What are the different phenotypes of hypertension?

Phenotypes of Hypertension

Hypertension manifests in distinct clinical phenotypes that differ by blood pressure pattern, underlying hemodynamic mechanisms, measurement context, and secondary causes—each requiring tailored diagnostic and therapeutic approaches.

Primary Classification Systems

1. Blood Pressure Pattern Phenotypes

The most clinically relevant classification distinguishes hypertension by which blood pressure component is elevated 1, 2:

• Isolated Systolic Hypertension (ISH): SBP ≥130-140 mmHg with normal DBP

  • Most common in older adults (>60 years) due to arterial stiffening
  • Characterized by elevated aortic pulse wave velocity and peripheral vascular resistance (PVR)
  • Affects men and women equally in older age (~1:1 ratio)
  • In younger men (<30 years), ISH presents differently with elevated cardiac output and stroke volume rather than increased vascular resistance 3

• Isolated Diastolic Hypertension (IDH): Elevated DBP with normal SBP

  • More common in younger females
  • Associated with increased PVR without elevated arterial stiffness
  • Despite lowest mean age, carries the greatest likelihood of metabolic syndrome among hypertensive subtypes 4
  • Represents 25.3% of hypertensive patients with metabolic syndrome 4

• Systolic-Diastolic Hypertension (SDH): Both SBP and DBP elevated

  • Most common phenotype in middle-aged adults (30-60 years)
  • Characterized by elevated PVR in both sexes
  • In younger females, also shows elevated aortic pulse wave velocity 3

2. Office vs. Out-of-Office BP Phenotypes

These phenotypes are critical for avoiding inappropriate treatment or missing true hypertension 1, 2:

• White-Coat Hypertension (WCH): Office BP ≥130/80 mmHg but normal out-of-office BP

  • Prevalence low when office BP ≥160/100 mmHg
  • Associated with no risk to moderately increased CVD risk, primarily in older adults with high baseline risk
  • Important caveat: Among those on antihypertensive medication, WCH shows significantly increased risk of cerebral microbleeds (adjusted OR 6.75) 5
  • Requires exclusion via ABPM or home BP monitoring before initiating treatment (except when office BP ≥160/100 mmHg) 1

• Masked Hypertension (MH): Normal office BP but elevated out-of-office BP

  • Higher CVD risk than sustained normotension
  • Associated with subclinical cerebrovascular disease, particularly microbleeds 5
  • Requires high index of suspicion and out-of-office BP confirmation

• White-Coat Effect: Elevated office BP in treated patients with controlled out-of-office BP

  • HBPM preferred over ABPM for detection in treated patients 1

• Masked Uncontrolled Hypertension: Controlled office BP but uncontrolled out-of-office BP in treated patients

  • Requires HBPM for detection and management adjustment

3. Hemodynamic Phenotypes

Based on cardiac output (CO) and systemic vascular resistance (SVR), hypertension divides into distinct patterns 6:

Among patients with SBP 140-159 mmHg:

• High SVR/Normal-Low CO phenotype: 70% of cases—characterized by increased peripheral resistance
• High CO/Normal-Low SVR phenotype: 15% of cases—driven by increased cardiac output
• Normal-Low CO and SVR phenotype: 15% of cases—mixed or indeterminate mechanisms

Clinical implication: Age and body mass index negatively correlate with the CO/SVR ratio, though these factors explain only weak variation (R-square 0.09-0.16), suggesting phenotype-specific therapy targeting the primary hemodynamic abnormality could improve outcomes 6.

4. Resistant Hypertension Phenotypes

Resistant hypertension is defined as BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic 7.

Critical distinction: Approximately 50% have pseudoresistance rather than true resistant hypertension 7. Before pursuing extensive workup, exclude:

• Poor BP measurement technique
• White-coat effect (use out-of-office monitoring)
• Medication nonadherence
• Suboptimal drug choices or dosing
• Substance/drug-induced hypertension

True resistant hypertension affects ~10% of hypertensive individuals and increases risk of coronary disease, heart failure, stroke, end-stage renal disease, and mortality 7.

5. Secondary Hypertension Phenotypes

Identifiable in 5-10% of hypertensive patients 7. Most common types:

• Renal parenchymal disease: Most common secondary cause 8
• Renovascular hypertension: ~2% prevalence 8
• Primary aldosteronism
• Chronic sleep apnea: Moderate (AHI 15-30) and severe (AHI >30) require CPAP, which improves BP control 2
• Drug/substance-induced: Including anticancer drugs (80-90% with VEGF inhibitors), NSAIDs, corticosteroids, oral contraceptives 2

Screen for secondary causes when 7:

• Early onset (<30 years) without risk factors
• Resistant hypertension (after excluding pseudoresistance)
• Sudden deterioration in BP control
• Hypertensive urgency/emergency
• Strong clinical clues on history/exam

6. Ethnic/Environmental Phenotypes

African populations demonstrate distinct phenotypes 9:

• Greater prevalence of low-renin, salt-sensitive hypertension
• Lower plasma renin regardless of geographic location
• However, Africans living in Europe show higher aldosterone (466 vs. 259 pmol/L) and greater left ventricular mass index (103 vs. 89 g/m²) compared to those in Africa, despite similar low-renin state
• This suggests environmental factors (possibly higher potassium intake or other exposures) contribute significantly to cardiac remodeling beyond genetic predisposition

7. Heart Failure-Related Hypertension Phenotypes

The 2023 Canadian guidelines identify specific HF phenotypes requiring tailored approaches 10:

• Wet hypertensive HF: Easiest to manage; elevated SBP allows broader treatment options; decongestion performed alongside guideline-directed medical therapy
• De novo HF: Requires introduction of 4 pillars of GDMT, personalizing order based on individual characteristics
• Worsening HF: Marker of poor prognosis; motivates GDMT optimization and consideration of advanced therapies
• Cardiorenal phenotype: Requires correct volume assessment; renal function usually improves with decongestion
• Frail/hypotensive HF: Requires careful drug titration and cardiac rehabilitation consideration

Clinical Approach Algorithm

1. Confirm diagnosis: Use proper BP measurement technique; obtain out-of-office BP (ABPM or HBPM) to exclude white-coat hypertension or detect masked hypertension

2. Identify BP pattern: Determine if ISH, IDH, or SDH based on age, sex, and hemodynamic context

3. Assess for secondary causes: Screen based on age of onset, severity, resistance to treatment, and clinical clues (basic labs: sodium, potassium, eGFR, TSH, urinalysis)

4. Evaluate hemodynamic profile: Consider impedance cardiography when available to determine if high CO vs. high SVR predominates

5. Screen for complications: Assess for subclinical organ damage (ECG, echocardiography for LVH, renal function, fundoscopy) and metabolic syndrome components

6. Tailor therapy: Match treatment to predominant mechanism (e.g., diuretics/ACE inhibitors for high SVR phenotype; beta-blockers for high CO phenotype; spironolactone for resistant hypertension with K+ <4.5 mmol/L and eGFR >45) 7

Key Pitfalls to Avoid

• Do not treat white-coat hypertension without confirmation via out-of-office monitoring, except when office BP ≥160/100 mmHg requires immediate treatment 1
• Do not miss masked hypertension in patients with normal office BP but high CVD risk or target organ damage
• Do not pursue extensive secondary hypertension workup in resistant hypertension before excluding pseudoresistance 7
• Do not assume all hypertension in young patients is essential—screen for secondary causes, especially in those <30 years without risk factors 7
• Do not overlook drug-induced hypertension, particularly in patients on anticancer therapy, NSAIDs, or corticosteroids 2