complications \200 Gentle exercise Prognosis \200 Life expectancy is about two-thirds of normal. \200 Cardiovascular death in over 90 % of cases is due to aortic dissection or heart failure. MARFAN SYNDROME 637 Ghent criteria for Marfan syndrome Skeletal system involvement (two major or one major and two minor criteria) Major criteria Minor criteria 1. Pectus carinatum 1. Moderately severe pectus excavatum 2. Pectus excavatum requiring surgery 2. Joint hypermobility 3. Reduced upper to lower segment ratio or arm span to height ratio > 1.05 3. High arched palate with teeth crowding 4. Wrist and thumb signs 5. Scoliosis exceeding 20 o or 4. Facial appearance (dolichocephaly, malar hypoplasia, down-slanting palpabral \201 ssures, retrognathia) or spondylolisthesis 6. Elbow extension <170 o 7. Medial displacement of the medial malleolus causing pes planus, or 5. Enophthalmos 8. Protrusio acetabulae Ocular system involvement (one major or two minor criteria) Major criteria Minor criteria 1. Ectopia lentis 1. Abnormally \202 at cornea 2. Axial globe lengthening 3. Iris or ciliary muscle hypoplasia Cardiovascular system involvement (one major or one minor criterion only) Major criteria Minor criteria 1. Mitral valve prolapse with or without mitral regurgitation 1. Ascending aortic dilation involving at least the sinuses of Valsalva with or without aor tic regurgitation and 2. Main pulmonary artery dilatation 2. Ascending aortic dissection 3. Mitral annulus calci \201 cation 4. Descending thoracic or abdominal aortic dilatation or dissection Pulmonary system involvement (requires one minor criterion) 1. Spontaneous pneumothorax or apical blebs Skin and integument involvement (requires one of the following): 1. Striae atrophicae without marked weight change, pregnancy, or repetitive stress, or 2. Recurrent or incisional herniae (Continued) 638 CHAPTER 13 Multisystem disorders Dural involvement (one major criterion) 1. lumbosacral dural ectasia A contributory family or genetic history (one major criterion) 1. Parent, child, or sibling meeting diagnostic criteria independently 2. Known \201 brillin-1 mutation or 3. Presence of haplotype around \201 brillin-1 inherited by a descendent known to be asso ciated with unequivocally diagnosed Marfan syndrome in the family This page intentionally left blank 640 CHAPTER 13 Multisystem disorders Ehlers \200\223Danlos syndrome Epidemiology \200 1 in 5000 live births; incidence is abou t 1 in 400 000 \200 Typically presents between childhood and early adulthood \200 No ra cial or sex bias is known. Pathology \200 Inherited (autosomal dominant or recessive and X-linked recessive) defects in synthesis and metabolism of different types of collagen producing connective tissue def ects A new form has recently been described due to a de \201 ciency of tenascin-X (extracellula r matrix protein) with normal collagen Six subtypes: classic, hypermobile, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis. There is much overlap between types in up to 50 % case s. Clinical features \200 Joint hypermobility, skin hyperextensibility, tissue fragility, an d poor wound healing. Patients classically get \200\230cigarette paper \200\231 scarring o ver the knees. Mitral valve prolapse is seen in classic, hypermobile, and vascular forms. A minority of pa tients progress to severe mitral regurgitation requiring surgery. Recent echocardiographic studies suggest cardiac defects are less frequent than previously thought, although coronar y artery aneurysm can be devastating. Aortic root ectasia with dilated sinuses of Valsalva is also seen. Rarely, severe or progre ssive and aortic root replacement is exceptional. \200 The vascular form also exhibits pr ominent veins, low weight, short stature, spontaneous pneumothorax, and rupture of medium- and large-sized arteries and bowel perforation. Joints are affected less frequently. The sk in is fragile but not hyperextensible. Differential diagnoses include Marfan syndrome, Menkes kinky hair disease, Williams syndrome, Stickler syndrome, cutis laxa, and pseudoxanthoma elasticu m. Treatment \200 There is no speci \201 c medical therapy. High-dose vitamin C may provide some bene \201 t there are but no controlled studies Patient education and preventive strategies. Avoid excess and repetitive lifting, and contact sports Avoid suturing wounds if possible \200 Regular eye and dental assessments \200 Antibiot ic chemoprophylaxis for mitral valve prolapse \200 Genetic counseling; there is a limited role for genetic testing EHLERS \200\223DANLOS SYNDROME 641 Prognosis \200 Increased mortality in vascular form. Median age is 50 years, with death from spontaneous arterial and gastrointestinal rupture. Other forms usually have normal life expectancy, with increased morbidity from recurrent di slocations, poor wound healing, and scarring. 642 CHAPTER 13 Multisystem disorders Rheumatic drug therapy and the heart Only rheumatic drug therapies with speci \201 c relev ance to the cardiovas- cular system are considered here. NSAIDs and cyclo-oxygenase (COX)-2 inhibitors \200 A 2006 meta-analysis of clinical trial s found that selective COX-2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high-dose regimens of ibuprofen and diclofenac, but high-dose n aproxen is not associated with such an excess. 1 Associated with a tenfold risk of symptomatic heart failure in patients with a history of cardiac disease (and doubling of risk in those without). 2 Glucocorticoids \200 Avoided for long-term control of disease activity in view of adverse side-effect pro \201 le. High-dose steroid is associated with adverse effects on the cardiovascular system: endothelial dysfunction, impaired glucose tolerance and hypertension . Association of steroids with atherosclerosis is not clear. Some studies have shown a protec tive effect of low-dose steroid. It may be that by reducing in \202 ammation they have pro tective effects. Anti-TNF therapies (e.g. adalimumab, etanercept, in \202 iximab) \200 Immunosuppressive/ immune-modulatory effect. \200 Anti-TNF therapy is contraindicated in patients with New Y ork Heart Association (NYHA) class III or IV heart failure. Patients who develop new-onset heart failure while on anti-TNF therapy should have therapy discontinued and be evaluated for other causes of heart failure , keeping in mind that underlying diseases themselves may be causative. Zoledronic acid \200 In a double blind placebo-controlled RCT of 3889 participants, serio us atrial \201 brillation occurred more frequently (50 vs. 20) in the zoledronic acid gro up compared with controls. 3 1 Kearney, PM, Baigent C, Godwin J, et al. (2006). Do selective cyclo-oxygenase-2 inhibitor s and traditional non-steroidal anti-in \202 ammatory drugs increase the risk of atherothr ombosis? Meta-analysis of randomized trials. BMJ (Clin Res ed) 332(7553): 1302 \200\2238. 2 Page J, Henry D (2000). Consumption of NSAIDs and the development of congestive heart fail ure in elderly patients: an underrecognized public health problem. Arch Intern Med 160 (6): 777 \200\22384. 3 Black D, Delmas P, Eastell R, et al . (2007). Once yearly zolendronic ac id for treatment of postmenopausal osteoporosis. N Engl J Med 356 : 1809 \200\22322. RHEUMATIC DRUG THERAPY AND THE HEART 643 Peri-operative management of anti-TNF \200 British Society of Rheumatology guidelines rec ommend withholding treatment with anti-TNF for patients with RA 2 \200\2234 weeks prior to major surgery. Treatments may be restarted postoperatively if there is no evidence of infection and once wound healing is satisfactory. Interrupting immune-suppression may trigger \202 ares of disease. \200 Flares of rheuma toid arthritis can often be managed with oral/ intramuscular steroid (e.g. Depo-Medrone ). 644 CHAPTER 13 Multisystem disorders Erectile dysfunction De \201 nition Erectile dysfunction (ED) is the inability to achieve or maintain a penile erection that is suf \201 cient for satisfactory penetrative sexual i ntercourse. Epidemiology \200 Currently 150 million men worldwide have ED \200 ED increases with ag e \200 40 % of men over 40 years have ED \200 70 % of men over 70 years have ED Causes \200 In men over 30 years of age, vascular causes are the most common \200\224 endothelial dysfunction (atherosclerosis) The incidence of ED in diabetes is over 70 % , and in hypertension it is over 60 % Psychological (usually younger men with premature ejaculation), neurological (multiple sclerosis, Parkinson \200\231s disease, radical non-nerve- sparing p rostatectomy), endocrine (diabetes, hypogonadism), drug related (antihypertensives, antidep ressants) Obesity, physical inactivity, depression, hyperlipidaemia, smoking, alcohol excess Coronary disease (50 \200\22375 % of men) \200 Metabolic syndrome Investigations \200 Fasting glucose, lipid pro \201 le \200 Hypothyroid check \200 T estosterone (free) and sex-hormone-binding globulin (SHBG) before 11 am ED is a marker for asymptomatic cardiovascular disease (CVD) occurring 2 \200\2235 years be fore a cardiac event \200\224 assess CVD risk (e.g. blood pressure (BP)) Waist measurement Treatment (general) \200 Sensitive counseling \200 Ask routinely (men take up to 3 year s to volunteer their ED) \200 Minimize CVD risk \200 Lifestyle advice (smoking, weight, exercise) \200 If ED occurs within 1 month of starting a drug (e.g. thiazide), change medication Assess physical \201 tness for sexual intercourse Treatment (speci \201 c) Phosphodiesterase type 5 (PDE-5) inhibitors \200 Sildena \201 l, tadala \201 l, vardena \201 l \200 On demand or daily therapy (tadala \201 l) ERECTILE DYSFUNCTION 645 Titrate to effect \200 Not with nitrates or nicorandil (hypotension risk) \200 Require stimulation (not aphrodisiacs) \200 Take one hour before intercourse for full effect and last 6 \200\2238 hours (sildena \201 l, vardena \201 l) or 36 hours (tadala \201 l) 80 % success rate (60 % in individuals with diabetes) \200 Act to prevent breakdown of cy clic GMP (smooth muscle relaxant) by PDE5, prolonging relaxation Common side-effects are headache, \202 ushing, indigestion, and nasal congestion Uncommon, blue vision (sildena \201 l), back pain (tadala \201 l) \200 Caution with alp ha-blockers Prostaglandins \200 Alprostadil by intracavernosal injection or pellet insert ed into the urethra Dose titrated to effect (10 \200\22315 minutes) \200 Powerful smooth muscle relaxant \200 Injections once a day, three times a week maximum, over 80 % successful (erection lasts 30 \200\22360 minutes) Pellets daily, success 45 % (not popular) \200 Careful technique needed \200 Priapism 1 \200\2232 % ; \201 brosis <1 % \200 Injections can cause pain and haematoma, and pelle ts burning \200 Avoid with penile curvature or high risk of priapism (leukemia, sickle cell disease) Manual dexterity problems \200\224 partner to inject Vacuum devices \200 Failed PDE-5 in hibitors or contraindicated \200 Sucks blood in and rubber band holds it in \200 Bruisi ng sometimes with anticoagulants \200 Lack of spontaneity, penis feels cold Penile implan ts \200 Specialist referral Testosterone \200 A low testosterone <10 nmol/L increases C VD risk \200 Affects sex drive as well as ED \200 Low levels <12 nmol/L reduce success of PDE-5 inhibitors \200 Measure before 11 am \200 Replace with topical gel/patches or injections Summary ED is common, destroys relationships, and leads to depression and lack of self-este em. Treatment requires asking, advising, and tailoring therapy to lifestyle advice and is s uccessful in over 80 % of cases. ED is a marker for asymptomatic CVD. 646 CHAPTER 13 Multisystem disorders Chronic kidney disease as a cardiovascular risk factor Chronic kidney disease (CKD) is a po werful cardiovascular (CV) risk factor and, conversely, cardiac dysfunction tends to impair renal function. A consensus group suggested renal evaluation in patients with cardiac prob lems. The assessment of renal function is based primarily on two parameters, the glomerular \201 ltration rate (GFR) and urinary excretion of albumin (in more advanced stages of CKD t here is unselective proteinuria). In early stages of CKD, a major reduction of GFR is still compatible with serum creatinine concentrations within the normal range because serum- cre atinine depends also on non-renal factors, particularly muscle mass. More accurate estimate s of GFR (eGFR) are possible by measurement of serum-creatinine with validated methodology (Cleveland Clinic Protocol) and by correcting for age, sex, and ethnicity: eGFR = 175 x (standardized serum creatinine) \200\223 1.154 x (age) \200\223 0.203 x 0.74 2 (for females) x 1.212 (for black individuals) At an eGFR > 60 mL/min/1.7 m 2 , the above estimate becomes imprecise and such numerical values should not be reported. In this range, cystatin C is more precise than eGFR, but the measurement is costly and currently not rout inely available. Apart from GFR, urinary excretion of albumin is a powerful predictor of CV risk. For histor ic reasons, one still distinguishes between normoal- buminuria and microalbuminuria (de \201 nition: 30 \200\223300 mg albumin/day), but the cardiovascular risk increases steadily even in the range of normoal- buminuria. The most convenient and adequately sensitive proc edure is to measure albumin in the morning urine without correction for urinary creatinine concentration. Both GFR and albuminuria independently contribute to CV risk. In the absence of albuminuria , the CV risk conferred by reduced renal function is markedly less. Impaired renal function impacts on CV risk not only in patients with primary kidney disease , but reduced renal function is also a major risk factor for cardiac events in patients wit h primary cardiac disease, particularly coronary heart disease and congestive heart failure . The mechanisms by which renal impairment affects cardiac function include: \200 i blood pressure \200 sympathetic overactivity and reduced breakdown of catecholamines (renalase) lipid abnormalities, e.g. Lp(a), small dense low-density lipoprotein (LDL), remnants, modi \201 ed apolipoproteins increased oxidative stress and microin \202 ammation \200 increased serum phosphate (a n ovel powerful CV risk factor) and the phosphaturic hormone FGF23 asymmetric-dimethyl arginine (ADMA). CKD AS A CARDIOVASCULAR RISK FACTOR 647 A major cause of CV risk is elevated blood pressure. Renal patients, par- ticularly diabeti c patients with nephropathy, are characterized by noc- turnal non-dipping, and because of v ascular stiffening by increased blood pressure amplitude. Ambulatory blood pressure measure ments are a valuable tool. To halt progression of CKD and to reduce CV risk, current guidel ines recommend a target blood pressure of 130/80 mmHg (or even lower values if proteinuria exceeds 1 g/day) in patients with diabetic and non-diabetic CKD. 1 In patients with coronar y heart disease, it is wise to not lower systolic BP to values <130 mmHg and diastolic BP<7 0 mmHg. Renin \200\223angiotensin system (RAS) blockade further intensi \201 es reduction of proteinuria, in part independently of blood pressure. Cardiac arrest (sudden death) is t he most frequent cause of death, followed by heart failure and death from other cardiac cau ses, e.g. aortic valvular disease. MI is more frequent than in the background population bu t accounts only for roughly 9 % of deaths. In CKD, particularly in uraemia, patients develop cardiac hypertrophy (both left and right ventricle), cardiac \201 brosis, microvessel disease with reduced coronary reserve and re duced capillary density, and reduced ischaemia tolerance, and in dialysed patients stunning is frequently observed during dialysis sessions. 1 Mancia G, De Backer G, Dominiczak A , et al. (2007). 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens 25: 1751 \200\22362. 648 CHAPTER 13 Multisystem disorders CKD: which examinations are appropriate? Initial renal work-up of a patient with cardiac pr oblems should include assessment of eGFR and albuminuria or proteinuria, respectively. If t here is a suspicion of primary kidney disease, also carry out urinary sediment and renal ul trasonography; if renovascular disease is suspected, use duplex sonography. Initial cardiological work-up of the patient with renal disease includes ECG and echocardio graphic evaluation to detect inappropriate left ventricular (LV) hypertrophy, LV malfunctio n, and, in advanced stages, pericardial effusion. In patients with endstage kidney disease, metabolic myopathy of skeletal muscles usually precludes meaningful evaluation by treadmil l testing. Pharmacological stress testing permits non-invasive ischaemia detection (particu larly relevant if renal transplantation is under consideration). MRI technology is very hel pful but application of gadolinium is contraindicated in advanced CKD (see later). Coronary angiography remains the gold standard for the diagnosis of coronary artery disease (CAD). It is often underused due to concerns about radiocontrast nephropathy, but should d e \201 nitely not be withheld in patients with acute coronary syndrome. To assess large-vessel disease as an important contributor to CV risk, pelvic and abdominal X-ray to assess calci \201 cation of the iliac arteries and aorta are sensible. SIDE-EFFECTS OF CARDIOLOGICAL INVESTIGATIONS 649 Side-effects of cardiological investigations in patients with CKD Acute renal failure is a feared complication of radiocontrast administra- tion in CKD patients, particularly in thos e with diabetes. Mortality is sig- ni \201 cantly increased by radiocontrast nephropathy ( odds ratio up to 5 \200\22310). Long-term outcome is worse in patients with acute renal fai lure and pre- existing CKD; even after recovery from an episode of acute renal failure, the risk of delayed progression to endstage kidney disease is high. The best prevention is adequate hydration, reduction or temporary cessation of diuretic tre atment, and avoidance of drugs that predispose to kidney damage (NSAIDs, aminoglycosides, e tc.). It is controversial whether blockade of the RAS aggravates or reduces the risk of acu te renal failure. The only effective prophylaxis is administration of normal saline. The evidence for sodium bicarbonate or N-acetyl-cysteine is not convincing. The in \202 uence of the type of radiocontrast agent administered is currently uncertain. Isosmolar radiocontrast agents are more viscous, and it has been suggested to reduce renal risk by warming up of the radiocontrast. MRI, using gadolinium-containing contrast agents is contraindicated in advanced CKD because of the risk of acute reactions and chronic toxicity, i.e. nephrogenic systemic \201 bros is. 1 1 Thomsen HS (2009). How to avoid nephrogenic systemic \201 brosis: current guidelines in Europe and the United States. Radiol Clin North Am 47: 871 \200\223875, vii. 650 CHAPTER 13 Multisystem disorders Prevention and treatment of cardiovascular sequelae in renal patients Limited controlled ev idence is available, but current strategies for prevention and treatment include those list ed next: \200 The most important component of treatment is blood pressure control (see b Chronic kidney disease as a cardiovascular risk factor, p. 646). In patients on hemodialysi s, antihypertensive medication increases the risk of hypotensive episodes during \202 uid removal by ultra \201 ltration. \200 Reduction of salt intake facilitates blood pressur e lowering and reduces proteinuria (a predictor of progression of renal function loss). Blockade of the RAS : inappropriate activation of the RAS is a hallmark of CKD. RAS blockad e confers bene \201 t beyond blood pressure lowering and mitigates loss of renal function at least in proteinuric patients. Renin inhibitors on top of RAS blockade cause further red uction of proteinuria, but evidence for the effect on harder end-points is currently not (y et) available. Beta-blockers : in view of the highly elevated sympathetic activity in renal patients, it is rational to administer B-blockers, speci \201 cally those without me tabolic side-effects (carvedilol, nevibolol), even in the absence of controlled evidence. Mineralocorticoid receptor blockers : there is good evidence that addition of spironolacton e or eplerenone further reduces proteinuria in CKD patients in whom proteinuria is not adeq uately lowered by RAS blockade or increased after an initial decrease (so-called \200\230e scape \200\231). There are concerns with respect to hyperkalaemia, and appropriate controls of serum potassium are absolutely necessary. Statins : in patients with CKD, statins de \201 nitely reduce CV events, and some reduction of proteinuria is an added bene \201 t. Evidence for their ef \201 cac y in patients on haemodialysis is currently not available, but at least in patients with CH D who are entering dialysis with statin therapy, statins should be continued independently of LDL cholesterol (which is often spuriously lowered because of the in \202 ammatory stat e of uraemia). Phosphate binders : hyperphosphataemia (and elevated concentration of the phosphaturic horm one FGF23) are strong predictors of death in patients with CKD. Evidence for cardiovascular bene \201 t from lowering phosphate is not (yet) strong, but lowering of phosphataemia to normal values by oral phosphate binders (calcium carbonate, lanthanum carbonate, sevelamer ) or phosphate transportation inhibitors (nicotinamide) is clearly indicated even in the ab sence of controlled data. Vitamin D : a great proportion of CKD patients have vitamin D de \201 ciency (de \201 ned as 25(OH)D below 30 ng/mL); in this case, oral cholecalcifero l should be administered; in observational studies, low 25(OH)D concentrations were also as sociated with an increased risk of CV events. Active vitamin D (1,25(OH) 2 D 3 ) is synthes ized in the kidney and its concentration decreases progressively and is speci \201 cally PREVENTION AND TREATMENT OF CARDIOVASCULAR SEQUELAE 651 low in end-stage kidney disease, triggering elevation of parathyroid hormone (PTH). Active vitamin D should be administered if the PTH concentration is above the recommended range (w hich is currently still under dispute). Erythropoietin (EPO) and iron : there is currently uncertainty about EPO treatment. Treatme nt is reasonable if hemoglobin values are less than 9 g/dL after adequate treatment of iron de \201 ciency, if present. See Fig. 13.1 . 10.9% (ml/min) <15 300,000 (0.1%) 5 15 \200\22329 400,000 (0.2%) 4 30 \200\22359 3 7,600,000 (4.3%) 2 60 \200\22389 5,300,000 (3.0%) >90 5,500,000 (3.3%) 1 Fig. 13.1 Stages of chronic kidney disease: prevalence in the general population. Reproduce d with permission from Levey, American Journal of Kidney Disease , (2002) S1 : S1 \200\223S 266. Further reading Ritz E , Remppis A ( 2009 ). What have nephrologists and cardiologists learned from each ot her? Nat Clin Pract Nephrol 5 : 1 . Sarnak MJ , Levey AS , Schoolwerth AC , et al. ( 2003 ) . Kidney disease as a risk factor for development of cardiovascular disease: a statement fr om the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention . Circulation 108 : 2154 \200\223 69 . Stevens LA , Coresh J , Greene T , et al. ( 2006 ). Assessing kidney f unction measured and estimated glomerular \201 ltration rate . N Engl J Med 354 : 2473 \200\223 483 . This page intentionally left blank 653 Chapter 14 Cardiovascular disease in less-developed countries Burden of cardiovascular disease in less-developed countries 654 Infectious disease and the heart 656 Diphtheria 657 HIV and the cardiovascular system 658 C hagas \200\231 disease and the heart 660 Cardiovascular syphilis 662 Beri-beri (thiamine de \201 ciency) 664 Tetanus 666 Keshan disease 667 Restrictive cardiomyopathy 667 Endomyocar dial \201 brosis 668 Loef \202 er endocarditis 670 654 CHAPTER 14 Cardiovascular disease Burden of cardiovascular disease in less-developed countries Approximately 80 % of the worl d \200\231s people reside outside Western Europe and Canada/USA. Although cardiovascular di seases (CVD) occur throughout the world, their form and the burden change as a country unde rgoes economic development. Less-developed countries begin with a disease burden dominated by infectious, perinatal, and nutritional diseases and, in the process of development, make the transition to one dominated by non-communicable disease (NCD), particularly CVD. The f our stages of transition are shown in Table 14.1 . Table 14.1 Deaths caused by cardiovascular disease at different stages of development 1 Stage of development Deaths from CVD ( % of total) Predominant CVDs Regional Examples Sub-Saharan Africa, rural India, and South America Age of pestilence and famine 5 \200\22310 Rheumatic heart disease, tuberculous pericarditis, and infectious and nutritional cardiomyo pathies China, urban South Africa Age of receding pandemics 10 \200\22335 As above, plus hypertensive heart disease, haemorrhagic stroke, and renal failure Urban India, formerly socialist economies 35 \200\22355 All forms of stroke, ischaemic heart disease at relatively young ages Age of degenerative and man-made diseases Western Europe, North America, Australia, New Zealand <50 Stroke and ischaemic heart disease at older ages Age of delayed degenerative diseases Many less-developed countries have a triple burden of disease, encompassing disorders that characterize the \201 rst three phases of the epidemiologic transition. In 2000, CVD accounted for 16.7 million deaths globaly; 31 % of all global deaths are due t o CVD. Coronary heart disease (CHD) and stroke account for 71 % of CVD deaths. Low- and mid dle-income countries contribute 78 % of all CVD deaths, and 86 % of disability-adjusted lif e years \200\231 (DALYs \200\231) loss attributed to CVD. The relative importance of CHD an d stroke varies across regions and countries. For example, more than twice 1 Howson CP, Reddy KS, Ryan TJ, Bale JR (1998). Control of Cardiovascular Diseases in Less Developed Countries: research, development, and institutional strengthening. Washington DC: Institute of Medicine, National Academy Press. BURDEN OF CARDIOVASCULAR DISEASE 655 as many deaths from stroke occur in the less developed countries as in developed countries. NCDs rank \201 rst in most less-developed countries, in developed countries, and worldwid e as a cause of death. CVD accounts for about half of all NCD deaths. In 1990, CVDs were th e leading cause of death for all major geographic regions of the developing world except In dia and sub-Saharan Africa. There is an early age of CVD deaths in less-developed countries compared to developed count ries. In 1990, the proportion of CVD deaths occurring below the age of 70 years was 26.5 % in developed countries, compared to 46.7 % in less-developed countries. Therefore, the cont ribution of the less-developed countries to the global burden of CVD, in terms of DALYs los t, was nearly three times higher than that of developed countries. Rheumatic heart disease (RHD) is the most common cause of CVD in children and young adults in less-developed countries. At least 15.6 million persons are estimated to be to be affect ed with RHD globaly. More than 2 million require repeated hospitalization and 1 million wil l need heart surgery over the next 20 years. Annually, 233 000 deaths occur as a result of RHD. Many poor persons, who are preferentially affected, are disabled because of lack of ac cess to the expensive medical and surgical care demanded by the disease. The prevalence of RHD in less-developed countries ranges from 20 to 40 per 1000 (by echocardiographic screeni ng of schoolchildren). The incidence of rheumatic fever ranges from 13 to 374 per 100 000, and the rate of recurrence is high. Managing with limited resources The management of CVD is often technology intensive and exp ensive. Procedures for diagnosis or therapy, drugs, hospitalization, and frequent consultat ions with healthcare providers all contribute to the high cost. The high expenditure on ter tiary care in most less-developed countries probably has a large contribution from CVD. Thi s may divert scarce resources from developmental needs and from the un \201 nished agenda of infectious and nutritional disorders. Thus there is an urgent need for cost- effective p reventive strategies and case-management approaches that are based on the best available ev idence, and generalized to the context of each developing country. 656 CHAPTER 14 Cardiovascular disease Infectious disease and the heart Numerous infectious diseases may involve the endocardium ( see b Infective endocarditis, Chapter 4, pp. 187 \200\223209), myocardium (see b Heart musc le diseases, Chapter 8, pp. 417 \200\223457), and the pericardium (see b Pericardial diseas es, Chapter 9, pp. 459 \200\223476). This section deals with a miscellaneous group of infec tious diseases that are of particular relevance to cardiology practice outside Western Euro pe, e.g. human immunode \201 ciency virus (HIV) infection, Chagas \200\231 disease, diphth eria, syphilis, and tetanus. Although occa- sional examples have been reported, myocardial involvement is so rare as to be of little clinical signi \201 cance in tuberculosis (apart from pericarditis), typhoid fever, scrub typhus, poliomyelitis, infective hepatitis, virus pneumo- nias, and other respiratory tract infections. DIPHTHERIA 657 Diphtheria Cardiac damage in diphtheria is due to a circulating exotoxin that inhibits prot ein synthesis in target tissues, with a high degree of af \201 nity for the conduction sys tem. Myocarditis occurs in up to 25 % of cases of diphtheria and carries a mortality of app roximately 60 % . Pathological examination shows a \202 abby dilated heart with a \200\230streaky \200\231 appearance of the myocardium. Microscopy reveals characteristic fatty in \201 ltration of the myocytes, and other features of myocarditis. Sinus tachycardia, gallop rhythm, cardiomegaly, and hypotension typically appear in the second week of illness. The electrocardiogram (ECG) abnormalities are useful in diagnosis and fall under two headings: \200 tracings showing evidence of diffuse myocardial damage: low voltage, prolongation of the QT interval, and T-wave \202 attening or inversion \200 t racings showing evidence of damage to the conduction system with all degrees of atrioventricular (AV) block. The development of bundle branch block or compl ete heart block is a particularly ominous \201 nding, and the reported mortality rates va ry from 54 % to 100 % despite the insertion of transvenous pacing. The presence of myocardi al damage is con \201 rmed by marked elevation of the serum creatine kinase (CK) level; a high level is associated with poor prognosis. The ECG eventually returns to normal but conduction abnormalities may persist for years. Treatment Treatment consists of supportive measures for heart failure, antibiotics (procain e penicillin G 600 000 U IM 12 hourly for 10 days or erythromycin 250 \200\223500 mg PO 6 h ourly for 7 days) to prevent secondary infection and eliminate the diphtheria organisms in the throat, and temporary pacing in cases of AV heart block. Antitoxic serum should not be given at this stage because the exotoxin is already \201 xed and because of the risk of f atal serum reactions. Intubation and ventilation may be required for those patients with ev idence of respiratory failure. 658 CHAPTER 14 Cardiovascular disease HIV and the cardiovascular system The clinical effects of HIV on the heart are relatively u ncommon, relative to the impact of HIV infection on the lungs, gastrointestinal tract, cent ral nervous system, and skin. There are similarities in the pattern of CVD involvement in p eople living in developed and less-developed countries, but differences in the causative or ganisms implicated. The main presen- tations are (1) pericardial effusion; (2) cardiomyopat hy; (3) pulmonary hypertension; (4) large vessel aneurysms; and (5) metabolic complications associated with anti-retroviral drug use. Pericardial effusion Pericardial effusion is one of the early presenting features of HIV in fection in patients living in sub-Saharan Africa. Whereas in western countries, a large eff usion is usually idiopathic in 80 % of patients with acquired immune de \201 ciency syndro me (AIDS), the disease is caused by tuberculosis in over 80 % of Africans living with HIV. Purulent pericarditis is not uncommon, while involvement with Kaposi \200\231s sarcoma and B-cell lymphoma is rare. Treatment of tuberculous pericarditis is with a standard anti-tube rculous regime similar to that used in HIV-negative patients, and the short-term outcome is similar. The role of adjuvant steroids is uncertain. Cardiomyopathy Cardiomyopathy is found in 50 % of acutely ill hospitalized patients, and in 15 % of ambulatory asymptomatic patients living with HIV. Myocarditis is present in a prop ortion of the cases. In western series, the myocarditis is associated with cardiotropic vir us, whereas in Africa, preliminary data suggest that it may be associated with non-viral op portunistic infections such as toxoplasmosis, cryptococcosis, and Mycobacterium avium intra cellulare infection. HIV-positive patients with cardiomyopathy should be considered for end omyocardial biopsy to exclude a treatable cause of myocarditis. Otherwise, treat as for hea rt failure. Prognosis is poor, with a median survival of 100 days without anti-retroviral d rugs. Pulmonary hypertension HIV-associated pulmonary hypertension is estimated to be 1/200, much higher than the 1/200 000 found in the general population. Primary pulmonary hypertension is found in 0.5 % of hospitalized AIDS patients and is a cause of cor pulmonale and death. The pathogenesis is poorly understood. Arterial aneurysm HIV-related arterial aneurysm is a distinct clinical and pathological ent ity that is associated with advanced HIV disease. HIV-related aneurysms affect young patien ts (median age 30 years) with no risk factors for atheroscle- rosis, occur mainly in periph eral arteries (carotid, distal super \201 cial femoral, and popliteal sites), are usually multiple (1 \200\22310 per patient), and have been reported more frequently in black patien ts than in white individuals. The in \202 ammatory process involves the vasa vasorum of th e adventitia with sparing of the media and intima. The most frequent mode of presentation i s that of a painful mass of increasing size. The diagnosis is con \201 rmed by HIV AND THE CARDIOVASCULAR SYSTEM 659 duplex sonography or computed tomography (CT). Arterial angiography is performed to delinea te the extent of aneurysm. Serological testing for syphilis, typhoid, HIV, and autoimmune d isease is indicated. Treatment is by operative intervention for symptomatic aneurysm in pat ients with an acceptable surgical risk and anticipated life expectancy. Metabolic abnormalities The use of protease inhibitors and nucleoside reverse transcriptase inhibitors is associated with the following metabolic abnormalities: fat redistribution (l ipodystrophy), increased total cholesterol and triglycerides, decrease in high-density lipo protein (HDL), impaired glucose tolerance, and increased intra-abdominal fat. These changes translate into a small increase in the risk of myocardial infarction (MI) with the long-te rm use of anti-retroviral drugs. It is prudent to modify cardiovascular risk factors and tr eat the metabolic complications when they arise, according to standard guidelines in affect ed patients. 660 CHAPTER 14 Cardiovascular disease Chagas \200\231 disease and the heart Chagas \200\231 disease is a myocarditis of parasitic origin that is caused by the protozoa Trypanosoma cruzi . The disease is a major public he alth problem in South and Central America; 15 \200\22318 million people are infected with t he parasite, and 65 million people are at risk. Chagas \200\231 disease is transmitted by c ontamination of the bite wound of the \200\230assassin \200\231 or \200\230kissing \200 \231 reduviid bugs with the infected feces of the insect. Natural history The natural history of Chagas \200\231 disease is characterized by three ph ases: acute, latent, and chronic. Acute Chagas \200\231 disease occurs predominantly in chi ldren in less than 10 % of infected cases; it is fatal in 10 % of cases. It is characterize d by fever, lymphadenopathy, hepatosplenomegaly, and facial oedema. Acute myocarditis is co mmon and may be fatal. Rarely, menin- goencephalitis or convulsive seizures may occur, some times causing per- manent mental or physical defects or death. Recovery is usual, however, and the disease is quiescent for the next 10 to 15 years ( latent Chagas \200\231 disease ) . Chronic Chagas \200\231 disease may be asymptomatic, mild, or accom- panied by cardiomyop athy, megaoesophagus, and megacolon, with a fatal outcome. The late manifestations probably result from lymphocyte- mediated destruction of muscle tissue and nerve ganglions during t he acute stage of the disease. Trypanosoma cruzi may be found in degener- ated muscle cells , especially in the right atrium. The disease is characterized clinically by anginal chest pain, symptomatic conduction syste m disease; severe, protracted, congestive cardiac failure, often predominantly right sided, is the rule in advanced cases. Bifascicular block is present in more than 80 % of cases an d death from asystole and arrhythmia is common. Autonomic dysfunction is common. Apical ane urysms and left ventricular dilatation increase the risk of thromboembolism and arrhythmias . Diagnosis Chagas \200\231 disease is identi \201 ed by demonstration of trypanosomes in th e peripheral blood or leishmanial forms in a lymph node biopsy, or by animal inoculation or culture, xenodiagnosis (i.e. the patient is bitten by reduviid bugs bred in the laboratory ; the subsequent identi \201 cation of parasites in the intestine of the insect is proof o f infection in the human host), or sero- logic tests (e.g. Machado \200\223Guerreiro comple ment \201 xation test). The chest X-ray (CXR) demonstrates cardiomegaly. The ECG is abnor mal as a rule in the late course of the disease. The echocardiographic features in advanced cases are those of dilated cardiomyopathy; a left ventricular posterior wall hypokinesis a nd relatively preserved interventricular septum motion, associated with an apical aneurysm is distinctive. Radionuclide ventricu- lography may show ventricular wall motion abnormalit y in the absence of overall depression of global ventricular function. Perfusion scanning w ith thallium-201 may show \201 xed defects (corresponding to areas of \201 brosis) as w ell as evidence of reversible ischaemia. Gadolinium-contrast magnetic resonance imaging (MR I) can identify patients with more active myocardial disease. CHAGAS \200\231 DISEASE AND THE HEART 661