Cardiology Intensive Board Review, 3 ed.

Hypertension

Amanda R. Vest • Leslie S. Cho

ANSWERS

1.c. Preeclampsia. Chronic hypertension is characterized by blood pressure ≤140/90 mmHg present before pregnancy, before the 20th week of gestation, or persisting beyond the 42nd postpartum day. Conversely, gestational hypertension develops beyond 20 weeks of gestation and usually resolves within 42 days postpartum. Preeclampsia is characterized by hypertension presenting beyond 20 weeks of gestation with >300 mg protein in a 24-hour urine collection or >30 mg/mmol in a spot urine sample, although in rare cases hypertension or proteinuria can be absent. Thrombocytopenia in this patient is very concerning for HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), a life-threatening condition showing significant overlap with preeclampsia. Eclampsia is the occurrence of seizures in a pregnant woman with preeclampsia. Edema is no longer considered to be part of the diagnostic criteria for preeclampsia because it occurs in more than half of normal pregnancies.

2.b. Duplex ultrasonography of the renal arteries. This young woman likely has hypertension secondary to fibromuscular dysplasia (FMD). FMD is a noninflammatory, nonatherosclerotic vascular condition typically affecting young women. It most frequently presents with hypertension, transient ischemic attack, stroke, or an asymptomatic cervical bruit. Sudden onset of pulmonary edema and a significant rise in creatinine after ACEI/ARB initiation are also common manifestations and reflect the presence of renal artery stenosis. About 60% to 75% of cases of FMD involve the renal arteries. Duplex ultrasonography is a noninvasive investigation that is highly specific and sensitive for renal artery stenosis, whether the stenosis is caused by atherosclerosis or FMD, and therefore is often the first test for diagnosis of this condition. Duplex ultrasonography of the carotids would also have been a good choice in this patient given the presence of a carotid bruit. The classic “string-of-beads” appearance of the arteries may be seen on angiography. The clinical history is not suggestive of pheochromocytoma (Answer c) or Cushing syndrome (Answer d).

3.d. Discontinue doxazosin and start lisinopril 5 mg daily. The likely culprit of this patient’s postural dizziness and falls is doxazosin. Elderly patients are more susceptible to drug side effects and management of hypertension should take into account such symptoms. Doxazosin demonstrated less effective blood pressure lowering than a thiazide in the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT) study and was associated with excess cardiovascular events and incident heart failure. It would therefore be appropriate to discontinue doxazosin. There is minimal additional efficacy increasing from 25 to 50 mg of hydrochlorothiazide. The β-blocker should be continued due to the coronary artery disease history, but increasing to 100 mg metoprolol risks bradycardia. Clonidine 0.4 mg twice daily would also lower the heart rate and would be an excessive dose for initiation in an elderly patient who is already near blood pressure goal. The JNC recommendation of a “start low, go slow” approach in the elderly is intended to limit drug side effects, including hypotension. The discontinuation of doxazosin and initiation of 5 mg lisinopril is therefore the most appropriate option.

4.a. Aliskiren. The U.S. Food and Drug Administration issued a black box warning in 2012 that aliskiren should not be used with ACEIs or ARBs in patients with diabetes, because of the risk of renal impairment. There is also a warning to avoid the use of aliskiren with ACEIs or ARBs in patients with a glomerular filtration rate <60 mL/min. Conversely, methyldopa usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Normal or elevated plasma renin activity may decrease during methyldopa therapy. Hydrochlorothiazide may be a useful addition in stage III CKD but is unlikely to be effective in patients with a glomerular filtration rate <30 mL/min. Amlodipine is also a reasonable add-on medication to consider in this scenario.

5.b. Hydralazine and ankle edema. Vasodilatory lower extremity edema is most commonly seen with direct arteriolar dilators such as hydralazine and minoxidil. Dihydropyridine calcium antagonists, such as amlodipine, and α-adrenergic antagonists, such as doxazosin, are also associated with extremity edema. ACEIs are associated with an approximate 20% incidence of cough, which is purported to be bradykinin mediated. Angiotensin receptor antagonists, such as valsartan, do not directly inhibit angiotensin-converting enzyme activity or inhibit the breakdown of bradykinin. However, there are reports of angiotensin receptor antagonist-associated cough, but the incidence, severity, and frequency of dry cough in patients receiving valsartan or losartan are equivalent to those receiving placebo. Sleep disturbance is a side effect of β-blockers, especially those that cross the blood-brain barrier (e.g., propranolol and metoprolol). Constipation is a frequent side effect of verapamil.

6.d. Losartan. Both brothers carry the gene mutation for Marfan syndrome; presumably their father’s fatal aortic dissection was also a result of this connective tissue disease. Recent data suggest that the ARB losartan may slow the progression of aortic root dilatation in Marfan syndrome. Initially promising animal model studies demonstrating the benefits of transforming growth factor-beta pathway blockade by losartan have now translated into human clinical trials demonstrating benefit for patients with Marfan syndrome. In a randomized controlled trial of 233 Marfan patients, aortic root dilatation rate per MRI was significantly lower in the losartan group, when compared with controls, at a mean of 3-year follow-up.

7.a. Diabetes. There are no established links between hypertension and oral or subcutaneous therapies for diabetes. However, all four other conditions can be treated with medications that may be iatrogenic causes or contributors to hypertension. Approximately 20% to 30% of patients who receive erythropoietin intravenously for anemia of CKD develop an elevation in diastolic pressure of 10 mmHg or more. Secondary hyperparathyroidism is common in CKD patients, and cinacalcet can lower parathyroid hormone levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. However, hypertension is an adverse effect in approximately 7% of patients. Systemic absorption of ophthalmic drops is limited, but α-adrenergic agonists such as brimonidine may raise the pulse and blood pressure. Nonsteroidal anti-inflammatory medications such as ibuprofen are a common cause of fluid retention and hypertension exacerbation, especially for patients with renal dysfunction.

8.e. Access through a femoral artery, radiofrequency ablation of bilateral renal arteries. Current renal denervation catheters are introduced via standard femoral artery access. These catheters have a radiofrequency energy electrode tip that delivers a series of 2-minute ablations along the lumen of each renal artery to disrupt the sympathetic nerve fibers. Symplicity HTN-2 was a randomized, controlled trial comparing 54 patients receiving standard medical therapy for resistant hypertension with 52 patients who underwent percutaneous renal sympathetic denervation. The denervation group demonstrated a mean 32/12 mmHg blood pressure reduction at 6 months, compared with a 1/0 mmHg reduction in controls. However, the larger Symplicity 2 study did not show any difference. Thus, at this time, renal denervation cannot be recommended as therapy.

9.b. Female gender. ACEIs are the leading cause of drug-induced angioedema in the United States because they are so widely prescribed, accounting for 20% to 40% of all emergency room visits for angioedema. ACEIs induce angioedema in approximately 0.2% of recipients and the risk appears equivalent between the different ACEI medications. Severe reactions can be observed many months or even years after initiation of ACEI therapy. One large Veteran’s Affairs study by Miller et al. documented an almost fourfold higher rate of ACEI angioedema in blacks compared with whites, a 50% higher rate in women and a 12% lower rate in patients with diabetes. Patient age quartiles were unassociated with angioedema risk.

10.b. Peripheral arterial disease. There is now evidence to support the specific use of ramipril in patients with peripheral arterial disease and intermittent claudication. Ramipril has been associated with a significant increase in pain-free and maximum treadmill walking times at 6 months, as compared with placebo. Relative to placebo, ramipril also significantly improved the physical functioning component of a quality of life score. Although blood pressure control is an important management component for hypertensive patients with HFPEF, there is no compelling evidence for superiority of one medication over another in this setting. There is also no strong evidence to guide a specific antihypertensive choice for a patient with sleep apnea, although the presence of increased sympathetic nerve activity and a nocturnal diuresis in sleep apnea patients may explain reports that β-blockers tend to lower blood pressure more than thiazide diuretics in this setting. β-Blockers and ACEIs or ARBs are commonly used for blood pressure control in patients with aortic aneurysms.

11.a. Bicuspid aortic valve. This young man has a classic presentation of coarctation of the aorta. This secondary cause of hypertension is the result of stenosis of the aorta, usually at the embryonic site of the ligamentum arteriosum and is typically distal to the origin of the left subclavian artery. The presentation in adulthood is varied and is twice as common in men. Symptoms of hypertension or congestive heart failure are common. The electrocardiogram is characterized by left ventricular hypertrophy. Right ventricular hypertrophy is common if a concomitant ventricular septal defect is present. The most common associated valvular abnormality is a bicuspid aortic valve seen in 22% to 42% of cases. Intracranial aneurysms are seen in up to 10% of cases. Patients will often have a characteristic systolic precordial murmur secondary to the development of collateral arteries. Long-term management involves surgical or transcatheter correction. Patients will often continue to have systemic hypertension after repair and should be treated accordingly.

12.b. Stage 2, 130/80 mmHg. The most recent JNC 8 guidelines recommend that patients with diabetes have blood pressure goal of less than 140/90 mmHg based on the large ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes — Blood–Pressure-lowering arm) study. The new guideline makes no distinction between patients with CKD or diabetes mellitus with no or with otherwise uncomplicated hypertension in patients less than 60 years of age. The most controversial aspect of the new guideline involves patients >60 years whose treatment goal is now <150/90 mmHg if they have no CKD or diabetes mellitus.

13.d. Direct renin inhibitor. Aliskiren is a direct renin inhibitor. The renin enzyme controls the rate-limiting step in the generation of angiotensin II. Aliskiren reaches peak concentration in 2 to 4 hours with a half-life of 24 to 36 hours. It is 50% protein bound. Diarrhea is the most common side effect occurring in up to 9.5% of patients. A dose of 150 mg daily will decrease systolic blood pressure on average 12.5 mmHg with a further 2.7 mmHg decrease when the dose is increased to 300 mg PO daily as compared with placebo. Aliskiren has been shown to have similar blood pressure-lowering effects when compared with thiazide diuretics as well as ACEIs. However, to date there are limited data on the effect of aliskiren on hypertension-induced end-organ damage and clinical outcomes.

14.a. Patient has essential hypertension; start thiazide diuretic. The patient likely has essential hypertension. The age of onset is typically between the early 20s to the late 50s. The presence of a family history of hypertension, the mild elevation in blood pressure, and the gradual onset make the diagnosis of essential hypertension more likely. First-line therapy in this individual, assuming she is not trying to become pregnant, is the use of a thiazide diuretic. Reevaluation in 1 year would not be appropriate, given the long-term complications associated with uncontrolled hypertension. A repeat evaluation in a few weeks is not necessary, given the documented hypertension over the past few years. The presence of unilateral renal artery stenosis from vascular hyperplasia is a possibility; however, the clinical history is most consistent with essential hypertension.

15.b. Renal MRI. The distinction between essential hypertension and secondary causes is critical in the management of a patient with long-standing hypertension that is difficult to control. In this scenario, the inability to control the patient’s blood pressure with multiple medications increases the pretest probability of a secondary etiology. In this individual, the presence of multiple cardiac risk factors, along with repeat episodes of noncardiogenic pulmonary edema, suggests the diagnosis of bilateral renal artery stenosis. Addition of further antihypertensive medications would be indicated, but not prior to initiating a workup for renal artery stenosis. A renal MRI would be the most appropriate of the mentioned answers.

16.b. Twofold. Increasing blood pressure beginning at 115/75 mmHg is noted to be a risk factor for stroke, heart failure, and myocardial infarction. For every 20 mmHg increase in systolic blood pressure and for every 10 mmHg in diastolic blood pressure, there is a twofold increase in the risk of cardiovascular disease. For the above patient, her risk of cardiovascular disease has increased by twofold.

17.b. Methyldopa. The central α-agonist methyldopa is known to cause an autoimmune hemolytic anemia in up to 20% of patients taking the medication. Other common side effects include sedation, insulin resistance, and galactorrhea. Methyldopa is not a first-line agent for treatment of hypertension and is usually reserved for pregnant patients and those with resistant hypertension.

18.c. 35% increase in creatinine. According to the JNC 7 guidelines, patients initiated on an ACEI should be continued on that medication unless the creatinine increases by more than 35% or another indication for discontinuation presents itself.

19.a. Calcium channel blocker. The Blood Pressure Lowering Treatment Trialist Collaboration Study found that calcium channel blockers provided a greater benefit in the reduction of stroke when compared with other antihypertensive agents. However, there was no difference in cardiovascular mortality or overall cardiovascular events.

20.b. She should have a repeat blood pressure measurement at a later time point during her visit and return in a few weeks to obtain repeat testing if that measurement is elevated. The JNC 7 guidelines suggest that the diagnosis of hypertension requires at least two separate blood pressure measurements during a clinic visit. The patient should be resting in a chair for at least 5 minutes and should have her arm supported at heart level when the blood pressure is measured. Blood pressure measurements should be evaluated in the contralateral arm and while standing as well. Elevations in blood pressure should be confirmed in a timely manner on a repeat visit, the timing of which is dependent on the level of hypertension and the presence of comorbid conditions. The patient in this vignette has mild isolated hypertension and should return in a few weeks (6 to 8 weeks). Those with more elevated blood pressure should return sooner. Antihypertensive medications should not be initiated on this initial visit as diurnal variations in blood pressure are common and she may not have hypertension. Ambulatory monitoring of blood pressure should be attempted. An evaluation for secondary cause is premature as the diagnosis of hypertension is not confirmed. Waiting to reevaluate the patient in 1-year time is unacceptable, as hypertension, if left untreated, increases the risk of stroke, myocardial infarction, heart failure, and renal insufficiency.

21.d. Urine metanephrines. The initial assessment of any patient with a new diagnosis of hypertension requires evaluation for evidence of hypertension-induced end-organ damage. All patients with a new diagnosis of hypertension should have the following testing: serum hematocrit, blood urea nitrogen, serum creatinine, serum potassium, serum calcium, blood glucose, an electrocardiogram, an ophthalmologic examination, a fasting lipid panel, and a urinalysis. Evaluation for secondary causes of hypertension should be limited to those with uncontrolled hypertension after treatment.

22.b. Urine metanephrines. This patient’s medical history is consistent with a diagnosis of pheochromocytoma. Pheochromocytomas arise from chromaffin cells. These tumors are most commonly found in the adrenal glands, but may be present anywhere there are sympathetic nerves. Classic symptoms are episodic palpitations, headaches, and diaphoresis. Rarely, patients may present with orthostatic hypotension. Initial diagnostic testing would involve the evaluation of a urine specimen for urine metanephrines. A toxicology screen is not indicated given his clinical history. An MRI of the abdomen would be helpful to evaluate for intra-abdominal masses, but an MRI of the thorax would be of limited benefit. Starting a thiazide diuretic would be beneficial, but ultimately the patient requires surgical therapy for correction of his hypertension.

23.c. Metoprolol. The initial choice of antihypertensive medication in this patient should be a β-blocker. Multiple studies have shown the benefit of β-blockers in the post-myocardial infarction period. The morphine in acute myocardial infarction (MIAMI-1) and International Study of Infarct Survival (ISIS-1) trials in the fibrinolytic era both showed trends toward a decrease in mortality with the use of intravenous β-blockers. The clopidogrel and metoprolol in myocardial infarction (COMMIT) trial found decreases in the rate of reinfarction and ventricular fibrillation with intravenous metoprolol followed by oral metoprolol; however, there was a 30% increase in the risk of cardiogenic shock. A meta-analysis of the post-myocardial infarction use of β-blockers has shown up to a 40% decrease in cardiovascular mortality. The American Heart Association 2013 ST-segment elevation myocardial infarction (STEMI) guidelines recommend initiation of oral β-blockers in the first 24 hours, providing that heart failure signs, evidence of a low-output state, risk factors for cardiogenic shock, or other contraindications to β-blockers are absent. However, intravenous β-blockers carry a class IIa indication in STEMI, given the concern for possible complications.

24.a. Calcium channel blocker. Calcium channel blockers are the most effective of the antihypertensive regimens at reducing carotid atherosclerosis. Studies comparing various calcium channel blockers with thiazide diuretics, ACEIs, and β-blockers have shown that calcium channel blockers have greater ability to decrease carotid intimal thickness.

25.d. Decreased peripheral resistance. The initial mechanism of action for lowering blood pressure is a decrease in plasma volume secondary to natriuresis. This triggers an increase in the activity of the rennin-angiotensin system, resulting in a return of plasma volume to normal. However, there is a long-term decrease in peripheral resistance that produces the chronic antihypertensive effects of thiazide diuretics.

26.c. Captopril. Aside from mycophenolate, the ACEI captopril is the most likely cause of this patient’s leukopenia. When immunosuppressive therapy is combined with ACEIs, there are reports of the development of anemia, neutropenia, leukopenia, and agranulocytosis. The best treatment strategy in this patient would be to use an alternative antihypertensive agent and monitor blood counts closely.

27.b. Start hydrochlorothiazide and lisinopril. The most appropriate initial step in the management of the patient in this clinical vignette is the initiation of two antihypertensive medications as recommended in the JNC 7 guidelines. In general, if patients have a blood pressure of greater than 20/10 mmHg above goal, they should be initiated on two antihypertensive agents because monotherapy will typically be ineffective in achieving target blood pressure. Most patients should be started on a thiazide diuretic when commencing treatment of hypertension, as confirmed by the results of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack trial. Care should be taken in patients at risk for hypotension, specifically elderly patients, those with diabetes, and those with autonomic dysfunction.

28.c. Do nothing as he has white coat hypertension. The patient in the above clinical vignette has a diagnosis of white coat hypertension. It is defined as a clinic blood pressure of >140/80 mmHg in at least three clinic settings, with blood pressure measurements of <140/80 mmHg in at least two nonclinic settings, and with absence of end-organ damage. Multiple studies have been undertaken to evaluate if isolated elevations in blood pressure in the medical setting are associated with increased cardiovascular events. A 10-year follow-up study comparing cardiovascular events between patients with white coat hypertension and those with sustained hypertension found worse outcomes in those with sustained hypertension. The risk of myocardial infarction was two times greater and the risk of a cerebral vascular event was four times greater in the sustained hypertension group. Comparison of normotensive patients with those with white coat hypertension has noted a greater prevalence of left ventricular hypertrophy in the white coat hypertension group. However, there are no clear data that white coat hypertension increases long-term cardiovascular events. Treatment of white coat hypertension is associated with decreases in clinic blood pressure with no significant decrease in ambulatory blood pressure. Patients with white coat hypertension should be monitored closely for development of sustained hypertension, but do not need to be initiated on antihypertensive therapy.

29.a. Intravenous nitroprusside. Treatment of hypertensive emergency requires the use of intravenous medications to decrease the mean arterial blood pressure by 25% in the first few hours. Lower target blood pressure goals increase the risk of inducing a cerebral vascular event from decreased cerebral perfusion. Sublingual nifedipine is no longer used for hypertensive emergencies due to its dramatic and unpredictable blood pressure–lowering effects and the associated adverse clinical outcomes. Nitroprusside, labetalol, and nitroglycerin are all reasonable options. However, given the rapid onset and offset of nitroprusside, and the evidence of conduction delay that may limit labetalol use, nitroprusside would be the most appropriate medication for rapid and safe titration of blood pressure.

30.b. Lisinopril. The patient in the vignette has a target blood pressure of 130/80 mmHg according to the JNC 7 guidelines. The correct choice of initial blood pressure medication in this patient would be an ACEI. The ALLHAT study suggested that patients with diabetes mellitus have better long-term outcomes when using a thiazide diuretic compared with an ACEI. However, the patient in this vignette has evidence of protein in his urine. JNC 7 recommends that a thiazide diuretic should be first-line therapy, unless there is a specific indication. In this patient, the presence of proteinuria and diabetes mellitus makes the choice of an ACEI a better option than the thiazide. α-Blockers are not considered first-line therapy in hypertensive patients. In the ALLHAT study, there was an increased incidence of heart failure when comparing the α-blocker group (doxazosin) with the thiazide group.

31.c. Captopril. ACEIs and ARBs are contraindicated during pregnancy, because of the increased risk of congenital malformations. Methyldopa is the medication most commonly used to control blood pressure in pregnancy. There is significant evidence that it does not produce any harmful outcomes to the fetus. β-Blockers have been used in pregnancy with what appear to be safe results. However, the data are contradictory. There is some evidence that β-blockers, especially when used early in pregnancy, may increase the risk of fetal bradycardia, hypoglycemia, small placental weight, and a small-for-gestational-age fetus. Calcium channel blockers have been used in pregnancy without deleterious results, but the number of published cases is small. In general, methyldopa is the safest antihypertensive during pregnancy. β-Blockers and calcium channel blockers may be used with caution. ACEIs and ARBs are absolutely contraindicated due to teratogenic effects including renal dysplasia and intrauterine growth restriction.

32.c. Atenolol 25 mg PO daily. The least effective option is atenolol. The ALLHAT study showed that the use of thiazide diuretics as first-line therapy for treatment of uncomplicated hypertension was as effective as, if not superior to, amlodipine and lisinopril in preventing fatal coronary artery disease and nonfatal myocardial infarction. The choice of an ACEI would be reasonable, given the presence of glucose intolerance. β-Blockers would not be indicated as first-line therapy in this patient. Multiple meta-analysis comparing β-blockers with placebo or other antihypertensive agents have shown no statistically significant decreases in mortality, myocardial infarction, and stroke. The Anglo Scandinavian Cardiac Outcomes Trial (ASCOT) trial comparing atenolol with amlodipine found a 23% greater risk of stroke in the atenolol group versus the amlodipine-based regimen.

33.b. Conversion of patient to a calcium channel blocker and thiazide diuretic. Analysis of the clinical trials in hypertension has noted that there are differences in the effectiveness of antihypertensive medications between different ethnic groups. African Americans are more responsive to calcium channel blockers and thiazide diuretics than other antihypertensive agents. This patient is on an ACEI and a β-blocker. Altering his regimen to include more effective antihypertensive agents would be indicated rather than increasing his medications, adding additional medications, or evaluating him for secondary causes of hypertension. The new JNC 8 guidelines make recommendation of medication based on the race of the patient.

34.c. 24-Hour urine cortisol test. This patient’s medical history is consistent with a secondary cause of hypertension, in particular, Cushing syndrome. This syndrome is characterized by an excess of cortisol. It may be secondary to a pituitary tumor/hyperplasia (Cushing disease), an adrenal tumor, or ectopic adrenocorticotropic production. Clinical manifestations include diabetes mellitus, hypertension, obesity, hypokalemia, osteoporosis, and fungal infections. The initial step in diagnosis is a 24-hour urine free cortisol test. Treatment is surgical.

35.a. Metoprolol. Pheochromocytoma is a rare cause of hypertension. Treatment ultimately requires surgical removal. The use of β-blocker monotherapy is contraindicated as part of the medical management of pheochromocytomas. The catecholamines secreted by these tumors activate both peripheral α- and β-receptors. Blockage of these peripheral β-receptors results in unopposed α-activation. This can result in severe hypertension. Typical medical management of pheochromocytomas involves the use of antihypertensives with α-blocking capability. For example, prazosin or phenoxybenzamine may be used. Only once α-blockade is established should the use of a β-blocker be entertained.

36.a. Aggressive lifestyle modification. Patients with prehypertension are at increased risk for cardiovascular events compared with normotensive individuals; therefore, care of these patients should be focused on aggressive control of all cardiovascular risk factors. Analysis of the Women’s Health Initiative compared cardiovascular outcomes in prehypertension patients with normotensive patients and found that the prehypertension patients had hazard ratios indicating a 1.58 (95% confidence interval [CI], 1.12 to 2.21) greater risk for cardiovascular death; 1.76 (95% CI, 1.40 to 2.22) greater risk for myocardial infarction; 1.93 (95% CI, 1.49 to 2.50) greater risk for stroke; 1.36 (95% CI, 1.05 to 1.77) greater risk for hospitalized heart failure; and a 1.66 (95% CI, 1.44 to 1.92) greater risk for any cardiovascular event. Not only are these patients at increased risk for cardiovascular events, but they also have a high incidence of hypertension development. In the Trial of Preventing Hypertension (TROPHY) trial, patients with prehypertension were randomized to candesartan or placebo. Over a period of 4 years, 67% of the untreated group developed hypertension as defined by the JNC 7 guidelines. These data suggest that patients with prehypertension are a high-risk population and should be treated aggressively. According to the JNC 7 guidelines, these individuals should increase their activity level, modify their diet, avoid excessive alcohol, and attempt weight loss. Initiation of antihypertensive medications should be reserved for those who progress to evident hypertension.

37.a. 140/90 mmHg. JNC 8 guidelines recommend that in patients with CKD or diabetes mellitus, the target blood pressure should be <140/90 mmHg.

38.c. Diltiazem. Patients who have undergone heart transplantation often have preexisting hypertension or develop hypertension subsequent to the heart transplant. This is a unique patient population as many of the immunosuppressive medications used after transplantation have multiple drug interactions. With respect to antihypertensive agents, most if not all calcium channel blockers have been shown to increase cyclosporine levels. Diltiazem and verapamil, in particular, are potent inhibitors of protein P-glycoprotein and CYP3A4. These enzymes are critical for the metabolism of diltiazem, and their inhibition can increase cyclosporine levels up to sixfold. It is recommended that patients who require diltiazem and are on cyclosporine have their cyclosporine dose decreased by 25% to 50%. Diltiazem can also increase tacrolimus levels.

39.b. Minoxidil. Pericarditis is a known complication of the direct vasodilator minoxidil often accompanied by a pericardial effusion. Its other major side effect is hirsutism. Prompt withdrawal of the medication once the diagnosis of a pericardial effusion or pericarditis is made is recommended. Minoxidil is a potent peripheral vasodilator and is typically reserved for patients with severe or difficult-to-control hypertension.

40.b. Morning renin and aldosterone concentrations. The patient in this vignette has secondary hypertension from Conn syndrome. This is primary hyperaldosteronism from uncontrolled secretion of aldosterone. Classic laboratory findings include hypokalemia and mild hypernatremia. The initial diagnostic test of choice is an aldosterone-renin ratio. A ratio of >20 is considered diagnostic. In this patient, the presence of lisinopril complicates the testing. ACEIs are known to decrease renin levels, and ideally the test should be done in the early morning after withdrawal of ACEI therapy. Adrenal vein sampling would be helpful in the diagnosis of primary hyperaldosteronism; however, it is not the initial test of choice. A 24-hour urine test would be more appropriate if Cushing syndrome were suspected. The patient’s clinical description is not consistent with this diagnosis. The presence of FMD should be suspected in any young woman with suspected secondary hypertension. However, the laboratory abnormalities are more suggestive of Conn syndrome than renal artery stenosis.

41.b. Polysomnography. The patient’s clinical history is consistent with the presence of obstructive sleep apnea; therefore, polysomnography (an overnight sleep study) would be the best option. Multiple studies have found evidence for increased risk of hypertension in patients with obstructive sleep apnea. There is no definitive evidence that treating patients with sleep apnea can lower blood pressure; however, there is an increasing hypertension risk as the number of overnight apneic episodes increases. Patients with >30 apnea or hypopnea episodes per hour have an odds ratio of 1.37 of developing hypertension versus those patients with <1.5 apnea or hypopnea episodes per hour.

42.a. Hydralazine. Hydralazine is known to cause a lupus-like syndrome in 5% to 20% of patients taking the medication. This syndrome is characterized by arthralgias, myalgias, pericarditis, fever, and rash. Lisinopril, metoprolol, and hydrochlorothiazide are not known to induce lupus. Other side effects of hydralazine include nausea, vomiting, tachycardia, anorexia, flushing, and diarrhea. Treatment of hydralazine-induced lupus involves withdrawal of the medication.

43.a. Restart clonidine. Rebound hypertension is a known complication of clonidine. Immediate treatment of clonidine withdrawal involves reinstitution of therapy with a slow taper. The mechanism of action is thought to be an increase in sympathetic nervous system activity.

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