Cardiovascular Valvular Heart Disease: Infectious and Non-Infectious - A Comprehensive Review

OVERVIEW

PART I: INFECTIOUS VALVULAR DISEASE

1. Infective Endocarditis (IE)

Definition and Classification

• Acute IE: Rapidly progressive, destructive infections with substantial morbidity and mortality even with appropriate therapy
• Subacute IE: Insidious onset; protracted course over weeks to months; most patients recover with antibiotic therapy

Epidemiology and Risk Factors

• Rheumatic heart disease
• Mitral valve prolapse (now the leading preexistent risk factor in developed countries)
• Bicuspid aortic valves
• Calcific valvular stenosis
• Prosthetic heart valves - account for 10-20% of all IE cases
• Sterile platelet-fibrin deposits at pacemaker lines, indwelling catheters, or endocardial damage from flow "jets"

Causative Organisms

Pathogenesis

Morphology (Gross and Microscopic)

• Aortic and mitral valves most commonly affected
• Vegetations may be single or multiple, and may involve more than one valve
• Can erode into myocardium to produce ring abscess (abscess cavity)
• Shedding of septic emboli is common - leads to septic infarcts and mycotic aneurysms at embolization sites

Clinical Features

• Fever - the most consistent sign
• In subacute IE (especially elderly): nonspecific fatigue, weight loss, flu-like syndrome; splenomegaly common
• Acute IE: rapidly developing fever, chills, lassitude
• Murmurs present in 90% of left-sided lesions
• Peripheral stigmata (from microemboli):
  • Petechiae
  • Nail bed (splinter) hemorrhages
  • Roth spots - retinal hemorrhages
  • Janeway lesions - painless erythematous lesions of palm/sole
  • Osler nodes - painful fingertip nodules
• Diagnosis: positive blood cultures + echocardiographic findings

Complications and Prognosis

• Glomerulonephritis - immune complex deposition; hematuria, albuminuria, renal failure
• Arrhythmias (extension to conduction system)
• Systemic embolization - stroke, splenic/renal infarcts
• Heart failure from valvular destruction
• Left untreated: generally fatal
• With appropriate antibiotics ± valve replacement: mortality significantly reduced

Diagnosis

• Echocardiography (TTE/TEE): strongly supported in virtually all suspected IE cases
• TEE preferred when: TTE is poor quality, negative findings with high suspicion, prosthetic valve involvement, staphylococcal bacteremia, or elderly patients with valvular abnormalities
• TEE is particularly important for prosthetic valve endocarditis where TTE is less sensitive

Prevention (AHA 2021 Guidelines)

• Presence of prosthetic cardiac valve or material
• Transcatheter implanted prosthetic valves
• Cardiac valve repair with annuloplasty rings
• Prior history of IE
• Unrepaired or recently repaired cyanotic congenital heart defects
• Ventricular assist devices and implantable hearts (added 2021)

• Amoxicillin remains preferred (90% of penicillin-allergic patients have negative skin testing and can receive it)
• Clindamycin eliminated as alternative due to Clostridioides difficile risk
• Doxycycline added as alternative for truly penicillin-allergic patients
• Shared decision-making with patient education emphasized
• Good oral health maintenance is fundamental

PART II: NON-INFECTIOUS VALVULAR DISEASE

2. Rheumatic Valvular Disease (Rheumatic Heart Disease)

Pathogenesis

Epidemiology

• 35-72% of acute rheumatic fever patients develop clinical carditis
• RHD has declined greatly in high-income countries due to improved socioeconomic conditions, rapid streptococcal treatment, and reduced streptococcal virulence
• In low-income countries, RHD remains the most important form of acquired heart disease in children and young adults
• Remains a leading cause of bacterial endocarditis and cardiovascular morbidity in endemic regions

Valve Involvement Pattern

• Mitral valve: affected nearly 100% of the time
• Aortic valve: involved in 20-30% of cases (regurgitation more common than stenosis)
• Tricuspid valve: histologic evidence of disease in 15-40%, but usually not clinically relevant
• Pulmonic valve: rarely involved

Morphology

• Small, warty inflammatory vegetations along the lines of valve closure (1-2 mm)
• Unlike infective endocarditis, these are NOT destructive
• Aschoff bodies (pathognomonic) - granulomatous foci with large cells (Aschoff giant cells) in the myocardium
• Pancarditis: pericarditis, myocarditis, endocarditis

• Progressive fibrosis and thickening of valve leaflets
• Fusion of commissures
• Calcification
• Chordae tendineae thicken, fuse, and shorten
• Classic "fish-mouth" or "buttonhole" deformity of mitral valve in stenosis

Clinical Presentation and Management

• Classic murmurs present on auscultation; echocardiography key to diagnosis
• Secondary prophylaxis: intramuscular benzathine penicillin G to prevent recurrent acute rheumatic fever and disease progression
• Severe valvular disease typically appears in the 3rd-4th decade of life
• In endemic regions, echocardiographic screening can detect latent RHD to guide prophylaxis

3. Degenerative / Calcific Valvular Disease

Calcific Aortic Stenosis (AS)

• Calcification of a trileaflet aortic valve (tricuspid AV) - majority of older patients
• Patients with congenital bicuspid valves present 1-2 decades earlier (4th-5th decade)
• Process resembles atherosclerosis: lipid deposition, inflammation, calcification along mechanical stress lines

• Angina: 3-5 years survival
• Syncope (exertional): 2-3 years
• Heart failure (dyspnea): 1-2 years

• Aortic valve area <1.0 cm² (or <0.6 cm²/m² BSA)
• Mean gradient ≥40 mmHg
• Peak flow velocity ≥4 m/sec
• LV stroke volume index ≥35 mL/m² (classic high flow, high gradient)
• Low-flow, low-gradient AS: >40% of older patients have lower gradients; about half also have LV stroke volume index <35 mL/m²

• Surgical AVR (SAVR): Standard for lower-risk patients
• Transcatheter AVR (TAVR): Transformative for high-risk and intermediate-risk surgical patients; now proven in low-risk patients (composite risk death/stroke/hospitalization at 1 year: 8.5% TAVR vs. 15.1% SAVR in low-risk trial)
• ACC/AHA 2020 guidelines: SAVR or TAVR after shared decision-making for symptomatic patients ages 65-80 years; TAVR preferred ≥80 years
• Tissue valve generally preferred over mechanical in older patients (avoid anticoagulation)
• Bioprosthetic valves deteriorate more slowly in older patients

Mitral Annular Calcification

• Degenerative calcification of the mitral annulus
• Common in the elderly, especially women
• Rarely causes significant valvular dysfunction alone but increases risk of arrhythmias, conduction disturbances, and stroke

4. Myxomatous Degeneration / Mitral Valve Prolapse (MVP)

Pathogenesis

Morphology

• Ballooning (hooding) of the mitral leaflets - enlarged, redundant, thick, rubbery leaflets
• Chordae tendineae are elongated, thinned, occasionally rupture
• In primary mitral disease: concomitant tricuspid valve involvement in 20-40% of cases; aortic and pulmonic valves less commonly affected

Clinical Features

• Most patients are asymptomatic - valvular abnormality discovered incidentally
• Minority: palpitations, dyspnea, atypical chest pain
• Auscultation: midsystolic click (pathognomonic) ± regurgitant murmur
• ~3% develop complications:
  • Hemodynamically significant mitral regurgitation and CHF (especially with chordal/leaflet rupture)
  • Infective endocarditis (increased risk)
  • Sudden cardiac death from ventricular arrhythmias
  • Stroke/systemic infarcts from left atrial thrombi (rare)

5. Nonbacterial Thrombotic Endocarditis (NBTE) / Marantic Endocarditis

Definition

Pathogenesis and Causes

• Vegetations are small (1-5 mm), usually on previously normal valves
• Hypercoagulable states are the usual precursor
• Underlying malignancy is the most common cause - particularly mucinous adenocarcinomas (colon, pancreas, lung), related to circulating mucin and procoagulants
• Other causes: chronic DIC, hyperestrogenic states, endocardial trauma from indwelling catheters

Morphology

• Small, bland, nondestructive vegetations along the line of valve closure (compare to IE: large, irregular, destructive; compare to RHD: small, at line of closure, inflammatory)
• Histology: bland thrombus, virtually no inflammation in the valve cusp; thrombus only loosely attached

Clinical Consequences

• Local valvular effect usually trivial
• Major risk: emboli from easily-dislodged, inflammation-free vegetations → infarcts in brain, heart, kidneys, spleen
• NBTE can serve as a nidus for bacterial colonization → development of infective endocarditis (bridge between non-infective and infective disease)

6. Libman-Sacks Endocarditis (LSE)

Definition

Pathogenesis

• Probable mechanism: immune complex deposition with associated inflammation and fibrinoid necrosis of the valve adjacent to the vegetation
• Subsequent fibrosis and serious deformity can result in lesions resembling chronic RHD
• Similar lesions occur in antiphospholipid antibody syndrome

Morphology

• Small to medium-sized inflammatory vegetations that can be attached on either side of the valve leaflets (unique - unlike other endocarditis types)
• Can occur on chordae, atrial, or ventricular endocardium
• Heal with scarring

7. Individual Valve Lesions - Summary

Mitral Stenosis (MS)

• Etiology: Almost exclusively RHD; rarely congenital
• Pathophysiology: Fixed obstruction to LV inflow → LA hypertension → pulmonary hypertension → right heart failure
• PH affects >50% of MS patients; tracks strongly with symptoms
• Patients with PASP >60 mmHg have higher restenosis rates after valvuloplasty and decreased 3-year survival after valvotomy
• Intervention: Balloon mitral valvuloplasty (BMV) for pliable valves; mitral valve replacement for rigid/calcified valves

Mitral Regurgitation (MR)

• Etiologies: Primary (degenerative/MVP, ruptured chordae, RHD, IE) vs. secondary/functional (LV dilatation, ischemic cardiomyopathy)
• Pathophysiology: Volume overload of LA and LV → LV dilatation → eventually LV dysfunction
• Moderate/severe PH observed in >50% of severe primary MR patients
• Average 5-year survival ~25% less with PH compared to those without
• Intervention: Surgical repair preferred over replacement; MitraClip transcatheter repair for high-risk patients

Aortic Stenosis (AS)

Aortic Regurgitation (AR)

• Etiologies: Valve leaflet disease (bicuspid AV, IE, RHD) or aortic root disease (aortic dissection, Marfan, syphilitic aortitis, hypertension)
• Pathophysiology: Volume + pressure overload of LV → eccentric hypertrophy → eventual LV dilatation and systolic dysfunction
• Clinical signs: Wide pulse pressure, water-hammer (Corrigan's) pulse, Duroziez sign, Quincke pulse
• When AR is combined with MR: Blood may reflux from aorta through both left heart chambers into pulmonary veins - a severe and poorly tolerated combination
• Intervention: AVR when symptomatic or when LV EF <55% or LV end-systolic dimension >50 mm

Tricuspid Valve Disease

• Tricuspid regurgitation (TR): Most commonly functional (from RV dilatation/pulmonary hypertension) rather than primary organic disease
• Organic TR: carcinoid syndrome (deposits on RV side), IE in IV drug users, Ebstein anomaly, RHD
• Carcinoid heart disease: Fibrous plaques on RV endocardium, tricuspid and pulmonic valves → regurgitation + stenosis; relates to serotonin/substance P excess

Pulmonary Valve Disease

• Rarest clinically significant valvular disease
• Pulmonary stenosis: Usually congenital (isolated or part of Tetralogy of Fallot)
• Pulmonary regurgitation: Usually secondary to pulmonary hypertension

8. Pulmonary Hypertension in Valvular Disease

• Aortic stenosis: 30-36% of asymptomatic AS patients have at least mild PH; severe PH in 20%
• Mitral stenosis: PH in >50% of patients; key determinant of management and outcomes
• Mitral regurgitation: Moderate/severe PH in >50% of severe primary MR
• Secondary MR (HFpEF): ~40% PH prevalence

9. Multivalvular Disease

COMPARATIVE SUMMARY: Types of Endocarditis

KEY DIAGNOSTIC TOOLS

• Echocardiography (TTE/TEE): First-line for all VHD - anatomy, hemodynamics, severity grading
• Doppler: Gradients, valve areas, regurgitant volumes, pulmonary pressures
• CT/MDCT: Aortic valve calcium scoring (especially for low-flow AS), structural planning before TAVR
• Cardiac catheterization: Hemodynamic assessment when non-invasive data discordant
• Blood cultures x3: Before antibiotics in all suspected IE
• 3D echocardiography: Better morphological assessment of complex valvular lesions

KEY MANAGEMENT PRINCIPLES

1. Antibiotics are curative for IE; valve repair/replacement when significant destruction occurs
2. Rheumatic fever: Primary prevention (treat strep throat); secondary prevention (benzathine penicillin prophylaxis for years to life)
3. Symptomatic severe AS: SAVR or TAVR based on age, surgical risk, anatomy
4. Chronic severe MR: Surgery when symptomatic OR before significant LV dysfunction (EF <60%, ESD >40 mm)
5. Watchful waiting with serial echocardiography for asymptomatic mild-moderate disease
6. NBTE: Treat underlying cause; anticoagulation for embolic events; address malignancy
7. Libman-Sacks: Treat SLE; antithrombotic therapy for APS

• Robbins & Kumar Basic Pathology, pp. 365-370 (endocarditis, RHD, NBTE, LSE, MVP)
• Braunwald's Heart Disease, 12th Ed., pp. 1036-1042; 2394-2410 (AS, multivalvular disease, IE prevention/management)
• Goldman-Cecil Medicine, p. 3044 (rheumatic heart disease)
• Fuster and Hurst's The Heart, 15th Ed., pp. 595-624 (multivalvular disease, individual lesion combinations)
• AHA 2021 Scientific Statement on IE Prevention - cited within Braunwald's
• Recent PubMed: Carcinoid heart disease surgical management meta-analysis, 2024 [PMID: 38572311]; Aortic stenosis with cardiac amyloidosis meta-analysis, 2025 [PMID: 39955158]