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Systemic and Pulmonary Hypertension

SYSTEMIC HYPERTENSION

Definition and Global Burden

• 45% of stroke deaths
• 49% of ischaemic heart disease deaths
• 17% of all global deaths

Epidemiology

• Hypertension is the most common cardiovascular risk factor in older adults, with prevalence ~70% in those aged ≥75 years
• It has the greatest population-attributable risk for CHD, cerebrovascular disease, and peripheral arterial disease
• Over 70% of older adults presenting with MI, stroke, acute aortic syndromes, or heart failure have pre-existing hypertension
• Hypertension is the most prevalent antecedent of heart failure, especially HFpEF, and of chronic kidney disease
• After age 70, isolated systolic hypertension (ISH) accounts for >90% of all hypertension cases

Risk Factors and Associations

• High-sodium diet
• Low physical activity
• Low fruit and vegetable intake
• Obesity
• Excessive alcohol use
• Socioeconomic factors (in high-SDI countries, lower socioeconomic groups and younger individuals are most likely to be untreated)

Key Landmark Trials

Management

• Aerobic exercise
• Reduced body weight
• Reduced sodium and alcohol intake
• Stress reduction and smoking cessation
• DASH diet (Dietary Approaches to Stop Hypertension)

1. Diuretics (thiazides/thiazide-like, e.g., indapamide)
2. ACE inhibitors (ACEI)
3. Angiotensin receptor blockers (ARB)
4. Calcium channel blockers (CCB)

• ~Two-thirds of older adults require 2 or more drugs to reach target BP
• Combination therapy allows lower individual doses, reduced side effects, additive organ protection
• In the elderly: start low, go slow; check standing BP (orthostatic hypotension risk)
• In CHD patients: avoid excessive lowering of DBP below 60-65 mmHg (impairs coronary flow)

• Post-cardiac transplant: CCBs and ACEIs commonly used; calcineurin inhibitor (CNI) use leads to refractory hypertension in 92% within 5 years
• Chronic kidney disease is worsened by CNI-mediated nephrotoxicity; target BP control is especially important

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PULMONARY HYPERTENSION

Definition

• Isolated post-capillary PH: mPAP ≥25, PAWP >15, PVR ≤3 WU (passive pulmonary venous congestion)
• Combined pre- and post-capillary PH: mPAP ≥25, PAWP >15, PVR >3 WU (structural arterial remodeling superimposed)
• Pre-capillary (PAH): mPAP ≥25, PAWP ≤15, PVR >3 WU

WHO Clinical Classification (5 Groups)

Group 1: Pulmonary Arterial Hypertension (PAH)

Epidemiology and Natural History

• Prevalence: approximately 15-52 per million population
• Incidence: 2.4-7.1 cases per million per year
• Female:male ratio ~1.7:1 (though men present with more severe disease, especially before age 45)
• NIH registry (pre-treatment era): 1-, 3-, 5-year survival - 68%, 48%, 34% respectively
• Modern era (multi-drug therapy): 3-year survival now approaches 84%

Subtypes of PAH

• BMPR2 variant most common genetic risk factor - found in 70% of familial PAH and 10% of sporadic iPAH
• BMPR2 causes: PA smooth muscle cell proliferation, endothelial dysfunction, apoptosis-resistance, dysregulated cellular metabolism
• Other genes: ACVRL1, ENG (associated with hereditary haemorrhagic telangiectasia), EIF2AK4 (PVOD)

• Most common CTD-associated PAH
• Prevalence: at least 24 per million; affects 12-20% of SSc patients
• Leading cause of death in SSc, mortality 4x greater than iPAH
• RV dysfunction occurs at much lower afterload due to intrinsic RV cardiomyocyte fibrosis

• Schistosomiasis: most common cause of pre-capillary PH in developing countries (200-300 million infected worldwide); eggs transported to pulmonary vasculature causing granulomatous remodeling
• HIV: 0.46% of consecutive HIV+ patients have PAH by RHC; viral load >500 copies/mL and CD4 <200 cells/μL increase risk

Pathology

• Hypertrophic concentric muscularisation
• Fibrotic and microthrombotic effacement of distal pulmonary arterioles
• Plexogenic vasculopathy (pathognomonic for PAH): focal dense lesions with endothelial proliferation, microchannel networks, irregular SMC orientation in glomeruoid pattern - seen in iPAH, certain CHD-PAH, HIV-PAH, Schistosomiasis-PAH
• PVOD: obliteration of small pulmonary veins by sclerotic/fibrous thickening; biallelic EIF2AK4 mutation
• CTEPH: organised clot with heavily fibrotic intimal/medial lesions; webbing, dearborisation, collateralisation

Pathobiology

• Pulmonary artery endothelial cells, smooth muscle cells, pericytes, and adventitial fibroblasts

• Warburg effect: preferential lactic acid synthesis even under oxygen-rich conditions
• Apoptosis-resistance in SMCs
• Post-transcriptional regulation of pro-fibrotic proteins
• Epigenetic events
• T-cell (Treg cell) dysfunctional self-tolerance

Systemic Manifestations of PH

• Renal failure (acute or chronic exacerbation)
• Leaky bowel syndrome (gut oedema)
• Volitional muscle atrophy including diaphragmatic weakness
• Cognitive impairment
• Hepatic congestion from elevated right atrial pressure
• Neurohumoral overactivation: elevated catecholamines, secondary hyperaldosteronism
• Depression, diabetes mellitus, metabolic syndrome as tertiary consequences
• Thrombocytopenia in ~20% of PAH patients
• Thyroid dysfunction in ~25% of iPAH

Clinical Presentation

• Dyspnoea on exertion (most common)
• Fatigue, weakness
• Abdominal distension, lower limb oedema
• Bendopnea (dyspnoea on bending)
• Syncope, chest pain - high-risk presentations indicating PAH emergency (severely impaired CO or RV ischaemia)

• Loud or paradoxical P2 (accentuated pulmonic closure)
• Right-sided S3
• RV heave/lift
• ↑ Jugular venous pressure
• Pulsatile liver
• Cor pulmonale (end-stage): systemic hypotension, cool extremities, mental status changes

PAH vs. PVOD - Key Distinguishing Features

Management of PAH

Supportive Care

• Loop diuretics: attenuate pulmonary vascular congestion
• Supplemental oxygen: reduces hypoxic pulmonary vasoconstriction
• Potassium-sparing diuretics (spironolactone, eplerenone): ~1/3 of trial patients; inhibit aldosterone-mediated pulmonary vascular injury
• Digoxin: increases CO ~10% in RV failure; attenuates adverse catecholamine effects
• Vaccination: influenza and pneumococcal (recommended, though not evidence-based in PAH specifically)
• Anticoagulation: no longer recommended routinely

Exercise

High-Risk / Emergency: Parenteral Prostacyclin

• NYHA FC IV
• Cardiogenic shock (signs of impaired perfusion, cardiac index <2.1 L/min/m²)
• Syncope
• Chest pain (RV ischaemia or LMCA compression)

Initial Treatment of Treatment-Naïve PAH

• Ambrisentan (selective endothelin receptor type-A antagonist) + Tadalafil (PDE-5 inhibitor) vs. monotherapy
• At median 517 days: composite endpoint (death, hospitalisation, disease progression) occurred in:
  • 18% - combination
  • 34% - ambrisentan monotherapy
  • 28% - tadalafil monotherapy
• 50% relative risk reduction with combination therapy

1. Endothelin receptor antagonists (ERA): ambrisentan, bosentan, macitentan
2. PDE-5 inhibitors: sildenafil, tadalafil
3. Prostacyclin pathway: epoprostenol (IV), iloprost (inhaled), selexipag (oral)

Therapeutic Escalation and End-Stage Disease

• Low threshold to escalate (dose uptitration or sequential addition of new drug class) in progression or failure
• Referral for bilateral lung transplant when suboptimal response to therapy
  • 5-year post-transplant survival: up to 75% in PAH (improving)
  • Limited by donor lung availability
• Bridging measures: RV assist device, VA-ECMO
• Balloon atrial septostomy / percutaneous Potts shunt: palliative right-to-left shunt for non-transplant candidates

Genetic Counselling

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Summary Comparison

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Note on "Oxford" textbook: The medical library does not contain an Oxford title (e.g., Oxford Handbook of Clinical Medicine, Oxford Textbook of Cardiology). The content above is sourced from Braunwald's Heart Disease - widely considered the most comprehensive cardiology reference available. If you meant a specific Oxford publication, please let me know and I can search further.

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Hypertension Management - Malaysian CPG (5th Edition 2018 / 6th Edition 2026)

Note on editions: The publicly available edition is the 5th Edition (2018), published by the Malaysian Society of Hypertension and MOH Malaysia. A 6th Edition (2026) has been referenced in the 2026 ACS CPG but is not yet fully in the public domain. The content below reflects the 5th Edition with key updates noted.

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1. Definition

• SBP 120-139 and/or DBP 85-89 mmHg - should be treated in certain high-risk groups

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2. Classification of Blood Pressure

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3. Epidemiology in Malaysia

• Prevalence of hypertension in Malaysians aged ≥18 years: 35.3% (NHMS 2015), up from 33.6% in 2011
• For every 2 diagnosed patients, there are 3 undiagnosed patients (unchanged since 2011)
• Only 44.6% of treated patients achieved BP control in 2015 (improved from 34.7% in 2011)
• Hypertension is largely a silent disease - BP must be measured at every chance encounter

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4. Initial Assessment

Baseline Investigations

• Urine analysis (protein, blood, glucose)
• Serum electrolytes, urea, creatinine
• Fasting blood glucose
• Lipid profile (total cholesterol, HDL, LDL, TG)
• ECG
• Fundoscopy (for target organ damage)

Secondary Causes to Exclude

Target Organ Damage (TOD) / Complication (TOC)

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5. Cardiovascular Risk Stratification

• Smoking
• Total cholesterol >6.5 mmol/L
• Family history of premature CVD
• TOD/TOC
• Diabetes mellitus
• Previous MI, stroke, or clinical atherosclerosis

Key principle: Treatment decisions should be based on global vascular risk, NOT on the level of BP alone.

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6. Blood Pressure Treatment Targets

Once target BP is achieved: follow up at 3-6 month intervals

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7. Non-Pharmacological Management (All Patients)

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8. Pharmacological Management

Principle

Decisions on pharmacological treatment should be based on global vascular risks, NOT on the level of BP per se.

• Stage 1 HTN with no TOD/TOC: allow 3-6 months of lifestyle modification, review 2-monthly
• Stage 1 HTN with TOD or ≥1 risk factor: earlier drug initiation
• Stage 2 HTN: initiate with combination of ≥2 drugs from the outset

First-Line Drug Classes (5th Edition 2018)

1. ACE Inhibitors (ACEIs)
2. Angiotensin Receptor Blockers (ARBs)
3. Calcium Channel Blockers (CCBs)
4. Diuretics (thiazides / thiazide-like, e.g., hydrochlorothiazide, indapamide)
5. Beta-blockers (re-included in 5th Ed based on newer meta-analyses; particularly effective in patients <60 years)

Beta-blockers were reinstated as first-line options in 2018 (had been removed from the 4th Edition)

Effective Antihypertensive Combinations

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9. Compelling Indications - Drug Choice

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10. Treatment Algorithm

ALL HYPERTENSIVE PATIENTS
        ↓
Lifestyle modification + Investigate for secondary causes + Assess CV risk
        ↓
     Stage 1                              Stage 2
  (140-159/90-99)                      (≥160/100)
        ↓                                    ↓
  LOW risk: 3-6 months               Start ≥2 drugs immediately
  lifestyle modification              (ACEI/ARB + CCB or diuretic)
        ↓
  Still uncontrolled or
  MEDIUM/HIGH/VERY HIGH risk:
  Start monotherapy
  (ACEI / ARB / CCB / Diuretic / Beta-blocker)
        ↓
  Not at target on monotherapy:
  Add a 2nd drug (combination therapy)
        ↓
  Not at target on 2 drugs:
  Add a 3rd drug
        ↓
  BP still >140/90 on ≥3 drugs (including diuretic) at optimal doses
  → RESISTANT HYPERTENSION

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11. Resistant Hypertension

Before labelling as resistant, exclude:

• Medication non-compliance (most common cause)
• White coat / isolated office hypertension (ABPM or home BP monitoring)
• Pseudo-resistance (incorrect BP measurement technique)

True resistant HTN - investigate for:

• Secondary hypertension (primary aldosteronism, renovascular disease, phaeochromocytoma)
• Excessive sodium intake
• Alcohol
• Drug interactions (NSAIDs, sympathomimetics, oral contraceptives, liquorice)
• CKD / nephrosclerosis
• Loss of aortic distensibility

Management of Resistant HTN:

• Add spironolactone (25-50 mg/day) - most evidence for add-on therapy
• Consider alpha-blocker (doxazosin) or centrally acting agent (clonidine, methyldopa)
• Refer to specialist
• Consider device-based therapy (renal denervation) in selected cases

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12. Special Populations

Elderly (≥60 years)

• Target: <140/90 mmHg (not <130/80 unless diabetic/CKD)
• Start with low dose; titrate slowly
• Beware orthostatic hypotension - check standing BP
• Prefer long-acting agents once daily
• Isolated systolic HTN: thiazide diuretic or long-acting dihydropyridine CCB

Diabetes Mellitus

• Target: <130/80 mmHg
• First choice: ACEI or ARB (renoprotective, reduce microalbuminuria)
• Avoid thiazide diuretics in high doses (worsen glucose tolerance)
• Avoid beta-blockers in brittle T1DM (mask hypoglycaemic symptoms)

Chronic Kidney Disease (CKD)

• Target: <130/80 mmHg (especially with proteinuria)
• First choice: ACEI or ARB
• Monitor K+ and creatinine closely (especially if eGFR <45)
• Avoid ACEI + ARB combination (dual RAAS blockade)

Hypertension in Pregnancy

• Gestational HTN / pre-eclampsia: target <150/100 mmHg
• Severe HTN (≥170/110): IV labetalol or IV hydralazine acutely; oral labetalol, methyldopa, or nifedipine for maintenance
• Contraindicated in pregnancy: ACEIs, ARBs, direct renin inhibitors

Hypertensive Urgency and Emergency

• IV labetalol
• IV hydralazine
• IV nitroprusside (aortic dissection, hypertensive encephalopathy)
• IV glyceryl trinitrate (GTN) - acute pulmonary oedema, ACS

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13. Key Malaysian-Specific Notes

• 6th Edition CPG (2026) is now the current reference (cited in ACS CPG 2026) but not yet publicly downloadable; likely contains updated BP targets aligned with contemporary evidence
• The 5th Edition CPG full document is available from the Academy of Medicine of Malaysia
• The Malaysian CPG aligns more closely with ESC/ESH 2018 guidelines (HTN threshold ≥140/90) rather than the stricter ACC/AHA 2017 threshold (≥130/80) for the general population ≥60 years without comorbidity
• Control rates in Malaysia remain suboptimal - only 44.6% of treated patients achieved target BP (2015 data), underscoring the importance of combination therapy and adherence

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• BP classification from normal to Stage 3
• Treatment decision flowchart split by stage and CV risk
• BP targets by patient group (<140/90 uncomplicated; <130/80 for DM/CVD/CKD/HF)
• First-line drug classes (ACEI, ARB, CCB, Diuretic, Beta-blocker)
• Compelling indications matched to preferred agents
• Preferred drug combinations and what to avoid (ACEI + ARB)
• Hypertensive emergency management pathway
• The key principle: "Treat based on global CV risk, not BP level alone"