(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Acromegaly
Enlargement of the heart, premature coronary artery disease (CAD), heart failure, hypertension, intraventricular conduction defects, and cardiac arrhythmias may require management by a cardiologist. Mild hypertension occurs in more than 50 % of patients. Rarely acromegalic cardiomyopathy occurs. There is myocyte hypertrophy and an increase in the collagen content per gram of heart compared with normal myocardium. The defect in the myocardium causes arrhythmias, which weaken the myocardial force that leads to heart failure.
Management
Treatment of patients with somatostatin analogues that inhibit the secretion of growth hormone, octreotide and lanreotide, have shown beneficial effects in small studies. In some patients, when heart failure has been completely controlled the left ventricle mass index and mean wall thickness have shown improvement with this therapy. In patients with long-standing acromegaly, there is nonreversible interstitial fibrosis with little recovery. Hypertension can be controlled with diuretics and other antihypertensive agents.
Acromegalic cardiomyopathy may show some amelioration with the administration of octreotide. Treatment of the lesion with heavy particle, proton beam irradiation, or surgery is usually curative.
Carcinoid Syndrome
Carcinoid heart disease may occur in patients with carcinoid syndrome. The main symptoms of flushing, diarrhea, and bronchospasm are caused mainly by 5-hydroxytryptamine or serotonin, which is liberated from carcinoid tumors that originate from chromaffin cells (neuroendocrine cells) of the terminal ileum. Neurosecretory granules release amines that include serotonin, histamine, bradykinins, tachykinins, and prostaglandins. Involvement of the heart occurs in about 50 % of carcinoid syndrome cases and is usually a late manifestation seen mainly in patients with malignant tumors that have metastasized to the liver. In carcinoid heart disease, 5-hydroxytryptamine is metabolized by monoamine oxidase to 5-hydroxyindoleacetic acid (5-HIAA). Elevated levels of 5-HIAA in the urine confirm the diagnosis. Echocardiography reveals thickening of the tricuspid and pulmonary valves with tricuspid and pulmonary valve regurgitation and, in some cases, pulmonary valve stenosis. The lesions in the heart cause right heart failure. Because the tricuspid valve leaks, blood regurgitates into the veins of the neck and back toward the liver, which becomes pulsatile with each heartbeat. Examination of the jugular venous pulse reveals prominent pulsatile V waves of tricuspid regurgitation. A right ventricular lift or heave is often detected. Findings include a pansystolic murmur of tricuspid regurgitation, an early diastolic murmur of pulmonary regurgitation, and a systolic murmur of pulmonary stenosis best heard at the left sternal edge. Murmurs may be soft because of low output from the right ventricle. Ascites becomes prominent prior to mild edema of the ankles. When tricuspid regurgitation is prominent the enlarged liver is visibly pulsatile.
Management: There is no specific treatment for carcinoid heart disease. Octreotide reduces flushing diarrhea and urinary levels of 5-HIAA. Cardiac surgery offers definitive therapy for symptoms. Marked symptomatic improvement, of >1 New York Heart Association class, occurs after valve replacement (Castillo et al. 2008; Connolly et al. 1995, 2001).
Cushing’s Syndrome
This disorder is caused by either an ACTH-dependent adenoma or an ACTH-independent adenoma. Manifestations include truncal obesity that involves the abdomen, chest, and the upper back causing a buffalo hump. Cardiovascular complications such as hypertension may be severe. Diabetes may occur, and along with hypertension, this increases the risk for myocardial infarction. Accelerated atherosclerosis is a common finding in patients not treated early in the course of this disease.
Management: Cushing’s disease requires transsphenoidal pituitary surgery and adrenal tumors require adrenalectomy. Ectopic ACTH syndrome occurs and requires treatment of the underlying tumor. Correction of hypokalemia with potassium replacement and spironolactone or eplerenone and drugs that block steroid synthesis may be required.
Diabetes and the Heart
Patients with type 2 diabetes mellitus without a history of myocardial infarction (MI) have the same risk of a coronary event as patients without diabetes who do have a history of MI (Haffner et al. 1998). Much of their care therefore involves the prescriptions used for the management of patients with angina or post-acute coronary syndrome. Cardiologist and clinicians who care for cardiac patients, thus, have a role to play. The ACCORD trial on blood pressure (2008), and the ACCORD trials on intensive blood glucose control (2008) have failed to show that intensive glucose control in type 2 diabetes reduces the risk for CVD events.
Which Cardiovascular Drugs Are Best ACE Inhibitors/ARBS?
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are touted to cause a slightly reduced incidence of diabetes, but this has not been proven without doubt in RCTs. These inaccurate assumptions are based on secondary analyses of clinical trials. More importantly, many trialists fail to understand that the finding of glucose intolerance does not indicate a proven diagnosis of diabetes mellitus.
Nathan (2010) in an editorial emphasized that the only clinical trial that directly examined whether ACE inhibition would prevent diabetes failed to show that diabetes was prevented (The DREAM Trial Investigators 2006) or that there were any beneficial effects on insulin resistance or beta-cell function (Hanley et al. 2010). See Chaps. 3 and 4.
Beta-Blockers Underused in Diabetics
Because the majority of patients with long-standing type 2 diabetes over age 50 develop atheromatous obstructive CHD culminating in sudden cardiac death or fatal or nonfatal MI, it is necessary to maintain type 2 diabetics on a beta-blocker for hypertension control. Nebivolol, bisoprolol, or in non-brittle diabetics carvedilol are advisable. Also a statin, an ACE inhibitor, and chewable aspirin should be administered. The commonly used atenolol is not recommended because it is poorly effective; this widely prescribed beta-blocker should become obsolete (Khan 2011); see Chap. 1. Many type 2 diabetics older than age 50 unknown to have CHD are at high risk for CHD events. These agents do not cause diabetes, an unproved notion held by many learned physicians worldwide (see Chap. 2). Sudden death appears to be more common in diabetics than in non diabetic patients with known CHD. Only timolol and propranolol have been shown in soundly conducted RCTs to prevent sudden cardiac death (see Chap. 1). Guideline experts appear to be unaware of these facts.
Aspirin
Chewable soft aspirin 75–81 mg once daily after meal is strongly recommended for diabetics older than age 50 and is more reliably efficacious than enteric coated aspirin which should be used only if stomach irritation occurs with chewable aspirin. The enteric coated drug is often not 100 % absorbed, and aspirin resistance is incorrectly blamed. Absorption proved very variable and caused up to 49 % apparent resistance to a single dose of enteric coated aspirin but not to immediate release aspirin (0 %); pharmacologic resistance to aspirin is rare; the study failed to identify a single case of true aspirin resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric coated but not immediate release aspirin administration (Grosser et al. 2013).
The author abandoned the use of enteric coated aspirin in 2007 and instead prescribes soft chewable aspirin 81 mg for CVD prevention.
In addition if chest pain occurs the patient needs to take 3–4 chewable aspirin (not coated) while awaiting ambulance transport to an emergency.
Dyslipidemia in Diabetics
Diabetic patients with elevated LDL-C (>200 mg/dl, 4.0 mmol/l), mild elevation of triglycerides (<250 mg/dl), and lowered are best managed with atorvastatin. If triglycerides are not elevated rosuvastatin is advisable to attain goal LDL-C levels but should not be used if the eGFR is <40 ml/min. Reduce the dose in patients with mild renal dysfunction, the elderly, Asians, and patients with hypothyroidism. In diabetics with known CVD the LDL goal is <70 mg/dl (1.8 mmol/l). In the absence of CVD, an LDL goal of <2.6 mmol/l (100 mg/dl) is advisable.
Simvastatin is not recommended because of many interactions that can occur with this proven useful drug (see Chaps. 17 and 21).
Fenofibrates should not be combined with statins.
In ACCORD Lipid (2010) the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke, as compared with simvastatin alone.
Blood Pressure Control
The ACCORD Study Group Diabetic Blood Pressure Trial (2010) showed that among patients with type 2 diabetes at high risk for cardiovascular events, a target systolic BP of <120 mmHg was not superior to a target of <140 mmHg. This intensive target did not reduce composite cardiovascular events. In the intensive systolic BP group there were more serious adverse events, hypokalemia, and elevated serum creatinine.
The UKPDS 9-year follow-up showed that tight BP control was most useful. Importantly BP >160 mmHg was reduced only to <144 mm.
The notion commonly held in North America that the systolic BP should be decreased to <125 mmHg is false.
If kidney function is normal, and atherosclerotic disease is not present, a goal of systolic BP < 140 or diastolic < 90 is appropriate and avoids the use of 3–4 antihypertensive agents. Polypharmacy must be avoided.
If renal failure or atherosclerotic disease is present a BP < 135/85 mmHg appears appropriate until further trials are conducted. The UK and other guidelines suggest <130/80.
An ambulatory 24-h BP assessment is useful if home and clinic BP control is difficult to achieve.
Appropriate drugs include ACE inhibitors, calcium antagonists, beta-blockers, and diuretics.
Experts who formulate National guidelines express the view that diuretics and beta-blockers should be avoided because these commonly used drugs cause diabetes. Interestingly. The British guideline, and British national formulary 2011 state: “Beta-blockers, especially when combined with a thiazide diuretic, should be avoided for the routine treatment of uncomplicated hypertension in patients with diabetes or in those at high risk of developing diabetes.”
The notion that these agents cause genuine diabetes mellitus is false (see Chap. 2).
Murphy et al. (1982) reported on the results of a much-prolonged 14-year follow-up in hypertensive patients treated with a diuretic, showing a major increase in the incidence of glucose intolerance. But this effect was promptly reversed on discontinuation of the diuretic in more than 60 % of the individuals who had developed elevated glucose levels beyond the top limit of normal. Most important, this glucose elevation proved reversible (Murphy et al. 1982).
It must be emphasized that based solely on the finding of glucose intolerance, these knowledgeable clinicians did not classify their subjects who exhibited fasting glucose levels above normal as diabetics. These subjects developed benign reversible glucose intolerance which disappeared on discontinuing the long-term diuretic therapy. The doses used were far greater than that used during the past 30 years. The remaining 40 % of the individuals who exhibited elevated plasma glucose levels developed true diabetes because they were pre-diabetics. A similar reversible metabolic disturbance may occur in a few patients on long-term treatment with a beta-blocker. This trial information appears to have been missed by Trialists, and this article is not quoted by editorialists or investigators who have reviewed the topic. See Chap. 2.
Oral Diabetic Agents
Metformin
This old agent remains a mainstay of treatment, and is also particularly useful in patients administered insulin. The drug’s effect on peripheral insulin-sensitive tissues requires the presence of insulin for its full action. Renal failure needs dose titration: the dose should be reduced if eGFR is <50 ml/min; avoid if eGFR < 35 ml/min.
“Among patients with diabetes who were receiving metformin, the addition of insulin vs. a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.” Propensity score matching yielded 2,436 metformin + insulin and 1 2 1 80 metformin + sulfonylurea. Patient median follow-up was 1 4 months. There were 172 vs. 634 events for the primary outcome among patients who added insulin vs. sulfonylureas, P = 0.009). Acute MI and stroke rates were 41 vs. 229 events (10.2 and 11.9 events per 1,000 person-years; P = 0.52), whereas all-cause death rates were 1 37 vs. 444 events, respectively (33.7 and 22.7 events per 1,000 person-years; aHR, 1.44; 95 % CI, 1.15-1.79; P = 0.001) (Roumie et al 2014).
In addition overtreatment is common in the many elderly.
Patients with risk factors for serious hypoglycemia represent a large subset of individuals receiving hypoglycemic agents. In a recent study approximately one-half had evidence of intensive treatment (Andrews and O’Malley 2014).
Sulfonylurea
Sulfonylureas such as tolbutamide glipizide, gliclazide, glimepiride, and glibenclamide have a role if needed to achieve goal and are preferred to thiazolidinediones.
Sulfonylureas were used successfully in addition to metformin in a recent study (Roumie et al. 2014); the combination prevented more cardiac events compared with addition of insulin.
Thiazolidinediones
Caution: have been shown to have a mild effect on the lowering of blood glucose levels, but many have been withdrawn from the market because of adverse effects. Their use must be justified particularly in patients who are already using insulin plus metformin. Troglitazone was voluntarily withdrawn from the market because of severe hepatotoxicity. Pioglitazone (Actos) use is restricted in patients with a history of heart failure or EF < 40 %. This restriction is in place because they increase retention of sodium and water, which can precipitate or worsen heart failure.
The European Medicines Agency has advised that there is a small increased risk of bladder cancer associated with pioglitazone use. The drug reduces peripheral insulin resistance.
These agents produce significant weight gain and they should not be prescribed to persons with familial polyposis. In addition they cause fractures. Consistent with previous trials, rosiglitazone caused an increase in heart failure and fractures (Home et al. for RECORD 2009).
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