Introduction
For decades, heart failure was often equated with a weakened, poorly contracting heart—the image of a dilated left ventricle struggling to pump blood forward. While systolic dysfunction certainly represents one major form of heart failure, research over the last three decades has revealed another equally important, but often overlooked, player: diastolic dysfunction.
Diastolic dysfunction refers to abnormalities in ventricular filling and relaxation, leading to elevated filling pressures despite a “normal” left ventricular ejection fraction (LVEF). This condition is a defining feature of heart failure with preserved ejection fraction (HFpEF), which now accounts for more than half of all heart failure cases worldwide.
This article explores in detail the mechanisms, causes, clinical consequences, diagnostic approaches, and therapeutic strategies related to diastolic dysfunction, emphasizing its role as the “hidden culprit” in heart failure.
Understanding Diastolic Function
Phases of Diastole
Diastole is not simply a passive period between contractions—it is a complex, highly regulated process that ensures efficient ventricular filling. It consists of four overlapping phases:
- Isovolumetric relaxation – begins after aortic valve closure; the ventricle relaxes but volume remains constant.
- Rapid filling – the mitral valve opens, and blood flows quickly into the ventricle.
- Diastasis – a slower filling phase during mid-diastole.
- Atrial contraction – the atrium contracts to deliver a final “kick” of blood into the ventricle.
Efficient diastolic function depends on:
- Active myocardial relaxation (energy-dependent process).
- Passive ventricular compliance (ability of the ventricle to stretch without excessive pressure rise).
- Coordinated atrioventricular interaction.
What is Diastolic Dysfunction?
Diastolic dysfunction occurs when:
- The ventricle relaxes too slowly (impaired relaxation).
- The ventricle is too stiff (reduced compliance).
- Both abnormalities coexist, leading to elevated left atrial pressures and pulmonary venous congestion.
Pathophysiological Mechanisms
1. Impaired Myocardial Relaxation
- Relaxation is an active process requiring ATP-driven reuptake of Ca²⁺ into the sarcoplasmic reticulum (via SERCA pump).
- Ischemia, hypertrophy, or oxidative stress can slow Ca²⁺ clearance, prolonging relaxation.
2. Increased Ventricular Stiffness
- Myocardial fibrosis (from hypertension, diabetes, aging).
- Extracellular matrix remodeling and collagen cross-linking.
- Alterations in titin (a cytoskeletal protein regulating elasticity).
3. Elevated Filling Pressures
- Reduced compliance means small increases in volume cause large increases in pressure.
- Leads to backward transmission of pressure to the left atrium and pulmonary veins, producing congestion.
4. Neurohormonal and Inflammatory Pathways
- Activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system promotes hypertrophy and fibrosis.
- Inflammatory cytokines (IL-6, TNF-α) contribute to endothelial dysfunction and stiffness.
5. Microvascular Dysfunction
- Coronary microvascular inflammation and endothelial dysfunction impair oxygen delivery, worsening relaxation.
Causes and Risk Factors
Several conditions predispose individuals to diastolic dysfunction:
- Hypertension (most common cause): Chronic pressure overload causes concentric left ventricular hypertrophy and stiffness.
- Aging: Normal aging reduces compliance and prolongs relaxation.
- Diabetes mellitus: Promotes advanced glycation end-products (AGEs), fibrosis, and microvascular dysfunction.
- Obesity: Associated with systemic inflammation and myocardial remodeling.
- Coronary artery disease: Ischemia impairs relaxation and contributes to fibrosis.
- Valvular heart disease: Especially aortic stenosis and mitral regurgitation.
- Infiltrative diseases: Amyloidosis, sarcoidosis, hemochromatosis.
- Hypertrophic cardiomyopathy: Marked diastolic impairment despite preserved or increased systolic function.
Clinical Consequences
Heart Failure with Preserved Ejection Fraction (HFpEF)
- Diastolic dysfunction is the hallmark of HFpEF.
- Patients present with symptoms of heart failure (dyspnea, fatigue, exercise intolerance) despite a normal or near-normal LVEF.
Pulmonary Congestion
- Elevated left atrial pressure transmits backward to pulmonary veins and capillaries, leading to dyspnea, orthopnea, and pulmonary edema.
Exercise Intolerance
- During exertion, diastolic dysfunction prevents adequate rise in filling without excessive pressure, limiting stroke volume and cardiac output.
Atrial Fibrillation
- Loss of atrial contraction in AF is particularly detrimental in diastolic dysfunction, as the atrial “kick” contributes significantly to ventricular filling.
Increased Mortality and Morbidity
- Patients with diastolic dysfunction experience frequent hospitalizations, impaired quality of life, and mortality rates similar to those with systolic heart failure.
Diagnostic Evaluation
Echocardiography (Gold Standard)
Doppler echocardiography provides noninvasive assessment of diastolic function:
- Transmitral flow (E/A ratio)
- E = early filling; A = atrial contraction.
- Abnormal patterns reflect impaired relaxation or restrictive filling.
- Tissue Doppler imaging (TDI)
- Measures mitral annular velocity (e′).
- E/e′ ratio estimates left ventricular filling pressures.
- Left atrial size
- Chronic elevation of filling pressure enlarges the left atrium.
- Pulmonary venous flow patterns
- Provide additional insight into diastolic filling dynamics.
Additional Diagnostic Tools
- Cardiac MRI: Detects fibrosis and tissue remodeling.
- Biomarkers: BNP or NT-proBNP often elevated in diastolic dysfunction.
- Hemodynamic catheterization: Direct measurement of LV filling pressures.
Stages of Diastolic Dysfunction
Echocardiographic classification:
- Grade I (Impaired relaxation) – E/A ratio <1, normal LA pressure.
- Grade II (Pseudonormal) – Masked by elevated LA pressure, E/A ratio normal, but abnormal tissue Doppler findings.
- Grade III (Reversible restrictive) – Markedly elevated LA pressure, restrictive filling pattern, reversible with Valsalva.
- Grade IV (Fixed restrictive) – Advanced, irreversible restrictive filling, poor prognosis.
Diastolic Dysfunction in Special Contexts
1. Hypertensive Heart Disease
- Long-standing hypertension → concentric LV hypertrophy → stiff ventricle.
2. Hypertrophic Cardiomyopathy (HCM)
- Severe diastolic dysfunction from small LV cavity and hypertrophied septum.
3. Ischemic Heart Disease
- Recurrent ischemia or infarction causes both relaxation abnormalities and fibrosis.
4. Aortic Stenosis
- Pressure overload increases LV stiffness; diastolic dysfunction often precedes systolic failure.
5. Obesity and Diabetes
- “Metabolic HFpEF” phenotype, strongly linked to systemic inflammation and endothelial dysfunction.
Therapeutic Strategies
Unlike systolic heart failure, treatment options for diastolic dysfunction are more limited and challenging.
1. Lifestyle Modifications
- Blood pressure control (low-salt diet, exercise, weight loss).
- Glycemic control in diabetes.
- Weight reduction in obese patients.
2. Pharmacologic Therapy
- Diuretics: Relieve congestion by lowering filling pressures (symptomatic relief).
- Antihypertensives: ACE inhibitors, ARBs, calcium channel blockers, and beta-blockers help reduce hypertrophy and improve relaxation.
- Mineralocorticoid receptor antagonists (MRAs): Reduce fibrosis and improve diastolic parameters.
- SGLT2 inhibitors: Emerging evidence of benefit in HFpEF patients.
- ARNI (sacubitril/valsartan): Shown to reduce HF hospitalization in HFpEF subgroups.
3. Heart Rate Control
- Longer diastole improves filling.
- Beta-blockers and non-dihydropyridine calcium channel blockers (e.g., verapamil) are helpful.
4. Atrial Fibrillation Management
- Rhythm or rate control strategies are crucial, since atrial contraction is vital for filling.
5. Device Therapy
- Left atrial decompression devices under investigation to relieve elevated filling pressures.
Prognosis
- Diastolic dysfunction is associated with poor outcomes, particularly in elderly patients with comorbidities.
- Once symptomatic HFpEF develops, 5-year mortality rivals that of systolic HF.
- Early detection and intervention are key to improving prognosis.
Future Directions
Research continues to uncover new mechanisms and therapeutic targets:
- Molecular therapies: Targeting titin phosphorylation, fibrosis pathways, and microvascular dysfunction.
- Precision medicine: Tailoring therapy based on patient-specific phenotypes (e.g., metabolic HFpEF vs hypertensive HFpEF).
- Gene therapy and regenerative strategies: To restore myocardial compliance.
- Advanced imaging biomarkers: For early detection before clinical HF develops.
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