Cardiovascular

Secondary hypertension: workup for renovascular, endocrine, and structural causes

Clinical Overview and When to Suspect Secondary Hypertension

— Resistant HTN: BP above goal despite 3 drugs at optimal doses including a diuretic, OR controlled on ≥4 agents

— Early onset: new HTN before age 30, especially without family history or obesity

— Late onset: new severe HTN after age 55 (think renovascular/atherosclerotic)

— Accelerated/malignant HTN or hypertensive emergency in a previously controlled patient

— Acute rise in a previously stable hypertensive

— Hypokalemia (spontaneous or diuretic-induced disproportionate), metabolic alkalosis

— End-organ damage out of proportion to BP duration (LVH, retinopathy, CKD)

— Suggestive symptoms: episodic palpitations/headache/sweating (pheo), snoring/daytime somnolence (OSA), Cushingoid features, claudication

— Drug/substance use: NSAIDs, OCPs, decongestants, stimulants, glucocorticoids, licorice, VEGF inhibitors, calcineurin inhibitors

— Most common overall: OSA, primary aldosteronism, renal parenchymal disease

— Most common in young women: fibromuscular dysplasia (FMD)

— Most common in older patients with diffuse atherosclerosis: atherosclerotic renal artery stenosis

— Most common endocrine cause: primary aldosteronism (5–10% of all HTN, up to 20% of resistant)

Board pearl: Before launching an expensive secondary workup, confirm true resistant HTN by ruling out (1) white-coat effect with home/ambulatory BP, (2) nonadherence, (3) inadequate regimen (missing diuretic or wrong diuretic in CKD), and (4) volume overload from high salt intake or NSAIDs. Step 3 stems often hide the answer in a poorly designed regimen — e.g., HCTZ in a patient with eGFR 28, where the right move is switching to a loop or chlorthalidone-equivalent before invoking secondary causes.

Definition: Hypertension with an identifiable, often reversible, underlying cause — accounts for ~5–10% of adult HTN, but >25% in resistant or early-onset cases.

When to suspect (high-yield triggers):

Epidemiologic anchors:

Presentation Patterns and Key History

— Pheochromocytoma: paroxysmal "5 P's" — pressure, pain (headache), perspiration, palpitations, pallor; episodes triggered by anesthesia, micturition (bladder pheo), tyramine foods, or beta-blocker monotherapy

— Primary aldosteronism (Conn): often asymptomatic; muscle cramps, weakness, nocturia, polyuria from hypokalemia; family history of early stroke

— Cushing syndrome: weight gain, easy bruising, proximal myopathy, mood changes, new-onset diabetes, menstrual irregularity

— Hyperthyroidism: isolated systolic HTN with wide pulse pressure, tremor, heat intolerance

— Hypothyroidism: diastolic HTN, fatigue, constipation, weight gain

— Acromegaly: ring/shoe size change, prognathism, sleep apnea, diabetes

— OSA: loud snoring, witnessed apneas, nocturnal HTN, morning headaches, daytime sleepiness (Epworth >10)

— Renovascular (atherosclerotic): smoker, diffuse vascular disease, flash pulmonary edema (Pickering syndrome), acute Cr rise after ACEi/ARB

— FMD: young woman, headaches, pulsatile tinnitus, cervical bruit

— Coarctation: young patient, leg claudication with exercise, epistaxis, headaches, cold feet, differential BP between arms or arm–leg

— Age at HTN onset, trajectory of control

— Complete medication and substance review: NSAIDs, oral/nasal decongestants, OCPs, glucocorticoids, herbals (licorice, ephedra), cocaine/amphetamines, EPO, VEGF/TKI agents, cyclosporine/tacrolimus, MAOIs

— Sleep history: snoring, witnessed apneas, partner report

— Family history: pheo/paraganglioma syndromes (MEN2, VHL, NF1, SDHx), early stroke (aldosteronism), polycystic kidney disease

— Dietary salt, alcohol (>2 drinks/day raises BP), licorice/chewing tobacco

Step 3 management: When a stem mentions flash pulmonary edema with preserved EF in an older smoker, the answer is bilateral renal artery stenosis — order duplex US and avoid ACEi/ARB monotherapy acutely until anatomy is clarified.

Symptom clusters that point to a cause:

Targeted history must capture:

Physical Exam Findings (and Hemodynamic Assessment when relevant)

— 4-extremity BP is mandatory when coarctation is on the differential: upper-extremity HTN with >20 mmHg gradient to lower extremities or delayed/diminished femoral pulses (radio-femoral delay)

— Inter-arm difference >15 mmHg suggests subclavian stenosis or aortic pathology

— Orthostatic vitals: pheochromocytoma classically shows orthostatic hypotension despite supine HTN (volume contraction + impaired reflexes)

— Obesity, neck circumference >17 in (men)/16 in (women): OSA

— Moon facies, supraclavicular/dorsocervical fat pad (Cushing)

— Exophthalmos, lid lag, thyromegaly with bruit (Graves)

— Coarse features, frontal bossing, macroglossia (acromegaly)

— Carotid bruits — diffuse atherosclerosis; cervical bruit can occur in FMD

— LV heave, S4 (LVH); displaced PMI

— Continuous murmur over back/flank (renovascular bruit, ~40% sensitivity)

— Rib notching collateral murmurs in coarctation; systolic murmur radiating to back

— Abdominal bruit with systolic-diastolic component is highly suggestive of renovascular HTN

— Palpable kidneys (ADPKD)

— Striae (purple, >1 cm wide), central obesity, thin skin (Cushing)

— Proximal muscle weakness (Cushing, hypokalemic aldosteronism)

— Café-au-lait, axillary freckling, neurofibromas (NF1 → pheo, renal artery stenosis)

— Tremor, warm moist skin (hyper-T4); dry skin, delayed reflexes (hypo-T4)

— Diminished/absent femoral pulses with brachial-femoral delay (coarctation)

Board pearl: A young woman with HTN + pulsatile tinnitus + a cervical/abdominal bruit is FMD until proven otherwise — proceed directly to CTA or MRA of renal and cervicocerebral arteries (FMD has multifocal "string-of-beads" appearance and is associated with intracranial aneurysms — screen the brain too).

General/vital signs:

Head/neck:

Cardiopulmonary:

Abdomen:

Extremities/skin:

Fundoscopy: AV nicking, hemorrhages, exudates, papilledema → end-organ severity

Diagnostic Workup — Initial Labs / Imaging / ECG / Biomarkers

— BMP: Na, K, Cl, HCO3, BUN, Cr, glucose → flags aldosteronism (low K, high HCO3), CKD, diabetes

— CBC, lipid panel, HbA1c, TSH

— Urinalysis with albumin/Cr ratio — proteinuria/hematuria suggest renal parenchymal disease

— ECG for LVH (Sokolow-Lyon, Cornell criteria), strain pattern, prior MI

— Lipid panel for ASCVD risk

— Primary aldosteronism: morning plasma aldosterone/renin ratio (ARR); positive if aldosterone >10 ng/dL and ARR >20 (some labs >30). Correct hypokalemia first; ideally hold MRAs ×4–6 wks, but ACEi/ARB/CCB/α-blockers can usually be continued

— Pheochromocytoma: plasma free metanephrines (best initial; sensitivity ~99%) or 24-h urinary fractionated metanephrines (best specificity, esp. older/comorbid)

— Cushing syndrome: any of three — late-night salivary cortisol ×2, 1 mg overnight dexamethasone suppression test, 24-h urinary free cortisol ×2

— Renovascular HTN: renal duplex ultrasound (operator-dependent; resistive index, peak systolic velocity >200 cm/s) is first-line non-invasive; CTA or MRA if duplex inconclusive and eGFR allows

— Coarctation: transthoracic echo ± CTA/MRA aorta; CXR shows rib notching, "3 sign"

— OSA: Epworth + STOP-BANG; if intermediate-high risk → polysomnography (home sleep testing acceptable if uncomplicated)

— Thyroid: TSH; free T4 if abnormal

— Hyperparathyroidism/Ca-related: Ca, PTH

Key distinction: Plasma metanephrines = high sensitivity, best to rule OUT pheo; 24-h urinary fractionated metanephrines = better specificity, best to confirm. False positives from TCAs, labetalol, levodopa, acetaminophen interference, acute illness, and clonidine withdrawal — always review meds before drawing.

CCS pearl: Order ECG, BMP, UA, and lipid panel as standing orders on day 1 of any new HTN workup; layer secondary screens based on clinical triggers — shotgun ordering wastes points.

Baseline labs in every HTN patient (ACC/AHA):

Targeted first-tier secondary screen (when triggers present):

Diagnostic Workup — Advanced or Confirmatory Studies

— Oral salt loading with 24-h urinary aldosterone >12 µg/day on high-Na diet, OR

— Saline infusion test (2 L NS over 4 h) with post-infusion aldosterone >10 ng/dL, OR

— Fludrocortisone suppression, captopril challenge

— Adrenal CT to differentiate adenoma vs hyperplasia

— Adrenal venous sampling (AVS) is the gold standard for lateralization before unilateral adrenalectomy — required in patients >35 with bilateral abnormalities or normal-appearing glands

— CT or MRI abdomen/pelvis first (adrenal mass, often >3 cm, T2 hyperintense)

— 123I-MIBG scintigraphy or 68Ga-DOTATATE PET for extra-adrenal/metastatic disease

— Genetic testing in all confirmed cases (~40% have germline mutation: VHL, RET, NF1, SDHx)

— ACTH level: suppressed → ACTH-independent (adrenal) → adrenal CT

— ACTH normal/elevated → ACTH-dependent → high-dose dex suppression, CRH stimulation, pituitary MRI

— Inferior petrosal sinus sampling if MRI equivocal to distinguish Cushing disease from ectopic ACTH

— CTA preferred when eGFR ≥30; MRA if eGFR borderline (avoid gadolinium if eGFR <30)

— Captopril renography rarely used now

— Catheter angiography is gold standard, reserved for cases proceeding to intervention; FMD shows beaded appearance in mid/distal renal artery, ostial atherosclerotic lesions sit proximally

Board pearl: Do not biopsy an adrenal mass until pheochromocytoma is biochemically excluded — biopsy can precipitate a hypertensive crisis. This is a classic Step 3 patient-safety stem.

Primary aldosteronism — confirmatory testing (after positive ARR):

Pheochromocytoma — localization after positive biochemistry:

Cushing syndrome — after initial positive screen:

Renovascular HTN:

Coarctation: MRA/CTA aorta defines gradient and collaterals; cath with pressure gradient measurement if intervention planned

Risk Stratification or First-Line Management Logic

— Confirm the diagnosis biochemically before imaging for endocrine causes (incidentalomas are common and misleading)

— Confirm anatomy before intervention for structural causes

— Treat reversible drivers in parallel: weight loss, sodium <1.5–2.3 g/day, DASH diet, alcohol moderation, exercise 90–150 min/week, sleep hygiene

— Hypertensive emergency (BP >180/120 with end-organ damage) → IV agents in monitored setting, then workup

— Severe asymptomatic HTN → titrate oral therapy, expedite outpatient evaluation

— Stable resistant HTN → outpatient stepwise workup

1. OSA — high prevalence, CPAP improves BP modestly but reliably

2. Primary aldosteronism — high prevalence in resistant HTN; MRA therapy or adrenalectomy curative

3. Renal parenchymal disease (CKD) — manage with ACEi/ARB, volume control

4. Renovascular HTN — medical therapy first for atherosclerotic; revascularization selective

5. Pheochromocytoma — rare but high-stakes; surgical cure

6. Cushing, thyroid disease, hyperparathyroidism, acromegaly — treat underlying

Step 3 management: When confronted with resistant HTN, the highest-yield single move is to add spironolactone 25–50 mg (PATHWAY-2 trial) — it outperforms bisoprolol and doxazosin as 4th-line agent and both treats and partially screens for aldosteronism. If BP responds dramatically, formally screen for primary aldosteronism after washout.

Board pearl: Always reassess medication adherence, lifestyle, OBS (out-of-office BP), and interfering drugs (NSAIDs, decongestants) before declaring resistance — failure to do this is the most commonly missed step.

Decision framework once a cause is suspected:

Determine urgency:

Priority causes by yield/reversibility (Step 3 ranking):

General BP target (ACC/AHA 2017): <130/80 mmHg for most adults; individualize for frail elderly, orthostasis-prone

Pharmacotherapy — First-Line Drug Regimen

— ACEi or ARB (e.g., lisinopril, losartan) — first-line in diabetes, CKD, proteinuria, HFrEF

— Dihydropyridine CCB (amlodipine) — especially in Black patients, elderly, ISH

— Thiazide-type diuretic: chlorthalidone or indapamide preferred over HCTZ (longer half-life, better outcomes); switch to loop diuretic if eGFR <30

— Primary aldosteronism (medical therapy or bilateral disease): spironolactone 25–100 mg/day; eplerenone if gynecomastia/sexual side effects; monitor K+ and Cr at 1–2 wks

— Pheochromocytoma preoperative prep: α-blockade first with phenoxybenzamine (non-selective, irreversible) or doxazosin/prazosin × 10–14 days; add β-blocker only AFTER adequate α-blockade to prevent unopposed α-mediated crisis; liberalize salt/fluids 2–3 days preop to expand volume

— Renovascular HTN (atherosclerotic): ACEi or ARB with close Cr/K monitoring — a Cr rise <30% is acceptable and indicates effective RAAS blockade; statin, antiplatelet, smoking cessation

— Cushing: treat cause; ketoconazole, metyrapone, osilodrostat, mifepristone, pasireotide as medical bridges

— Hyperthyroid: β-blockers + antithyroid therapy

— OSA: CPAP + standard HTN regimen; consider MRA add-on

— Coarctation: β-blockers preferred; avoid ACEi/ARB before repair if severe (risk of distal hypoperfusion)

— β-blocker monotherapy in pheo → hypertensive crisis

— ACEi/ARB in bilateral RAS or solitary kidney with RAS → AKI

— Non-DHP CCBs (verapamil/diltiazem) with β-blockers → bradycardia/heart block

Board pearl: In suspected pheo, labetalol is NOT adequate α-blockade for preop preparation despite its mixed properties (α:β ratio ~1:7 PO) — use phenoxybenzamine or selective α1-blockers first, then add β-blocker for reflex tachycardia.

Foundational triple therapy for HTN before declaring "resistant":

Cause-specific pharmacology:

Drugs to avoid or use cautiously:

Procedures / Revascularization / Invasive Management

— Atherosclerotic RAS: CORAL trial showed no benefit of stenting + medical therapy over medical therapy alone for stable patients → medical therapy is first-line

— Indications for percutaneous transluminal renal angioplasty (PTRA) ± stent:

— Recurrent flash pulmonary edema (Pickering syndrome)

— Rapidly declining renal function despite optimal medical therapy

— Refractory HTN on ≥4 agents including diuretic and MRA

— Hemodynamically significant stenosis (>70%) with translesional gradient

— FMD: PTRA without stent is preferred — high cure rate, especially in young patients with short HTN duration

— Unilateral adenoma confirmed by AVS → laparoscopic adrenalectomy (cure or improvement in BP/K in ~95%)

— Bilateral hyperplasia → lifelong MRA (spironolactone or eplerenone)

— Laparoscopic adrenalectomy after 10–14 days of α-blockade + volume expansion + β-blockade for tachycardia

— Intraoperative crises managed with nitroprusside, phentolamine, esmolol

— Postop: monitor for hypotension and hypoglycemia (sudden catecholamine withdrawal + rebound insulin)

— Surgical repair or endovascular stenting for peak gradient ≥20 mmHg or significant collaterals; lifelong follow-up for restenosis, aneurysm, residual HTN

— Repaired adults still have increased HTN, stroke, aortic events — continue surveillance

CCS pearl: For pheo, the CCS sequence is: biochemistry → imaging → α-blockade ×10–14 days → β-blockade (after α) → volume expansion → laparoscopic adrenalectomy → post-op glucose/BP monitoring → lifelong biochemical surveillance (10% recurrence/metastasis).

Renovascular HTN — when to revascularize:

Primary aldosteronism — surgical vs medical:

Pheochromocytoma:

Coarctation of the aorta:

OSA: CPAP is procedural mainstay; oral appliances, hypoglossal nerve stimulation, bariatric surgery as adjuncts

Cushing: transsphenoidal resection (pituitary), adrenalectomy, or tumor resection (ectopic)

Special Populations — Elderly and Renal/Hepatic Impairment

— Atherosclerotic RAS is the dominant renovascular etiology — consider in any older smoker with new resistant HTN, worsening renal function on ACEi/ARB, or asymmetric kidney sizes (>1.5 cm)

— Isolated systolic HTN is the norm; target SBP <130 mmHg (SPRINT) if tolerated, but individualize for frailty, falls, orthostasis

— Start low, go slow — initiate single agents at half-doses; reassess orthostatic vitals at every visit

— Pheochromocytoma may present atypically: isolated orthostatic hypotension, paroxysmal HTN, new-onset diabetes, or as an adrenal incidentaloma

— Cushing easily mistaken for "metabolic syndrome" — low threshold to screen if rapid weight gain + new diabetes + osteoporotic fracture

— ACEi/ARB remain first-line for proteinuric CKD; an acute Cr rise up to 30% within 2–4 weeks is acceptable and expected, signals appropriate RAAS blockade — do NOT stop the drug for this

— Greater Cr rise → suspect bilateral RAS or RAS in solitary kidney → imaging

— Switch from thiazide to loop diuretic when eGFR <30 (HCTZ loses efficacy)

— Hyperkalemia risk with ACEi/ARB + MRA + CKD: use patiromer or sodium zirconium rather than discontinuing RAAS blockade

— Aldosteronism workup in CKD: ARR can be falsely elevated due to suppressed renin; interpret cautiously

— Avoid/dose-reduce labetalol, propranolol, verapamil (extensive hepatic metabolism)

— Ketoconazole (Cushing) is contraindicated in significant hepatic disease — use metyrapone or osilodrostat

— Spironolactone safe but watch for hyperkalemia in cirrhotic patients on potassium-sparing regimens

Step 3 management: In an 80-year-old with resistant HTN, eGFR 28, and K+ 5.2, the move is switch HCTZ → chlorthalidone is not sufficient — use a loop diuretic (furosemide BID or torsemide), continue ACEi cautiously, and add amlodipine before adding spironolactone (which would worsen hyperkalemia).

Elderly considerations:

Chronic kidney disease:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, or Other Demographic Subgroups

— Avoid ACEi, ARB, direct renin inhibitors, spironolactone, MRAs — all teratogenic/fetotoxic

— Safe agents: labetalol, nifedipine ER, methyldopa; hydralazine for acute control

— Pheochromocytoma in pregnancy = high maternal/fetal mortality if undiagnosed; present as preeclampsia mimic but without proteinuria and with paroxysmal features; α-blockade with phenoxybenzamine, deliver before 24 wks via adrenalectomy or after 24 wks via planned C-section with adrenalectomy

— Primary aldosteronism in pregnancy: placental progesterone partially antagonizes aldosterone, so BP may improve; avoid spironolactone (anti-androgen to fetus); use eplerenone or amiloride if needed

— FMD with renovascular HTN is common in young women — control medically through pregnancy, defer angioplasty if possible

— <6 years: secondary HTN is the rule — almost always renal parenchymal disease, renovascular disease, or coarctation

— Adolescents: primary HTN rising with obesity, but still screen for OSA, structural disease

— Always check 4-extremity BPs in any child with HTN — coarctation is the classic miss

— Workup: renal US with Doppler, urinalysis, BMP, plasma renin/aldosterone, echocardiogram

— Black patients: higher prevalence of salt-sensitive HTN and primary aldosteronism; thiazide + CCB more effective than ACEi/ARB monotherapy; lower renin generally

— Young women with HTN + headaches: FMD; screen cervicocerebral arteries

— Post–kidney transplant: calcineurin inhibitor–induced HTN; CCBs are first-line (reduce CNI vasoconstriction)

— Patients on stimulants/cocaine: treat with CCBs, α/β-blockers (labetalol acceptable acutely); avoid pure β-blocker in cocaine intoxication (unopposed α)

Board pearl: A pregnant woman with paroxysmal HTN, headaches, and palpitations but NO proteinuria is pheochromocytoma until proven otherwise — measure plasma free metanephrines; missing this diagnosis carries maternal mortality up to 50% in older series.

Pregnancy:

Pediatrics:

Special demographics:

Complications and Adverse Outcomes

— Cardiac: LVH, diastolic dysfunction → HFpEF, atrial fibrillation, accelerated CAD, sudden death

— Cerebrovascular: ischemic and hemorrhagic stroke, lacunar infarcts, vascular dementia

— Renal: hypertensive nephrosclerosis, accelerated CKD progression, ESRD

— Retinal: hypertensive retinopathy (Keith-Wagener-Barker grades I–IV)

— Vascular: aortic dissection, aneurysm, peripheral arterial disease

— Primary aldosteronism: disproportionately high rates of AF, stroke, MI, LVH, CKD compared with primary HTN at same BP — driven by direct aldosterone toxicity on cardiovascular tissue

— Pheochromocytoma: hypertensive crisis, takotsubo or catecholamine cardiomyopathy, intraoperative hemodynamic collapse, multi-organ failure; malignant pheo/paraganglioma in 10–15%, especially SDHB mutations

— Renovascular HTN: ischemic nephropathy → progressive CKD; Pickering syndrome (recurrent flash pulmonary edema with bilateral RAS); AKI from ACEi/ARB in bilateral disease

— Cushing syndrome: diabetes, osteoporotic fractures, infections (immunosuppression), VTE, psychiatric comorbidity, infertility

— Coarctation: systemic HTN persisting despite repair, intracranial berry aneurysms (rupture risk), bicuspid aortic valve (50–80%), endocarditis, restenosis, aortic dissection

— OSA: AF, HF, pulmonary HTN, MVA risk, daytime cognitive impairment

— Postsurgical hypotension and hypoglycemia after pheo resection (catecholamine withdrawal)

— Postadrenalectomy adrenal insufficiency (especially Cushing) — bridge with glucocorticoids, taper over months

— Contrast-induced AKI during angiography in renovascular workup — hydrate and minimize contrast

— Atheroembolic disease after renal angioplasty (livedo, AKI, eosinophilia)

Board pearl: Aldosterone causes cardiovascular harm independent of BP. A patient with PA and BP "controlled" on amlodipine alone is still under-treated — they need MRA or adrenalectomy to address the aldosterone effect itself. This is a frequent Step 3 trap.

End-organ damage from prolonged uncontrolled HTN (any etiology):

Cause-specific complications:

Procedural/iatrogenic complications:

When to Escalate Care — ICU, Consult, or Inpatient Triage

— Hypertensive emergency (BP >180/120 + acute end-organ damage: encephalopathy, ACS, pulmonary edema, aortic dissection, AKI, eclampsia, papilledema) → ICU for IV antihypertensives (nicardipine, clevidipine, labetalol, esmolol, nitroprusside)

— Aortic dissection suspected → ICU; target SBP 100–120 and HR <60 with IV β-blocker first (esmolol/labetalol), then vasodilator

— Pheochromocytoma crisis → ICU; phentolamine IV or nicardipine; avoid pure β-blocker; volume expansion

— Flash pulmonary edema with suspected bilateral RAS → ICU; loop diuretics, nitrates, NIV; expedite vascular imaging

— Severe hypokalemia (<2.5) with arrhythmia in suspected aldosteronism → telemetry, IV K+

— Endocrinology: confirmed or strongly suspected aldosteronism, pheo, Cushing, acromegaly; complex AVS coordination

— Interventional radiology/vascular surgery: renovascular intervention candidates, FMD requiring angioplasty

— Cardiothoracic surgery: coarctation repair, aortic complications

— Sleep medicine: OSA confirmation and titration

— Nephrology: resistant HTN with CKD, hyperkalemia limiting RAAS therapy, suspected renal parenchymal disease

— Genetics: all pheo/paraganglioma patients; familial aldosteronism phenotypes (early stroke + HTN families)

— BP >180/120 + chest pain/dyspnea/neuro change → ED → ICU

— Resistant HTN, stable → outpatient stepwise workup

— New adrenal incidentaloma + HTN → urgent biochemical screen before any biopsy or imaging-guided intervention

CCS pearl: In a pheo crisis CCS case, the orderable sequence is IV access ×2, ICU bed, continuous BP/ECG, phentolamine or nicardipine IV, fluid bolus, then add esmolol for reflex tachycardia — never order propranolol or metoprolol first. Document why β-blockade is deferred for safety credit.

Inpatient/ICU triage criteria:

Specialist consultations:

CCS triage anchors:

Key Differentials — Same-Category Causes

— Atherosclerotic RAS (>90% of renovascular cases): older, smokers, diffuse atherosclerosis; ostial/proximal lesions; bilateral in 30%

— Fibromuscular dysplasia (FMD): young women (15–50); mid-to-distal renal artery, "string of beads"; treat with PTRA without stent

— Takayasu arteritis: young Asian women, systemic inflammation, pulse deficits, elevated ESR/CRP; involves aorta and branches

— Mid-aortic syndrome / segmental aortic hypoplasia: pediatric/young adult HTN with diminished lower-extremity pulses

— Renal artery dissection or embolism: acute flank pain + sudden HTN + AKI

— Primary aldosteronism subtypes:

— Aldosterone-producing adenoma (Conn) — surgically curable

— Bilateral idiopathic hyperplasia — medical management

— Familial hyperaldosteronism types I–IV (FH-I = glucocorticoid-remediable; suppressed by dexamethasone)

— Pheochromocytoma vs paraganglioma: intra-adrenal vs extra-adrenal (organ of Zuckerkandl, head/neck); paragangliomas more often SDHx-mutated and malignant

— Cushing subtypes: ACTH-dependent (pituitary adenoma = Cushing disease, ectopic ACTH from SCLC/bronchial carcinoid) vs ACTH-independent (adrenal adenoma/carcinoma, exogenous steroids — most common overall)

— Apparent mineralocorticoid excess: licorice ingestion (glycyrrhizin inhibits 11β-HSD2), Liddle syndrome (ENaC mutation — amiloride-responsive), AME syndrome — all have low aldosterone, low renin, hypokalemia

— Thyroid disease, hyperparathyroidism, acromegaly, congenital adrenal hyperplasia (11β- or 17α-hydroxylase deficiency)

— Coarctation of the aorta (juxtaductal classic)

— Interrupted aortic arch (pediatric)

— Pseudocoarctation, aortic kinking, Takayasu-related stenosis

Key distinction: PA has high aldosterone + low renin (high ARR); renovascular HTN has high renin AND high aldosterone (secondary hyperaldosteronism); Liddle/AME has low renin AND low aldosterone with hypokalemia — the renin–aldosterone pattern is the diagnostic compass.

Within renovascular:

Within endocrine:

Within structural:

Key Differentials — Other-Category Causes

— NSAIDs (including COX-2): blunt antihypertensives, retain Na+

— Oral contraceptives, estrogens: estrogen-induced angiotensinogen

— Sympathomimetics: pseudoephedrine, phenylephrine, decongestants, weight-loss agents, cocaine, amphetamines, MDMA

— Glucocorticoids, mineralocorticoids, anabolic steroids

— Calcineurin inhibitors (cyclosporine, tacrolimus), mTOR inhibitors

— VEGF inhibitors (bevacizumab, sunitinib, sorafenib): predictable dose-related HTN

— Erythropoiesis-stimulating agents

— MAOIs with tyramine-containing foods: hypertensive crisis

— Licorice (glycyrrhizin), chewing tobacco

— SNRIs (venlafaxine high-dose), bupropion

— Withdrawal: clonidine, β-blocker, alcohol → rebound HTN

— CKD of any etiology — diabetic, hypertensive, glomerulonephritides

— ADPKD: family history, palpable kidneys, cysts, intracranial aneurysms

— Obstructive uropathy, reflux nephropathy, post-AKI scarring

— Increased intracranial pressure (Cushing reflex: HTN + bradycardia + irregular respirations)

— Autonomic dysreflexia in spinal cord injury above T6 (triggered by bladder/bowel distention) — life-threatening; remove the trigger first

— Severe pain, anxiety, withdrawal — exclude before workup

Step 3 management: When a patient on bevacizumab for metastatic colon cancer develops new HTN, the answer is continue chemotherapy and treat with ACEi or DHP-CCB, not stop the drug. VEGF-induced HTN is dose-related and manageable; the cancer treatment usually wins the priority calculation.

Drug- and substance-induced HTN (commonly missed):

Renal parenchymal disease (most common secondary cause overall):

Neurologic/other:

Obstructive sleep apnea — the single most common reversible secondary cause; always ask about snoring

Pseudoresistance mimickers: white-coat HTN, nonadherence, undertreatment, inappropriate cuff size, pseudohypertension in calcified arteries (Osler sign)

Secondary Prevention / Discharge Medications / Long-Term Plan

— Primary aldosteronism post-adrenalectomy: monitor BP and K+ at 1, 3, 6, 12 months; many need fewer agents but only 30–50% achieve complete cure; continue lifestyle measures

— Bilateral PA: lifelong MRA — spironolactone (titrate to lowest effective dose) or eplerenone; check K+ and Cr at 1–2 weeks, then every 3–6 months

— Pheochromocytoma post-resection: lifelong annual biochemical surveillance (plasma or urinary metanephrines) — 10% recurrence/metastasis; genetic testing dictates additional cancer screening (RET → MTC, parathyroid; VHL → renal cell, hemangioblastoma; SDHx → paraganglioma surveillance)

— Renovascular post-revascularization: continue antiplatelet, statin, ACEi/ARB if tolerated, BP monitoring, duplex US at 1, 6, 12 months then annually for restenosis

— Cushing post-surgery: glucocorticoid replacement during HPA recovery (months to a year); osteoporosis screening (DEXA), diabetes control, mental health follow-up

— Coarctation repaired: lifelong cardiology follow-up; surveillance imaging q3–5 years; endocarditis prevention with bicuspid AV

— OSA: verify CPAP adherence (≥4 h/night, ≥70% of nights), repeat sleep study if BP or symptoms persist

— BP goal <130/80 (ACC/AHA)

— Statin per ASCVD risk; HTN itself is a risk modifier

— Aspirin only for high ASCVD risk after bleeding assessment; not routine primary prevention

— Smoking cessation, weight management, DASH diet, alcohol moderation, exercise 150 min/wk moderate

— Annual influenza, pneumococcal per ACIP, COVID updates

— Home BP monitoring with validated upper-arm cuff; teach correct technique

Board pearl: Patients with confirmed primary aldosteronism need lifelong MRA therapy or unilateral adrenalectomy — never simply "treat the BP" with an ACEi/ARB and walk away. The cardiovascular event rate stays elevated until aldosterone-specific therapy is in place.

After cause-specific treatment, long-term goals:

Standard cardiovascular secondary prevention layered on top:

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— Visit or telehealth every 2–4 weeks until BP at goal

— After ACEi/ARB or MRA initiation: BMP at 1–2 weeks to assess K+ and Cr

— Home BP log: AM and PM readings, at least 7 days/month, discard day 1, average remaining

— Visits every 3–6 months; annual labs (BMP, lipid, HbA1c, UACR) and ECG as indicated

— Reassess medication adherence at every visit (pill counts, pharmacy refill data)

— Repeat 24-h ambulatory BP if discordance between home and clinic readings

— PA on MRA: K+ every 3–6 months; rising renin suggests adequate dose

— Pheo postop: plasma metanephrines at 2–6 weeks postop, then annually for life

— Renovascular post-stent: renal duplex at 1, 6, 12 months, then annually

— Cushing postop: AM cortisol and ACTH; assess HPA recovery

— OSA on CPAP: download adherence data at every visit; repeat PSG if symptoms recur

— Coarctation: lifelong cardiology, imaging q3–5 years

— DASH diet — fruits, vegetables, whole grains, low-fat dairy; Na+ <1.5–2.3 g/day

— Weight loss: ~1 mmHg SBP reduction per kg lost

— Alcohol ≤2 drinks/day men, ≤1 women

— Exercise 90–150 min/wk aerobic + 2–3 days resistance

— Stress reduction, sleep hygiene — 7–9 h, treat OSA

— Drug interaction education: NSAIDs, decongestants, herbals

— Cardiac rehab if comorbid CAD/HF

— Screen for depression and anxiety (PHQ-9, GAD-7) — bidirectional with HTN control

Step 3 management: Home BP monitoring is now a Step 3 expected order — when given options, choose "initiate validated upper-arm home BP monitoring with twice-daily readings" over repeating clinic BP for diagnostic clarification or titration follow-up.

Initial titration phase (weeks 0–8):

Maintenance phase (once at goal):

Cause-specific surveillance:

Patient counseling and lifestyle:

Cardiac rehab and behavioral health:

Ethical, Legal, and Patient Safety Considerations

— Adrenal biopsy in unrecognized pheochromocytoma is a sentinel safety event — institutional policy mandates biochemical exclusion of pheo before any adrenal mass biopsy, even when imaging suggests something else

— Genetic testing for pheo/paraganglioma syndromes requires pre-test counseling on implications for the patient and at-risk relatives (insurance, life planning, cascade testing) — document discussion of GINA protections and limits

— Discharge of a patient with newly diagnosed PA on spironolactone without scheduled K+/Cr labs at 1–2 weeks is a patient-safety failure — order labs at discharge with explicit follow-up appointment

— Post-pheo adrenalectomy hypotension and hypoglycemia require explicit handoff: standing orders for hourly BP, finger-stick glucose, IV fluids on the floor

— Patients discharged on CPAP without confirmed setup and adherence support frequently fall off therapy — coordinate with DME provider and schedule a 30-day check

— Combining ACEi + ARB is contraindicated (ONTARGET) — no added benefit, increased AKI/hyperkalemia

— MRA + ACEi/ARB + NSAID in CKD = high-risk hyperkalemia trio; reconcile carefully

— Avoid β-blocker without prior α-blockade in pheo — explicitly document the reasoning in the chart

— Resistant HTN is disproportionately diagnosed in Black patients; access to AVS, specialist endocrine care, sleep studies varies — advocate, refer, leverage telehealth

— Cost considerations: chlorthalidone, lisinopril, amlodipine, spironolactone are all generic and inexpensive — preferred when equivalent

— Untreated severe OSA with daytime sleepiness in commercial drivers: counsel patient, document advice not to drive heavy vehicles until treated; reporting laws vary by state — know your state's requirements

— Workplace safety in patients with paroxysmal pheo symptoms operating machinery

CCS pearl: Always order scheduled outpatient labs and a follow-up appointment with a specific date as part of discharge from any HTN admission — Step 3 CCS rewards explicit transition-of-care orders, not just "follow up in clinic."

Informed consent edge cases:

Transitions of care risks:

Polypharmacy and prescribing safety:

Health equity and access:

Mandatory reporting and driver safety:

High-Yield Associations and Rapid-Fire Clinical Facts

— MEN2A: RET → medullary thyroid CA + pheo + primary hyperparathyroidism

— MEN2B: RET → MTC + pheo + mucosal neuromas + marfanoid habitus

— VHL: hemangioblastomas, RCC, pheo, pancreatic NETs

— NF1: café-au-lait, neurofibromas, optic glioma, pheo (~5%), renal artery stenosis

— SDHB/SDHD: familial paraganglioma; SDHB → highest malignancy risk

— Familial hyperaldosteronism type I (glucocorticoid-remediable): chimeric CYP11B1/B2 gene; dexamethasone suppression of aldosterone confirms; early stroke history

— Liddle syndrome: ENaC gain-of-function; low aldo + low renin + hypokalemic alkalosis; amiloride/triamterene responsive, NOT spironolactone

— ARR positive: aldo >10 + ratio >20

— Renal artery PSV >200 cm/s suggests significant stenosis

— Cr rise <30% after ACEi initiation is acceptable

— Arm–leg BP gradient >20 mmHg = coarctation

— Pheo: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial (older rule; familial closer to 40%)

— "3 sign" on CXR: coarctation

— "String of beads": FMD

— T2 hyperintense adrenal mass ("light bulb sign"): pheo

— Rib notching: coarctation collaterals

— β-blocker alone in pheo → hypertensive crisis

— ACEi in bilateral RAS → AKI

— Spironolactone gynecomastia → switch to eplerenone

— Hydrochlorothiazide loses efficacy when eGFR <30 → use loop or chlorthalidone

— Clonidine abrupt stop → rebound HTN; taper or switch

— DASH: −8 to −14 mmHg SBP

— Weight loss: −1 mmHg per kg

— Na+ restriction: −2 to −8 mmHg

— Exercise: −4 to −9 mmHg

— Alcohol moderation: −2 to −4 mmHg

Board pearl: "Young woman + HTN + bruit" = FMD; "older smoker + flash pulmonary edema" = bilateral atherosclerotic RAS; "spontaneous hypokalemia + HTN" = primary aldosteronism; "paroxysmal HTN + headache + sweating" = pheo. Pattern recognition wins the section.

Syndromic pheo/paraganglioma:

Aldosteronism associations:

Numbers worth knowing:

Imaging signs:

Pharmacology trip-wires:

Lifestyle effect sizes (DASH/JNC):

Board Question Stem Patterns

Step 3 management: When the stem hints at multiple possible causes, the first move is almost always a noninvasive biochemical or imaging screen targeted to the strongest clue, not empiric therapy escalation or invasive testing.

Stem 1 — The hypokalemic patient: 45-year-old with BP 168/102 on three meds, K+ 3.0, HCO3 30, on no diuretic. Best next step: plasma aldosterone/renin ratio (after K+ replacement). Distractor: ordering adrenal CT first (biochemistry before imaging).

Stem 2 — Flash pulmonary edema in an older smoker: 72-year-old with recurrent acute pulmonary edema, preserved EF, BP 200/100, asymmetric kidneys on prior imaging. Best next step: renal duplex ultrasound. Best management: PTRA with stenting (one of CORAL's exceptions). Distractor: continue medical therapy alone.

Stem 3 — Young woman with refractory HTN: 32-year-old with headaches, pulsatile tinnitus, abdominal bruit, BP 158/96 on two agents. Best next step: CTA or MRA renal arteries. Best treatment: PTRA without stent (FMD).

Stem 4 — Paroxysmal episodes: 38-year-old with episodic palpitations, sweating, headaches; BP 220/120 during an episode, normal between. Best initial test: plasma free metanephrines. Pre-op: phenoxybenzamine ×10–14 days before β-blocker.

Stem 5 — Adrenal incidentaloma: 5-cm adrenal mass found on CT, patient hypertensive. Best next step: biochemical workup (metanephrines, ARR, dexamethasone suppression) BEFORE biopsy or surgery.

Stem 6 — Resistant HTN with normal K+: BP 156/94 on lisinopril, amlodipine, HCTZ. Best next step: add spironolactone (PATHWAY-2). Distractor: add β-blocker.

Stem 7 — Adolescent with HTN: 16-year-old with arm BP 160/95, weak femoral pulses, systolic murmur over back. Best next step: 4-extremity BPs and echocardiogram; then CTA aorta. Diagnosis: coarctation.

Stem 8 — New HTN on bevacizumab: Continue cancer therapy, treat with ACEi or DHP-CCB.

Stem 9 — Cr rise after starting ACEi: Cr 1.2 → 1.4 (17% increase). Best step: continue ACEi, recheck in 1–2 weeks. If rise >30% or bilateral asymmetry — image for bilateral RAS.

Stem 10 — Snoring obese man with resistant HTN: STOP-BANG high. Best next step: polysomnography → CPAP.

One-Line Recap

The single teaching point: In secondary hypertension, the winning strategy is pattern recognition → targeted biochemical screening → confirmatory imaging or testing → cause-specific therapy, all built on top of a verified, optimized first-line three-drug regimen.

Board pearl: If you remember nothing else, remember that aldosterone is cardiovascularly toxic independent of BP — so confirming and specifically treating primary aldosteronism (with MRA or adrenalectomy) is one of the highest-impact moves you can make for any patient with resistant hypertension.

Triggers to screen: resistant HTN, onset <30 or >55, spontaneous hypokalemia, paroxysmal symptoms, end-organ damage out of proportion to BP, abdominal/cervical bruits, asymmetric kidneys, drug-induced patterns — these are the stems' tells.

Order of operations: confirm true resistance (home BP, adherence, regimen optimization, NSAID/decongestant review) → biochemistry before imaging (ARR, plasma metanephrines, dexamethasone suppression, TSH) → imaging when biochemistry is positive (CTA/MRA, adrenal CT, renal duplex, echo, sleep study) → AVS or genetic testing when lateralization or syndromic suspicion exists → cause-specific definitive therapy (adrenalectomy, PTRA, CPAP, MRA, coarctation repair) → lifelong surveillance.

The five reversible big wins: OSA, primary aldosteronism, renovascular HTN (selected cases), pheochromocytoma, and drug/substance-induced HTN — these are where Step 3 stems live.

Safety non-negotiables: never give β-blocker before α-blocker in pheo; never biopsy an adrenal mass without excluding pheo biochemically; never combine ACEi + ARB; never use HCTZ when eGFR <30; never miss 4-extremity BPs in a young hypertensive; and never discharge a patient on a new MRA without scheduled K+/Cr follow-up labs.