39.4°C) and cyanosed with capillary blood oxygen saturations of 90% on 6 l/min inspired oxygen via a face-mask. His blood pressure was 120/70 mmHg with a tachycardia of 140/min. His chest contained bilateral crackles on auscultation. His peripheral blood white cell count was raised at 16 × 10⁹ /l and the chest X-ray markedly abnormal with evidence of a cavitating pneumonia (Box 8.5). He deteriorated markedly and required transfer to the Intensive Care Unit where he underwent artificial ventilation.

A pulmonary artery catheter was inserted and investigations showed the cardiac output to be high at 14 l/min with a normal pulmonary artery capillary wedge pressure (15 mmHg). The peripheral resistance was low (SVR 380 dynes s/cm⁵ - normal 770–1500 dynes s/cm⁵) and pulmonary vascular resistance PVR 80 dynes s/cm⁵ - normal <200 dynes s/cm⁵). At this time, peripheral blood, taken as part of a research study, contained markedly elevated concentrations of calcitonin gene-related peptide (CGRP).

Box 8.5

Chest X-ray of Clinical Case 8.2. The chest X-ray shows the appearances in the Emergency Room. The left lung shows extensive consolidation with cavitation. The X-ray shows the appearances in the Intensive Care Unit. The consolidation is now almost confluent (more...)

In sepsis, the presence of endotoxin and early inflammatory cytokines (e.g. TNF, IL-1) results in endothelial cell activation and disruption, disturbing the tonic release of the vasoconstrictor endothelin-1 (ET-1) and the vasodilators nitric oxide (NO) and prostacyclin (PGI₂). The activated cells (and also the smooth muscle cells) produce much larger quantities of ET-1, NO and prostaglandins.

The 21 amino acid endothelins, of which there are three isoforms (ET-1, ET-2 and ET-3, Box 8.6) are the most potent vasoconstrictors known. They are cleaved from the precursor pro-ET (sometimes referred to as big-endothelin) by a membrane-bound metallopeptidase enzyme. ET-1 is the dominant form in the human vasculature where it occurs mainly in endothelial cells, though it is also found in smooth muscle cells and cardiac myocytes. It is not stored but synthesized de novo. ET receptors occur in two forms ET-A and ET-B. ET-A has a high affinity for ET-1 and is expressed on smooth muscle cells. It is considered to mediate the direct vasoconstrictor effects via calcium influx through a non selective ion channel. ET-B receptors are expressed on both endothelial cells and smooth muscle cells in some vascular beds. ET-B stimulation leads to the release of NO (vasodilator) and the prostaglandins thromboxane (vasoconstrictor) and PGI₂ (vasodilator). The exact roles of the ET peptides in sepsis are not certain and, experimentally, the use of ET receptor antagonists produces variable results.

Box 8.6

Endothelins (ET) and their role in vascular homeostasis. Three isoforms of pro-endothelin (Pro-ET) and their sites of cleavage by endothelin converting enzyme (ECE) to active endothelins. They are products of different genes, but Pro-ET-1 is the most (more...)

Locally produced NO is synthesized from arginine by the action of the constitutively expressed form of endothelial nitric oxide synthase (eNOS). It induces relaxation of smooth muscle cells via paracrine activation of soluble guanylate cyclase that converts GTP to cGMP (Box 8.7). In sepsis, the increased NO production is the result of expression of the inducible isoform of NO synthase (iNOS) stimulated by exposure to endotoxin and cytokines. The lung is a major site of iNOS expression in sepsis and increases circulating concentrations of NO. At the same time the physiological action of eNOS is downregulated.

Box 8.7

Synthesis of nitric oxide (NO) and its vasodilatory effects on vascular smooth muscle cells. A rise in intracellular Ca²⁺, induced by chemicals or shear stress on the endothelial lining, activates endothelial nitric oxide synthase (eNOS) that converts (more...)

Prostaglandins (PGs) are important regulators of endothelial and kidney functions. A number of PGs is released by endothelial cells. PGI₂, like NO, induces vasodilatation whilst thromboxane A₂ is a potent vasoconstrictor. The kidney also produces PGs and PGA₂ and PGE₂ can antagonize the hypertension induced by the retention of salt and water.

PGs are synthesized by the cyclooxygenase enzyme(s) (COX) and, as with NOS, there is a constitutively expressed isoform, COX-1, and an inducible form, COX-2 (Box 8.8). The latter is rapidly induced at sites of inflammation to produce large quantities of prostaglandin and thromboxane. In sepsis, COX-2 is induced by endotoxin and cytokines whilst anti-inflammatory cytokines (e.g. IL-4 and IL-10) and glucocorticoids inhibit COX-2 expression.

Box 8.8

Overview of prostaglandin synthesis and related compounds. *These are the only two biosynthentic processes that occur in the microsomes of the cell. The rest take place within the plasma membrane.

As was seen in Clinical Case 8.2, septic shock is characterized by a markedly reduced peripheral resistance due to the effects of immune activation on local control of vasomotor tone. It has a mortality of about 50–70% and current treatments have little, if any, effect on the endotoxin and cytokine activated pathways discussed above. Selective COX-2 inhibitors, ET-1 antagonists and iNOS inhibitors are under active development but have not reached the stage of clinical use.

Clinical Case 8.2 had an acute cavitating pneumonia with secondary septicemia. When transferred to the Intensive Care Unit he had a high cardiac output with low peripheral resistance. CGRP, the most potent vasodilator peptide known, has been thought to play a role in the etiology of such pathological states, probably as a result of its release from peripheral nerve endings.

CGRP is a 37-amino-acid peptide, occurring in two forms (α and β) and derived, as its name suggests, from the calcitonin gene by tissue-specific alternative processing (see Box 5.38). It belongs to a family of peptides including amylin and adrenomedullin. It is widely distributed with its receptors (of which there are also two types), particularly in the brain and the cardiovascular system, but also the thyroid gland and gut. Target cells for CGRP have a cell surface endopeptidase that can cleave the peptide. The t_1/2 of the peptide in plasma is about 10 min and there is doubt as to whether it functions as a hormone or whether the blood concentration changes merely reflect ‘spillage’ of the peptide into the circulation. Its widespread distribution throughout the nervous and cardiovascular systems indicates a number of physiological roles. These include altering regional blood flow, direct chronotropic and inotropic effects on the heart, modulation of inflammation and pyrexia, reducing insulin and gastric acid secretion, modulation of sensory transmission. The use of CGRP analogs in a variety of vascular diseases is under active research.

Hormones and blood cell production - erythropoietin

The regulatory processes that control the production and differentiation of blood cells (hematopoiesis) comprise classical hormones, growth factors and cytokines that can act on bone, blood and, additionally, the liver and spleen. The actions of growth factors and cytokines are generally mediated by paracrine or autocrine mechanisms. Erythropoietin (Epo), secreted by the kidney is a classical hormone and stimulates the production of erythrocytes. A human must produce over a million of these red blood cells each minute to sustain a steady state in which production equals loss, allowing oxygen delivery to tissues and blood pH to be maintained. Clinical Case 8.3 introduces the endocrinology of erythropoietin.

Clinical Case 8.3

A 46-year-old woman presented to the Emergency Room complaining of shortness of breath. There was no evidence for asthma or heart failure but her electrocardiogram was abnormal with evidence of pulmonary hypertension. She was a non-smoker and took no regular medication. There was no family history of serious illness. Echocardiography confirmed the pulmonary hypertension. Her hemoglobin was noted to be markedly elevated at 24 g/d (NR 11.5–14.5 g/d) with a hematocrit of 0.60 (NR 0.37–0.47). Analysis of arterial blood gas showed that she was not hypoxic. Chest X-ray showed a prominent pulmonary artery compatible with pulmonary hypertension (Box 8.9). CT scan of the lungs (see website) confirmed pulmonary emboli.

Box 8.9

Radiology of Clinical Case 8.3. Chest X-ray MR scan of abdomen

In Clinical Case 3.1, thrombus formed in the cardiac atria, as a result of atrial fibrillation and the resulting embolus was arterial to the brain. In Clinical Case 8.3, it was probable that the thrombi were venous and embolization was to the lungs. It is apparent from her elevated hemoglobin that this patient had a marked increase in the number of circulating red blood cells (termed erythrocytosis) that led to an increased blood viscosity and the production of thrombus. Formation of thrombi within, or embolization to, the lungs led to the clinical presentation with dyspnea and pulmonary hypertension.

Erythropoiesis in bone marrow is regulated by the circulating concentration of Epo via the Epo receptor that belongs to the cytokine family of receptors. Signalling is via a number of kinases including JAK/STAT and Ras/MAP kinase pathways. Epo, a glycoprotein with a molecular weight of 34 000, has four effects on erythrocyte progenitor cells. It maintains their viability, promotes cell division, increases hemoglobin synthesis and stimulates morphological maturation. Mutations leading to truncation of the carboxyl terminus (thus removing a negative regulatory element) lead to inherited forms of erythrocytosis.

Epo has been used therapeutically prior to the removal of blood for autologous blood transfusion and illegally by athletes to improve oxygen carriage and, thus, performance. A mutation within the carboxyl terminus of the receptor that increases the sensitivity to Epo and results in a high hemoglobin concentration has been reported in a gold medallist in cross-country skiing in the Winter Olympics.

The cells making Epo are predominantly in peri-tubular interstitial sites in the kidney although other sites of synthesis (such as the liver and brain) are recognized. Epo synthesis is regulated by oxygen concentration via a poorly understood mechanism involving a heme-containing protein, probably resembling cytochrome b and the nuclear transcription factor HIF-1 leading to an increase in Epo gene expression.

It is clear that an increase in Epo secretion will occur in all forms of hypoxia whether these are physiological (e.g. altitude) or pathological (e.g. an abnormal hemoglobin or lung disease). It will also be apparent that renal failure will lead to Epo deficiency and anemia (Box 8.10).

Box 8.10

Causes of an increase or decrease in Epo concentrations. Physiological - hypoxia of altitude Pulmonary disease - e.g. emphysema

In Clinical Case 8.3, the excess of Epo (her venous Epo concentration was 65 mU/l, NR 10–20 mU/l) resulted from production by a renal tumor (Box 8.10). Other tumors causing erythrocytosis include those of the liver and cerebellar hemangioblastomas. Primary erythrocytosis termed polycythemia vera is caused by a clonal expansion of cells with an increased sensitivity to Epo though circulating Epo concentrations are low or normal. The exact mechanism underlying the increased sensitivity in polycythemia vera is not understood.

Clinical Case 8.3 required a nephrectomy to remove the source of the Epo excess. This was done after initial therapy to reduce the hematocrit (by isovolemic venesection) and the use of intravenous heparin. Patients with secondary erythrocytosis may need regular venesection whilst patients deficient in Epo benefit from adminstration of human recombinant Epo by subcutaneous injection.

Carcinoid

Episodic, short-lasting changes in vasomotor tone in the cardiovascular system are seen in endocrine deficiencies and excesses. For example, estrogen deficiency may lead to episodic vasodilatation (‘hot flushes’) whilst release of catecholamines and other peptides from tumors of the adrenal medulla (pheochromocytomas) can stimulate episodic symptoms of hypertension and tachycardia or hypotension (Clinical Case 4.7). The final clinical case demonstrates the effects of the paroxysmal release of a different amine, in this case 5-hydroxy-tryptamine or serotonin, from what are known as carcinoid tumors.

Carcinoid tumors are common and can be seen in 1:150 people at post-mortem and 1:300 appendectomies. The appendix is the commonest site for these tumors followed by the rectum, ileum, lungs, and stomach. Clinical presentations, however, are much less common (incidence ~5 per 100 000 per year) and they occur equally in both sexes with a mean age of about 50 years.

The cells of origin of carcinoids (and, thus, their biochemistry and clinical presentation) differ according to site of origin of the tumor (Box 8.11). Rarely, the production of peptides by the tumors leads to clinical presentation as acromegaly or Cushing's syndrome; these may cause great diagnostic difficulty. Classical carcinoid syndrome results from the effects of serotonin together with other contents of tumor secretory granules (including bradykinin, tachykinin, prostaglandins and histamine, depending on the cell of origin) that may be involved in the flushing. In approximately 60% of patients, fibrous plaques develop in the right side of the heart often affecting the tricuspid and pulmonary valves.

Box 8.11

Classification of carcinoid tumors.

The classical symptoms of the ‘carcinoid syndrome’ - flushing, diarrhea and wheeze - as seen in Clinical Case 8.4 arise when metastases to the liver result in the release of the amine into the general circulation. Only a minority of patients with carcinoid tumors suffer from the syndrome. The ability of many cells within the body to take amine precursors up and to decarboxylate them to form bioactive agents rise to the concept of the apud system. It was proposed that these cells shared a common embryonic origin in neuronal ectoderm. Related cells are found in a number of other tissues including the adrenal medulla and sympathetic ganglia. There are histological similarities between carcinoid tumors, medullary cell carcinoma of the thyroid and islet cell tumors. This, together with the observation that carcinoid tumors may occur in patients with other endocrine tumors and that carcinoid tumors may produce a number of other peptides, are compatible with this hypothesis.

Diagnosis of carcinoid syndrome depends in the main on measurement of serotonin metabolites in urine (Box 8.12), though measurement of other secreted products such as chromogranin A has also been advocated. When Clinical Case 8.4 was first seen, the 24 h urinary 5HIAA was 120 μmol/d (NR <30 μmol/d). Ultrasound confirmed widespread liver metastases and biopsy confirmed metastatic carcinoid (Box 8.13). The site of the primary tumor was not detected and he was followed in the out-patient clinic. He continued to work full-time and enjoyed his cricket. Some 4 years later, the 24 h urinary 5HIAA was 220 μmol/d. He remained in full-time employment. The 24 h urinary 5HIAA was 990 μmol/d after 21 years and he felt his symptoms warranted treatment. A radiolabeled octreotide scan was performed (Box 8.13). This showed marked uptake by the tumor and his symptoms were completely relieved by regular octreotide. He continued to play sport some 22 years after the original diagnosis.

Box 8.12

Synthesis and metabolism of 5-hydroxytryptamine (serotonin).

Box 8.13

Liver biopsy and ^99mTC-labeled octreotide scan results of Clinical Case 8.4. The core of tissue taken from the liver shows the replacement of normal liver with multiple areas of dark cells of carcinoid tissue. Two radionucleotide scans have been performed. (more...)

The benign clinical course of Clinical Case 8.4 illustrates why the term carcinoid was coined for this condition as the tumor generally behaves in a much more benign way than metastatic carcinoma. The relative rarity of the tumor, together with the variation in clinical behavior, indicates why comparative data on treatment outcomes (Box 8.14) are sparse. It also emphasizes the need for properly controlled therapeutic trials with adequate numbers of patients. Had Clinical Case 8.4 received any form of treatment when the tumor was first detected with distant metastases, it would have been regarded as a considerable success 22 years later.

Box 8.14

Treatment of carcinoid tumors.

Clinical case questions

Clinical Case Study Q8.2

A 73-year-old woman was seen in the Emergency Room. She had become increasingly short of breath over the previous 12 h. She was taking hydrochlorthiazide 5 mg with amiloride 5 mg daily. When seen she had a blood pressure of 130/70 with a sinus tachycardia of 120/min. The jugular venous pressure was raised 5 cm and the electrocardiogram and chest X-ray obtained are shown in Box Q8.2. Her serum sodium was reported to be 119 mmol/l (NR 135–145 mmol/l) with a potassium of 4.0 mmol/l (NR 3.5–4.7 mmol/l) and a urea of 8.0 mmol/l (NR 2.5–8.0 mmol/l). The electrocardiogram and chest X-ray are shown in Box Q8.2.

Box Q8.2

Electrocardiogram and chest X-ray of Clinical Case Study Q8.2.

Question 1: What is the diagnosis?

Question 2: What is the cause of her hyponatremia?

Question 3: How would you treat her?