Cardiovascular and Endocrine Issues

1. Cardiovascular and Endocrine Issues

2. A 65 yo patient with who is a smoker with an asymptomatic bruit of the Right Carotid Artery should have? • A. A carotid doplar • B. An Angiogram • C. An ultrasound of his aorta • D. evaluation for HTN and Lipid profile • E. Be advised to quit smoking

3. Answer • C. An ultrasound of his aorta • D. evaluation for HTN and Lipid profile • E. Be advised to quit smoking

4. Modification of which of the following risk factors appears most effective in reducing risk for stroke or transient ischemic attack? A) Smoking B) High low-density lipoprotein C) Elevated homocysteine D) Hyperglycemia

5. Answer • A) Smoking

6. Choose the correct statement about antiplatelet therapy in the prevention of secondary stroke. A) Most studies show aspirin alone prevents recurrent stroke better than aspirin and dipyridamole B) Clopidogrel more effective than aspirin and dipyridamole in preventing secondary stroke C) Clopidogrel and aspirin associated with increased risk for bleeding D) Clopidogrel and aspirin shown to reduce death, myocardial infarction, and stroke in most major studies

7. Answer • C) Clopidogrel and aspirin associated with increased risk for bleeding

8. Inclusion criteria for use of thrombolysis within 3.0 to 4.5 hr of onset of stroke include which of the following? A) Patient age <80 yr B) No diabetes C) No previous stroke D) All the above

9. Answer • D) All the above

10. Better outcomes after stroke are associated with: A) Anticoagulation after tissue plasminogen activator therapy and admission to hospital B) Blood pressure (BP) treatment resulting in systolic BP of 160 to 170 mm Hg C) Tight glucose control in patients with hyperglycemia D) Care in dedicated stroke unit

11. Answer •  D) Care in dedicated stroke unit

12. All patients admitted for stroke should undergo assessment for dysphagia. A) True B) False

13. Answer •  A) True

14. A trial of _______ may be effective in patients who develop significant depression after a stroke. A) Psychotherapy B) Selective serotonin reuptake inhibitor C) Electroconvulsive therapy D) Tricyclic antidepressant

15. Answer • B) Selective serotonin reuptake inhibitor

16. Compared to seizures, convulsive syncope is more often characterized by which of the following? A) Tongue biting B) Head turning C) A shorter postictal period D) Micturition

17. Answer • C) A shorter postictal period

18. Which of the following is most recommended in the work-up of syncope in elderly patients? A) Head computed tomography B) Electrocardiography (ECG) C) Carotid ultrasonography D) All the above

19. Answer • B) Electrocardiography (ECG)

20. Hypertrophic cardiomyopathy is usually detected on: A) Physical examination B) Chest x-ray C) ECG D) Holter monitoring

21. Answer • C) ECG

22. Which of the following is recommended for vasovagal syncope? A) Physical counterpressure maneuvers (eg, isometric exercises) B) β-blockers C) Steroids D) A pacemaker

23. Answer • A) Physical counterpressure maneuvers (eg, isometric exercises)

24. Case presentation • asymptomatic man 68 yr of age presents for routine physical examination • patient has hypertension and smokes 1 pack of cigarettes per day • current medications include combination of lisinopril and hydrochlorothiazide • No carotid bruits or murmurs • no signs of heart failure (HF) • Electrocardiography (ECG) shows voltage criteria for left ventricular hypertrophy (LVH) • chemistry panel normal

25. Risk factors • according to Framingham risk calculator, in next 10 yr, patient’s risk for stroke 33%, and risk for coronary event >30% • modifying risk factors —smoking cessation reduces risk from 33% to 22%; blood pressure (BP) control can further reduce risk to 17% • reducing low-density lipoprotein (LDL) to 100 mg/dL reduces risk for coronary artery disease (CAD) to 20%; women —in female patient with same history, risk for stroke in next 10 yr 32%; • modifying risk factors reduces risk by 50% • risk for CAD in next10 yr 21% • BP control, lipid control, and smoking cessation reduces CAD risk to 10%; evidence circumstantial about lipid control and risk for transient ischemic attack (TIA) and stroke

26. Treatment of stenosis • in past, carotid endarterectomy indicated if stenosis >60%, and if surgeon’s stroke rate <3% (small benefit number needed to treat [NNT] to prevent 1 stroke for 5 yr, 20) • In 2007, United States Preventive Services Task Force recommended against screening general population for asymptomatic carotid bruits due to small benefit and high risk for harm • according to meta-analysis looking at nonsurgical vs surgical treatment, nonsurgical treatment 3 to 8 times more cost effective, with similar outcomes • new recommendation nonsurgical treatment, risk factor modification, and antiplatelet therapy

27. Risk reduction • smoking cessation • BP control • lipid lowering • diet (eg, vegetables); exercise; data limited about glucose control and prevention of vascular events • elevated homocysteine associated with stroke, but treatment does not appear to prevent strokes (treatment with B vitamins not effective • 1 study saw increased rate of stroke

28. Transient ischemic attacks • risk for stroke after TIA, 5% to 10% in first month (20% in next 3 mo) • large artery distribution TIAs and strokes more likely to recur • recurrence half as likely in patients with exclusively retinal symptoms • associated with increased risk for myocardial infarction (MI) • ABCD2 score — age (1 point) • elevated BP (1 point) • clinical findings (eg, motor weakness [2 points], speech disturbance [1 point]) • duration (1 point; if >60 min, 2 points) • diabetes (1 point) • score of 6 indicates high risk for stroke or TIA • 18% risk for recurrence within 90 days

29. Recommendations • brain imaging (eg, head computed tomography [CT] or magnetic resonance imaging [MRI]) • neurovascular imaging (eg, ultrasonography [US], CT or MRI angiography) • cardiac evaluation (eg, ECG) • laboratory tests based on history and physical examination • treatment—manage risk factors • Complete work-up within 24 to 48 hr • consider admission if ABCD2 score • >3, or if completion of work-up in 24 to 48 hr unlikely

30. First-line antiplatelet therapy • in 1994, aspirin shown beneficial compared to placebo • Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study showed modest benefit of clopidogrel, but only in patients with peripheral vascular disease at onset, rather than in patients with predisposing CAD or cerebrovascular disease • Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial saw statistically significant improvement (2.1% absolute risk reduction) with clopidogrel compared to placebo (NNT, 50), but with 1% increase in major bleeding (for every 2 patients who benefited, 1 patient had major bleeding episode) • other studies —1) no benefit and increased risk for bleeding seen with combination of aspirin and clopidogrel, compared to clopidogrel alone • 2) no benefit (in combined end point of death, MI, and stroke) and increased bleeding seen with aspirin and clopidogrel, compared to aspirin alone • 3) combination of aspirin and dipyridamole more beneficial than aspirin alone (3% absolute risk reduction at 2 yr; no effect on outcome of death) • Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial saw no difference in end points in clopidogrel compared to dipyridamole and aspirin • summary —aspirin prevents recurrent stroke; aspirin inexpensive and reasonable first-line agent • aspirin with dipyridamole prevents recurrent stroke better than aspirin alone (consider as first-line therapy in patients at very high risk for recurrence) • clopidogrel and combination of aspirin and dipyridamole equal in preventing secondary stroke • clopidogrel and aspirin associated with increased risk for bleeding (consider in patients on drug-eluding stents with TIA • consider adding aspirin and monitor carefully) • 75 to 325 mg of aspirin recommended

31. Case presentation • woman 62 yr of age with hypertension and elevated lipids presents with new-onset atrial fibrillation (AF) • transesophageal echocardiography normal • no history of congestive HF (CHF), diabetes, or stroke • CHADS2 scoring — • CHF (1 point) • hypertension (systolic BP >160 mm Hg; 1 • point) • age >75 yr (1 point) • diabetes (1 point); previous • stroke (2 points) • warfarin indicated if score >2 • score of 1 indicates fairly low risk for stroke (consider warfarin at international normalized ratio [INR] of 2-3, or 75-325 mg/day of aspirin; NNT to prevent 1 stroke for 1 yr, 100) • to avoid bleeding complication, excellent control required • Management: woman has score of 1 • discuss risks and benefits of warfarin compared to aspirin, and dietary changes; INR • monitoring; shared decision making important

32. Inclusion criteria for thrombolysis • ischemic stroke with neurodeficit (perform CT to rule out hemorrhagic stroke) • Onset <3 hr • treatment within 3.0 to 4.5 hr acceptable if other specific criteria met (eg, patient <80 yr of age, no diabetes, no previous stroke, National Institutes of Health stroke scale score <25) • check laboratory and radiologic findings

33. Thrombolysis • tissue plasminogen activator (tPA) — in one study, NNT to improve final end point (combination of death and disability), 18 (in other study, NNT to reduce death or dependency at 1 yr, 7) • number needed to harm for intracranial hemorrhage (ICH), 14 (for fatal ICH, 40); • following inclusion and exclusion criteria important (retrospective study showed violation 97% of time, with increased mortality and ICH rate) • moderately effective if given with strict protocol • conclusion — thrombolysis absolutely ineffective without strict adherence to inclusion and exclusion criteria • anticoagulation after tPA and admission to hospital not recommended due to increased risk for ICH • prophylaxis for deep venous thrombosis (DVT) — heparin or low-molecular weight heparin appropriate and safe for patients at high or intermediate risk for DVT • consider compression hosiery and early ambulation

34. Considerations • hypertension — patient not candidate for • thrombolysis if systolic BP >185 mm Hg • according to American College of Cardiology (ACC), systolic BP >220 mm Hg and diastolic BP >120 mm Hg should be treated • small randomized controlled trial showed no adverse outcomes and improved mortality at 3 mo with BP treatment • resulting in systolic BP no less than 150 mm Hg or 15 mm from baseline) • best outcomes associated with systolic BP of 140 to 150 mm Hg; • hyperglycemia—indicator of poor prognosis in acute stroke • data limited; United Kingdom • Glucose Insulin in Stroke Trial did not show benefit with tight glucose control • blood glucose control recommended, but tight control not recommended; • hospital setting — care in dedicated stroke unit leads to reduced death, reduced institutionalized care at 1 yr, and reduced dependency • dysphagia — all patients admitted for stroke should undergo assessment (gag reflex and physical examination inadequate) • patients with dysphagia 3 times more likely to develop aspiration pneumonia (11 times more likely with frank aspiration on swallowing evaluation) • Interventions for prevention unclear

35. Follow-up • BP control — diuretic or ACE inhibitor recommended • combination of perindopril and indapamide showed 43% relative risk reduction for recurrent stroke • study showed candesartan for 7 days after stroke resulted in 50% fewer vascular events over 1 yr, compared to placebo (no benefit when started >1 wk after stroke) • PRoFESS trial showed telmisartan decreased BP but had no effect on vascular events and caused more harm (eg, syncope, AF); • depression — affects 33% of patients after stroke • often not detected • Pharmacotherapy shown to have small but significant effect with many side effects; selective serotonin reuptake inhibitors (SSRIs) cause seizures, falls, and delirium • difficult to determine whether benefits outweigh risks • no benefits seen with electroconvulsive therapy or psychotherapy • if patient significantly depressed, trial of SSRI acceptable with careful monitoring for side effects (start with low dose and titrate up slowly) • Surgical Management • Carotid disease: surgical treatment of symptomatic disease (stenosis >70%) effective and beneficial if performed early • advantage of surgery greater in higher-risk patients (based on age, sex, recent stroke or TIA) • stent placement indicated for high-grade stenosis in patients at high surgical risk (better outcomes shown with surgery, but consider stent placement in patients with stenosis >70% and high surgical risk) • management —consider full-dose aspirin, ACE inhibitor, and statin

36. Syncope • Characteristics: brief (10-40 sec) • spontaneous recovery (ie, not caused by, eg, hypoglycemia) • no neurologic deficits • patients return to baseline • caused by global hypoperfusion of brain • Not caused by TIA

37. Risk stratification • age (older patients at higher risk for more serious cause of syncope [eg, underlying cardiovascular disease or CHF]) • syncope while lying down cause for concern • family history • in syncope with exertion, consider structural • outflow obstruction • red flags in young patients — syncope with no prodrome • exercise-induced syncope • structural heart disease • positive family history of sudden death

38. History of episode • ask emergency medical services or family members about, eg, interventions required, seizure activity, incontinence, or shaking • convulsive syncope— not seizure disorder • does not require seizure work-up • usually briefer with shorter postictal period • seizures — tongue biting • head turning • Posturing • no memory of loss of consciousness • Cyanosis • longer duration of postictal confusion • snoring respirations • postictal headache • micturition (can occur with syncope or seizure, but more common in seizure) • medication review — 1 in 8 causes of syncope related to medication, eg, -blockers, diuretics, drugs that cause bradyarrhythmias, medications for Alzheimer disease, drugs that cause prolonged QT interval

39. Physical examination • vital signs; cardiac, abdominal, and neurologic examinations • orthostatic hypotension — 20-mm Hg drop in systolic BP while standing • 40% of patients >70 yr of age orthostatic • carotid sinus hypersensitivity — proposed as cause of syncope in elderly • 3 studies suggested benefit with use of pacemakers, but fourth and most thorough study recommended against use; look for other cause

40. Evaluation • ask, “how are you feeling?” to help determine whether cause of syncope serious (eg, acute coronary syndrome, aortic dissection, pulmonary embolism, abdominal aortic aneurysm, subarachnoid hemorrhage) or benign • Ask about chest pain, back pain, and headache • work-up in elderly — telemetry, cardiac enzymes, head CT, echocardiography, and carotid US usually not helpful • ECG strongly recommended (use discretion in young patients

41. San Francisco Syncope Rule • variables— history of CHF • Low hematocrit • ECG changes • low systolic BP • shortness of breath • admit patients with 1 variable (discharge patients with none); on internal validation (ie, use in San Francisco, • CA), sensitivity 96% to 98% (90% on external validation [ie, use in, eg, Los Angeles, CA]) • use with caution; • other syncope rules (eg, Boston Syncope Rule) validated internally but not externally (not recommended

42. ECG findings • Bradycardia • heart block • ventricular and atrial tachycardia • Wolff-Parkinson-White syndrome • long QT syndrome —can be acquired (from, eg, medications) or congenital (average age of onset 20-40 yr of age) • patients present with syncopal episodes • QT interval should be less than half of RR interval • Brugada syndrome —genetic predisposition in young southeast Asian men, but seen in all men and women • Detected on resting ECG • type 1 (coved-type ST segment elevations in leads V1 through V3 • look for right bundle-branch block or incomplete right-bundle branch block) • type 2 (look for elevated R and R waves, incomplete right-bundle branch block • concave-shape configuration • not as diagnostic) • hypertrophic cardiomyopathy (HCM) —genetic • HCM of left ventricle results in outflow obstruction • high mortality rate; incidence 1 in 500; autosomal dominant • can be asymptomatic, but manifestations generally include chest pain; outflow obstruction with exertion concerning (most common cause of sudden death in athletes) • not easily detected on physical examination (murmur noted in 30% -40% of patients) • chest x-ray often normal; ECG most commonly abnormal • signs of left ventricular hypertrophy • deep Q waves in inferior or lateral leads; treat with Beta-blockers

43. Testing • firm diagnosis made 75% of time • 25% of time syncope unexplained • ACC/American Heart Association guidelines recommend echocardiography and exercise stress testing (not supported by data) • use ECG monitoring, Holter monitoring, event recorders, or implantable loop recorders based on individual cases • tilt-table testing not recommended

44. Vasovagal syncope • trigger causes autonomic nervous system to pool blood in lower extremities, resulting in decreased venous return and BP and hypoperfusion of brain • can be situational (eg, cough); • management — physical counterpressure maneuvers (eg, isometric exercises); increase fluid intake in morning; consider midodrine • Beta-blockers, steroids, SSRIs, and pacemakers ineffective • Vaccination syncope: occurs with human papillomavirus vaccine in teenage girls

45. A 76-year-old woman is evaluated in the emergency department for a 2-month history of fatigue, anorexia, thirst, polydipsia, and polyuria. Squamous cell lung cancer was diagnosed 6 months ago; the patient has declined surgery and chemotherapy. She takes no medications. On physical examination, temperature is 37.5 °C (99.5 °F), blood pressure is 90/60 mm Hg, pulse rate is 118/min, respiration rate is 22/min, and BMI is 18. The patient appears cachectic. The remaining general physical examination findings are normal. Laboratory studies: Blood urea nitrogen 70 mg/dL (25.0 mmol/L)Calcium13.5 mg/dL (3.38 mmol/L)Creatinine 2.9 mg/dL (256.4 µmol/L)Parathyroid hormoneUndetectableAggressive volume replacement with intravenous normal saline is initiated.Which of the following drugs is likely to provide the most sustained benefit in decreasing this patient’s calcium level?ACalcitoninBCinacalcetCPrednisoneDZoledronate

46. Answer • This patient should receive an intravenous infusion of zoledronate. Malignancy is the most common cause of non-parathyroid hormone (PTH)–mediated hypercalcemia and the most frequent cause of hypercalcemia in hospitalized patients. Malignancy-associated hypercalcemia is differentiated into two forms: local osteolytic hypercalcemia and humoral hypercalcemia of malignancy. Local osteolytic hypercalcemia occurs when tumor growth in the skeleton leads to the release of calcium by the elaboration or stimulation of local cytokines and other osteoclast-activating factors. The classic associated tumor is multiple myeloma, although adenocarcinoma of the breast and certain lymphomas may also be responsible. Humoral hypercalcemia of malignancy results from the systemic effect of a circulating factor produced by neoplastic cells. The hormone most commonly responsible for this syndrome is PTH-related protein (PTHrP). This peptide’s N-terminal shares substantial homologic features with PTH. Tumors that elaborate PTHrP are most commonly squamous cell carcinomas, such as those of the lung (as in this patient), esophagus, or head and neck. PTHrP levels can be measured, but this is rarely needed to establish the diagnosis of humoral hypercalcemia of malignancy. • Bisphosphonates powerfully inhibit osteoclast-mediated bone resorption. They very effectively lower the serum calcium level, with their maximum effect seen in 2 to 4 days. Their duration of effect is usually several weeks and varies between patients and between types of bisphosphonate. Zoledronate appears to have the longest-lasting effect (1-1.5 months) and a faster onset of action than other bisphosphonates; it is approved for use in patients with hypercalcemia of malignancy by the U.S. Food and Drug Administration. • Because of the lag in the onset of effect, bisphosphonates should be combined with faster-acting therapeutic modalities, such as aggressive volume replacement with normal saline infusion and possibly calcitonin injections. However, calcitonin has a short-lived effect on hypercalcemia because of tachyphylaxis and therefore should only be used as an interim step. • Cinacalcet is a calcimimetic agent that occupies the calcium sensing receptor and lowers serum calcium levels in patients with primary and tertiary hyperparathyroidism associated with chronic kidney disease. It is not effective and not approved for use in malignancy-associated hypercalcemia. • Increased calcitriol production associated with activated macrophages (granulomatous diseases and lymphomas) can be diminished by using corticosteroids. However, prednisone does not lower PTHrP levels and therefore is not useful in humoral hypercalcemia of malignancy.

47. A 78-year-old woman who resides in a nursing home is seen for management of her diabetes mellitus. The patient’s blood glucose log shows levels ranging between 40 and 400 mg/dL (2.2 and 22.2 mmol/L). She otherwise feels well. She has been on insulin for more than 25 years after first taking oral agents for several years following her initial diagnosis. The patient has hypothyroidism treated with levothyroxine and remote history of Graves disease treated with radioactive iodine. Her diabetes is currently treated with neutral protamine Hagedorn (NPH) insulin, 25 units twice daily; the dosage has been gradually increased over the past 3 weeks. The only pertinent finding on physical examination is her lean body habitus (BMI of 19.3).Results of routine laboratory studies are all within the normal range. An anti–glutamic acid decarboxylase antibody titer is positive. Which of the following is the most likely diagnosis?ALate-onset autoimmune diabetes of adulthoodBMaturity-onset diabetes of the youngCType 1 diabetes mellitusDType 2 diabetes mellitus

48. Answer • This patient most likely has late-onset autoimmune diabetes of adulthood (LADA). Diabetes mellitus is categorized into several types. Most affected patients have type 2 diabetes, and a minority (5% to 10%) have type 1 diabetes. Patients with type 2 diabetes are usually overweight, if not frankly obese. Type 1 diabetes results from autoimmune destruction of pancreatic beta cells and results in absolute insulin deficiency, whereas type 2 is marked by insulin resistance and relative insulin deficiency. Type 1 diabetes is classically seen in younger patients, usually in children, teens, and young adults. However, type 1 diabetes can be diagnosed at any age. When diagnosed in older persons, especially those in whom hyperglycemia was once controlled with oral agents, this form of diabetes is referred to as LADA. In persons with LADA, beta cell destruction over time leads to the requirement for insulin therapy, as in type 1 diabetes. LADA typically occurs in leaner persons after glycemic control has become more labile and there is clear insulin dependency. Autoimmune markers (anti–islet cell autoantibodies) are present, including anti-glutamic acid decarboxylase antibody, the detection of which can confirm the diagnosis. • Maturity-onset diabetes of the young is typically diagnosed in adolescents or young adults and usually is marked by mild hyperglycemia, often with a strong family history of diabetes.

49. A 47-year-old woman is evaluated for difficult-to-control hypertension. She was previously treated for hypokalemia.On physical examination, temperature is 36.0 °C (96.8 °F), blood pressure is 178/100 mm Hg, pulse rate is 58/min, respiration rate is 16/min, and BMI is 29. No abdominal bruit is detected. Funduscopic examination shows mild arteriolar narrowing. Laboratory studies: ElectrolytesSodium143 meq/L (143 mmol/L)Potassium3.5 meq/L (3.5 mmol/L) (after replacement therapy)Chloride101 meq/L (101 mmol/L)Bicarbonate33 meq/L (33 mmol/L)AldosteroneBaseline23 ng/dL (635 pmol/L)3 Days after high salt intake15 ng/dL (414 pmol/L)Renin activityBaseline<0.1 ng/mL/h (0.1 µg/L/h)3 Days after high salt intake<0.1 ng/mL/h (0.1 µg/L/h)Aldosterone to renin activity ratio>50Which of the following is the most appropriate next step in management?AAdrenalectomyBBilateral adrenal vein catheterizationCCT of the adrenal glandsDDuplex ultrasonography of the renal arteries

50. Answer • The most appropriate next step is CT of the patient’s adrenal glands, with and without contrast. This patient has severe and difficult-to-control hypertension associated with laboratory findings characteristic of primary hyperaldosteronism. She had spontaneous, unprovoked hypokalemia and has metabolic alkalosis. The evaluation of unexplained hypertension and unprovoked hypokalemia begins with measurement of the plasma renin activity and aldosterone level. A serum aldosterone to plasma renin activity ratio greater than 20 and a serum aldosterone level greater than 15 ng/dL (414 pmol/L) strongly suggest primary hyperaldosteronism. On follow-up testing, the patient has an elevated serum aldosterone level that was not suppressed by high salt intake; plasma renin activity was suppressed. These are the biochemical features of primary hyperaldosteronism. After hyperaldosteronism is confirmed, a search for the anatomic or pathologic cause should begin. CT of the adrenal glands is the appropriate initial step in identifying the anatomic cause of the disease. • Aldosterone-producing adenomas respond to unilateral adrenalectomy. Within the first postoperative year, 67% of patients are normotensive and 90% are normokalemic. Medical therapy is the treatment of choice for adrenal hyperplasia. Neither partial nor complete adrenalectomy is indicated, however, until the anatomic and pathologic features have been defined by a CT scan. • Although bilateral adrenal vein catheterization and sampling can be helpful in defining the source of excessive aldosterone secretion (unilateral versus bilateral), the procedure is invasive, is technically difficult, and should not be performed before a CT scan is obtained. • Duplex ultrasonography of the renal arteries is used to investigate the possibility of renal artery stenosis. Such testing is not indicated in this patient, nor would it be helpful. The biochemical features of her case (suppressed plasma renin activity but elevated serum aldosterone level) practically rule out the possibility of renal artery stenosis. • Bibliography