Systolic vs. Diastolic HF — Systolic vs diastolic heart failure mechanisms - Pathophysiology

SECTION 1

Historical Context & Motivation

For most of medical history, heart failure was understood as a single syndrome: the heart simply could not keep up with the body's demands. Clinicians recognized the classic constellation of dyspnea, edema, and fatigue, but the underlying mechanisms were lumped together under the umbrella of "congestive heart failure." It was not until imaging and hemodynamic monitoring matured that investigators began to appreciate that the heart can fail by two fundamentally different pathways — one involving impaired contraction and the other involving impaired relaxation and filling. This distinction reshaped both diagnosis and treatment of heart failure in the twentieth and twenty-first centuries.

1628 • Harvey's Circulatory Model

William Harvey published De Motu Cordis, establishing that the heart functions as a pump propelling blood through a closed circulatory loop — the conceptual foundation for all future heart failure research.

1950s • Cardiac Catheterization Era

Right and left heart catheterization allowed direct measurement of intracardiac pressures and cardiac output, revealing that some patients had low ejection but others had high filling pressures despite seemingly normal contraction.

1970s–80s • Echocardiography Transforms Diagnosis

Two-dimensional and Doppler echocardiography enabled non-invasive assessment of both systolic function (ejection fraction) and diastolic function (transmitral flow patterns), firmly establishing two distinct pathophysiological categories.

2005 • HFpEF Recognized as a Major Entity

The European Society of Cardiology formally introduced guidelines for diagnosing heart failure with preserved ejection fraction (HFpEF), acknowledging diastolic dysfunction as equally prevalent and clinically important as systolic heart failure.

2021 • Universal Definition of Heart Failure

A consensus statement unified the terminology into HFrEF (reduced EF), HFmrEF (mildly reduced EF), and HFpEF (preserved EF), reflecting a spectrum rather than a strict dichotomy and guiding evidence-based therapies for each group.

The central question this lesson addresses is: How do the mechanisms of systolic and diastolic heart failure differ at the cellular, hemodynamic, and clinical levels, and why does this distinction matter for patient management? By understanding both forms, healthcare professionals can better interpret diagnostic findings, select appropriate therapies, and anticipate disease trajectories.

SECTION 2

Core Principles & Definitions

Heart failure is defined as a clinical syndrome in which the heart is unable to pump blood at a rate sufficient to meet the metabolic demands of the tissues, or can do so only at abnormally elevated filling pressures. The two principal mechanistic categories are systolic heart failure (also termed heart failure with reduced ejection fraction, HFrEF) and diastolic heart failure (also termed heart failure with preserved ejection fraction, HFpEF). Although the clinical presentations overlap considerably, the underlying pathophysiology and therapeutic approaches differ in important ways.

Systolic Dysfunction (HFrEF)

The ventricle loses its ability to contract forcefully. Ejection fraction (EF) falls below 40%. The chamber dilates, stroke volume drops, and forward cardiac output is reduced.

Diastolic Dysfunction (HFpEF)

The ventricle contracts adequately (EF ≥ 50%) but cannot relax and fill properly during diastole. Elevated filling pressures transmit backward to the pulmonary and systemic circulations, causing congestion.

Ejection Fraction (EF)

EF is the percentage of end-diastolic volume (EDV) ejected with each heartbeat: EF = (SV ÷ EDV) × 100. It is the primary metric used to classify heart failure type, though it has important limitations as a measure of contractility.

Neurohormonal Activation

Both forms trigger compensatory activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, which initially maintain perfusion but ultimately accelerate myocardial remodeling and clinical deterioration.

Frank-Starling Mechanism

In health, increased preload stretches sarcomeres, augmenting contractile force. In systolic HF, this curve is flattened and shifted downward; in diastolic HF, the curve may be preserved but the ventricle operates on a steeper pressure-volume relationship.

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KEY TAKEAWAY

Think of the heart as a water balloon. In systolic failure, the balloon has become overstretched and floppy — it fills easily but cannot squeeze hard enough to push the water out. In diastolic failure, the balloon has become thick and rigid — it squeezes well, but you cannot stretch it open to refill it. Both scenarios result in less water delivered per cycle, but the underlying problem — and therefore the fix — is very different.

SECTION 3

Visual Explanation — Pressure-Volume Loops

The pressure-volume (PV) loop is the gold-standard visual tool for comparing systolic and diastolic heart failure. Each cardiac cycle traces a loop on a graph where the x-axis represents left ventricular volume and the y-axis represents left ventricular pressure. By examining how the loop shifts in each type of heart failure, we can directly visualize the hemodynamic consequences of impaired contraction versus impaired relaxation.

The green normal loop shows a healthy cardiac cycle. In systolic HF (red, dashed), the loop shifts right and widens because of chamber dilation and reduced contractility — the end-systolic pressure-volume relationship (ESPVR) slope decreases. In diastolic HF (violet, dotted), the loop shifts leftward; the ventricle is smaller and stiffer, with a steepened end-diastolic pressure-volume relationship (EDPVR), meaning small increases in volume produce large rises in filling pressure.

Examining the diagram closely, notice that in systolic HF the end-systolic volume increases dramatically — the ventricle cannot empty itself adequately. The ESPVR (end-systolic pressure-volume relationship) slope, a load-independent index of contractility, shifts rightward and flattens. In contrast, diastolic HF preserves the ESPVR slope but shifts the EDPVR (end-diastolic pressure-volume relationship) upward and to the left. The ventricle is stiff: at any given filling volume, the pressure is disproportionately high, which transmits backward into the pulmonary veins and ultimately causes pulmonary congestion.

SECTION 4

Hemodynamic & Cellular Mechanisms

Hemodynamic Equations in Heart Failure

Several foundational equations allow us to quantify the hemodynamic derangements in heart failure. Understanding these relationships is essential for interpreting clinical data and predicting the downstream effects of each failure type on organ perfusion and venous congestion.

EJECTION FRACTION

EF = (SV ÷ EDV) × 100%

Where SV = stroke volume (mL), EDV = end-diastolic volume (mL). Normal EF = 55–70%. In HFrEF, EF < 40%; in HFpEF, EF ≥ 50%.

CARDIAC OUTPUT

CO = SV × HR

Where CO = cardiac output (L/min), HR = heart rate (beats/min). In systolic HF, SV is reduced primarily due to poor contractility; compensatory tachycardia may partially maintain CO initially.

STROKE VOLUME DETERMINANTS

SV = EDV − ESV

Where ESV = end-systolic volume. In systolic HF, ESV rises (poor emptying), so SV falls despite increased EDV. In diastolic HF, EDV is limited (impaired filling), so SV is reduced even though ESV remains relatively normal.

Cellular and Molecular Mechanisms

At the cellular level, systolic dysfunction arises from cardiomyocyte loss and contractile apparatus impairment. Following myocardial infarction or chronic ischemia, necrotic myocytes are replaced by fibrotic scar, which cannot contract. Remaining myocytes undergo eccentric hypertrophy — sarcomeres are added in series, causing the myocytes to elongate and the ventricle to dilate. Calcium handling becomes impaired: downregulation of SERCA2a (sarco/endoplasmic reticulum Ca²⁺-ATPase) slows calcium re-uptake, and phosphorylation changes in troponin I reduce cross-bridge cycling efficiency.

Diastolic dysfunction, by contrast, results primarily from increased ventricular stiffness. Concentric hypertrophy — sarcomeres added in parallel — thickens the ventricular wall in response to chronic pressure overload (e.g., hypertension, aortic stenosis). At the extracellular level, increased collagen deposition (types I and III) and cross-linking raise passive stiffness. Intracellularly, the giant protein titin undergoes isoform switching from the compliant N2BA form to the stiffer N2B form, reducing cardiomyocyte extensibility. Furthermore, impaired active relaxation due to delayed calcium re-sequestration means the ventricle does not fully relax before the next diastolic filling phase, elevating the minimum diastolic pressure.

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Clinical Pearl

In both forms of heart failure, neurohormonal activation — especially elevated norepinephrine, angiotensin II, and aldosterone — accelerates maladaptive remodeling. This is why RAAS inhibitors and beta-blockers are cornerstones of systolic HF treatment. However, these agents have shown less consistent mortality benefit in HFpEF, reflecting the distinct pathophysiology of diastolic dysfunction.

SECTION 5

Detailed Classification & Comparison

A systematic comparison of systolic and diastolic heart failure across multiple clinical dimensions highlights both the parallels and the critical differences between these two entities. The following diagram and table summarize the distinguishing features that guide clinical decision-making.

Side-by-side diagram showing the structural, volumetric, and etiologic differences between systolic HF (HFrEF) and diastolic HF (HFpEF). Note the dilated thin-walled chamber in systolic HF versus the small, thick-walled chamber in diastolic HF.

Feature	Systolic HF (HFrEF)	Diastolic HF (HFpEF)
Primary Defect	Impaired contraction (reduced inotropy)	Impaired relaxation and/or increased stiffness (reduced lusitropy)
Ejection Fraction	< 40%	≥ 50%
LV Chamber Size	Dilated	Normal or small
Wall Thickness	Normal or thin (relative to dilation)	Increased (concentric hypertrophy)
Typical Demographics	Younger; male predominance; post-MI	Older; female predominance; hypertensive, obese, diabetic
BNP/NT-proBNP	Markedly elevated (wall stretch stimulus)	Modestly elevated or at borderline (thick walls attenuate stretch)
S3 Gallop	Common (rapid filling into dilated ventricle)	Less common; S4 gallop more typical (atrial kick against stiff ventricle)
Proven Mortality-Reducing Therapies	ACEi/ARB/ARNI, beta-blockers, MRA, SGLT2i, hydralazine-nitrate	SGLT2i (empagliflozin, dapagliflozin); diuretics for symptom relief

Key clinical and pathophysiological differences between systolic and diastolic heart failure.

SECTION 6

Worked Example — Clinical Case Analysis

The following clinical scenario demonstrates how to integrate history, physical examination, labs, and echocardiography to distinguish between systolic and diastolic heart failure and calculate key hemodynamic parameters.

Case: 72-year-old woman with dyspnea on exertion

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Step 1 — Gather Clinical Data

A 72-year-old woman with a 15-year history of hypertension and type 2 diabetes presents with progressive dyspnea on exertion over 3 months. She has bilateral lower extremity edema and bilateral pulmonary crackles on auscultation. An S₄ gallop is heard at the apex. BNP is 320 pg/mL (mildly elevated). Echocardiography shows: end-diastolic volume (EDV) = 90 mL, end-systolic volume (ESV) = 35 mL, LV wall thickness = 14 mm (increased), and an E/e' ratio of 18 (elevated).
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Step 2 — Calculate Ejection Fraction

Using the EF formula: EF = (SV ÷ EDV) × 100. First, SV = EDV − ESV = 90 mL − 35 mL = 55 mL. Then, EF = (55 ÷ 90) × 100 = 61.1%.

EF = 61.1% → Preserved (≥ 50%)
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Step 3 — Assess Diastolic Function

The E/e' ratio is a tissue Doppler index that estimates LV filling pressures. An E/e' ratio > 14 suggests elevated left atrial pressure. This patient's E/e' of 18 is consistent with grade II or III diastolic dysfunction. The increased wall thickness (14 mm) indicates concentric hypertrophy, a hallmark of the pressure-overloaded, stiff ventricle.

E/e' = 18 → Elevated filling pressures confirmed
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Step 4 — Correlate Findings with HF Type

The preserved EF (61%), concentric LV hypertrophy, elevated E/e' ratio, S₄ gallop, and clinical profile (elderly woman, hypertension, diabetes) collectively point toward heart failure with preserved ejection fraction (HFpEF) — diastolic heart failure. The BNP is mildly elevated rather than markedly elevated, which is typical of HFpEF where thickened walls produce less wall stress per unit of filling pressure.

Diagnosis: HFpEF (Diastolic Heart Failure)
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Step 5 — Estimate Cardiac Output

If the patient's resting heart rate is 78 bpm, we can estimate resting cardiac output: CO = SV × HR = 55 mL × 78 beats/min = 4,290 mL/min ≈ 4.3 L/min. This is at the lower end of normal (4–8 L/min), consistent with early heart failure where compensatory mechanisms still partially maintain output at rest but fail during exertion — explaining her exertional dyspnea.

CO ≈ 4.3 L/min → Low-normal, explaining exertional symptoms

SECTION 7

Treatment Approaches & Limitations

One of the most clinically impactful consequences of distinguishing systolic from diastolic heart failure lies in the management approach. Decades of randomized controlled trials have established a robust evidence base for pharmacotherapy in HFrEF, including multiple drug classes that reduce mortality. In contrast, HFpEF treatment has historically been more limited, with most interventions targeting symptom relief rather than survival. This discrepancy underscores the importance of accurate classification.

Therapy	Role in Systolic HF (HFrEF)	Role in Diastolic HF (HFpEF)
ACE inhibitors / ARBs	First-line; reduce preload, afterload, and remodeling; proven mortality benefit (CONSENSUS, SOLVD)	May reduce hospitalizations; no consistent mortality benefit (CHARM-Preserved, I-PRESERVE)
Beta-blockers	Carvedilol, bisoprolol, metoprolol succinate reduce mortality by ~30% (COPERNICUS, MERIT-HF)	May help with rate control; no mortality benefit demonstrated
ARNI (sacubitril/valsartan)	Superior to ACEi alone; 20% reduction in CV death/HF hospitalization (PARADIGM-HF)	Reduced hospitalizations but not CV death (PARAGON-HF); benefit in lower EF range
SGLT2 inhibitors	Reduce HF hospitalization and CV death (DAPA-HF, EMPEROR-Reduced)	First class to show benefit in HFpEF: reduced HF hospitalization (EMPEROR-Preserved, DELIVER)
Loop diuretics	Symptom relief (decongest); no mortality benefit; risk of electrolyte depletion	Symptom relief; cautious dosing — excessive preload reduction may drop SV in non-compliant ventricle
MRA (spironolactone, eplerenone)	Reduces mortality (RALES, EMPHASIS-HF)	Reduced hospitalizations in subgroups; overall TOPCAT trial had neutral primary endpoint

Comparison of evidence-based pharmacotherapy in HFrEF vs. HFpEF.

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KEY TAKEAWAY

Think of HFrEF therapies as tools designed to lighten the load on a weakened engine — reducing the work the heart must do (afterload reduction) and blocking the toxic neurohormonal overdrive that accelerates engine degradation. In HFpEF, the engine is stiff rather than weak, so lightening the load alone does not fix the fundamental problem of impaired filling. This explains why so many HFrEF-proven drugs failed to show mortality benefit when tested in HFpEF populations. The emergence of SGLT2 inhibitors as the first therapy effective across the EF spectrum represents a paradigm shift, likely because these agents target systemic inflammation, volume status, and myocardial energetics — mechanisms relevant to both failure types.

SECTION 8

Connection to Advanced Cardiovascular Theory

The binary classification of systolic versus diastolic heart failure is a useful clinical framework, but contemporary cardiovascular science increasingly views heart failure as a continuum rather than two discrete entities. The introduction of HFmrEF (heart failure with mildly reduced ejection fraction, EF 41–49%) reflects this nuance. Patients may transition between categories: an individual with HFpEF may develop superimposed ischemic injury that reduces EF into the HFrEF range, while effective treatment of HFrEF may improve EF above 40% (so-called HF with improved EF, HFimpEF). These transitions have important therapeutic implications — withdrawal of GDMT after EF recovery often leads to relapse.

Concept	Basic Framework (This Lesson)	Advanced Framework
Classification	Binary: systolic (HFrEF) vs. diastolic (HFpEF) based on EF cutoff	Spectrum: HFrEF → HFmrEF → HFpEF; phenotypic clustering by comorbidities, biomarkers, and imaging
Pathophysiology	Impaired contraction vs. impaired relaxation	Systemic microvascular endothelial inflammation paradigm in HFpEF; metabolic heart disease; RV-pulmonary vascular coupling
Biomarkers	BNP/NT-proBNP for diagnosis and prognosis	Multi-marker panels: sST2, galectin-3, high-sensitivity troponin, GDF-15 for phenotyping and risk stratification
Imaging	2D echo with EF measurement and Doppler diastolic indices	Speckle-tracking strain imaging (global longitudinal strain), cardiac MRI with T1 mapping for diffuse fibrosis, exercise stress echocardiography
Therapeutics	GDMT for HFrEF; limited evidence for HFpEF	Precision phenotyping to identify HFpEF subgroups responsive to specific interventions (e.g., obesity-phenotype responds to GLP-1 RA; AF-phenotype responds to rhythm control)

Bridging from the basic systolic/diastolic dichotomy to advanced heart failure frameworks.

Looking forward, the field is moving toward phenotype-guided and precision medicine approaches to heart failure. Machine learning algorithms applied to large HFpEF registries have identified distinct sub-phenotypes — such as an obesity-metabolic cluster, a right heart failure-pulmonary hypertension cluster, and an atrial fibrillation-dominant cluster — each with differing prognoses and potential therapeutic targets. Understanding the basic systolic-versus-diastolic distinction remains the essential foundation upon which these advanced concepts are built.

SECTION 9

Practice Problems

Question 1: CONCEPTUAL

A patient presents with heart failure symptoms. Echocardiography reveals a dilated left ventricle, thin ventricular walls, and an EF of 28%. An S₃ gallop is present. Is this most consistent with systolic or diastolic heart failure? Explain which pathophysiological features support your answer.

Show answer

This presentation is most consistent with systolic heart failure (HFrEF). The EF of 28% is well below the 40% threshold that defines HFrEF. The dilated left ventricle indicates eccentric remodeling, where the chamber enlarges in response to volume overload or loss of contractile myocardium. Thin ventricular walls are consistent with this dilation, as the wall stretches and becomes relatively thinner (Laplace's law predicts increased wall stress in a dilated, thin-walled chamber). The S₃ gallop occurs during rapid passive filling in early diastole, when a large volume of blood rushes into a compliant but poorly contractile ventricle, creating a low-frequency sound.

Question 2: BASIC CALCULATION

A patient with heart failure has an end-diastolic volume of 200 mL and an end-systolic volume of 140 mL. Calculate the stroke volume, the ejection fraction, and classify the type of heart failure.

Show answer

Stroke volume (SV) = EDV − ESV = 200 mL − 140 mL = 60 mL. Ejection fraction = (SV ÷ EDV) × 100 = (60 ÷ 200) × 100 = 30%. An EF of 30% is below 40%, classifying this as HFrEF (systolic heart failure). Notably, the markedly elevated ESV (140 mL, normal ≈ 50–70 mL) indicates the ventricle cannot empty adequately due to poor contractility. The EDV is also elevated (200 mL, normal ≈ 120–150 mL), reflecting compensatory dilation as the ventricle attempts to use the Frank-Starling mechanism to maintain stroke volume.

Question 3: INTERMEDIATE

Two patients both present with NYHA Class III heart failure symptoms. Patient A has an EF of 25%, an EDV of 250 mL, and a BNP of 1,800 pg/mL. Patient B has an EF of 58%, an EDV of 80 mL, an E/e' ratio of 20, and a BNP of 280 pg/mL. Compare the stroke volumes of both patients. Explain why Patient B's BNP is lower than Patient A's despite both having symptomatic heart failure.

Show answer

Patient A: SV = EDV − ESV. Since EF = SV/EDV, SV = 0.25 × 250 = 62.5 mL. Patient B: SV = 0.58 × 80 = 46.4 mL. Interestingly, Patient B (HFpEF) actually has a lower stroke volume (46.4 mL) than Patient A (62.5 mL), despite having a higher EF. This occurs because Patient B's stiff ventricle cannot fill adequately (EDV only 80 mL), limiting the absolute volume ejected per beat. Regarding BNP: this natriuretic peptide is released primarily in response to myocardial wall stretch. Patient A's massively dilated ventricle (EDV 250 mL) generates substantial wall stretch, driving high BNP secretion. Patient B's thick, concentrically hypertrophied walls experience less stretch per unit of filling pressure, resulting in a proportionally lower BNP despite significant diastolic dysfunction. This is clinically important because using standard BNP cutoffs may underdiagnose HFpEF.

Question 4: APPLIED

A 65-year-old obese, hypertensive, diabetic woman is admitted with acute decompensated heart failure. She receives aggressive IV furosemide diuresis, losing 4 kg of fluid weight overnight. The next morning, her blood pressure drops to 85/60 mmHg, and she develops pre-renal acute kidney injury. Her EF on echocardiography is 55%. Explain the pathophysiological mechanism behind her hemodynamic collapse after diuresis, linking it to her type of heart failure.

Show answer

This patient has HFpEF (EF 55%). Her stiff, non-compliant left ventricle operates on a steep end-diastolic pressure-volume relationship (EDPVR). This means that while high filling pressures cause congestion, the ventricle actually depends on adequate preload to generate sufficient stroke volume. Aggressive diuresis removed too much intravascular volume, causing a precipitous drop in EDV. Because the EDPVR is steep, even a modest reduction in volume leads to a disproportionately large fall in filling pressure and thus stroke volume. Cardiac output dropped (CO = SV × HR), producing hypotension and reduced renal perfusion (pre-renal AKI). In contrast, a patient with HFrEF and a dilated, compliant ventricle is typically more tolerant of preload reduction because the flat portion of their EDPVR means volume can decrease substantially before stroke volume is significantly affected. This case illustrates why diuretic dosing in HFpEF must be more judicious — the therapeutic window between decongestion and hemodynamic compromise is narrow.

Question 5: CRITICAL THINKING

Despite decades of research, no pharmacological therapy (until SGLT2 inhibitors) demonstrated a significant mortality benefit in HFpEF, whereas multiple drug classes reduce mortality in HFrEF. Propose a pathophysiological explanation for this discrepancy. Consider how the heterogeneity of HFpEF phenotypes and the limitations of EF as a diagnostic criterion might contribute to negative clinical trial results.

Show answer

Several pathophysiological factors contribute to this discrepancy. First, HFrEF has a relatively unified mechanism centered on neurohormonal overdrive and contractile dysfunction — drugs that block maladaptive RAAS activation and sympathetic stimulation directly address the core pathology. HFpEF, however, is pathophysiologically heterogeneous. It encompasses patients whose diastolic dysfunction stems from hypertensive concentric hypertrophy, diabetic cardiomyopathy, obesity-related inflammation, amyloid infiltration, pericardial disease, and other causes. Each subgroup may respond to different interventions, but clinical trials enrolling all HFpEF patients together dilute treatment effects. Second, EF is a crude measure. A patient with EF 55% may have severely impaired global longitudinal strain (subclinical systolic dysfunction), while another at EF 55% may have purely diastolic pathology. Lumping them together introduces mechanistic noise. Third, the microvascular endothelial inflammation paradigm proposed by Paulus and Tschöpe suggests that HFpEF is driven by systemic comorbidity-induced inflammation → coronary microvascular endothelial dysfunction → reduced NO bioavailability → decreased PKG activity → increased titin stiffness and collagen deposition. This complex, multi-organ pathway is not easily reversed by a single drug. SGLT2 inhibitors may have succeeded because they address multiple downstream effects simultaneously: reducing volume overload, improving myocardial energetics (shifting fuel utilization toward ketone bodies), and attenuating inflammation. Future success in HFpEF therapeutics will likely require phenotype-specific trials rather than one-size-fits-all approaches.

SUMMARY

Lesson Summary

Summary

Heart failure is classified into two primary mechanistic categories. Systolic heart failure (HFrEF) is characterized by impaired ventricular contraction, reduced ejection fraction (< 40%), eccentric hypertrophy with chamber dilation, and elevated end-systolic volumes. Diastolic heart failure (HFpEF) is defined by impaired ventricular relaxation and filling with preserved ejection fraction (≥ 50%), concentric hypertrophy, and a stiff, non-compliant ventricle that generates elevated filling pressures at normal or reduced volumes.

The distinction is clinically critical because proven mortality-reducing therapies — ACE inhibitors, ARBs, ARNI, beta-blockers, and MRAs — are effective primarily in HFrEF, where they counteract neurohormonal overdrive and maladaptive remodeling. HFpEF management remains more limited, though SGLT2 inhibitors have emerged as the first class with demonstrated benefit across the EF spectrum. Key diagnostic tools include echocardiography (EF, E/e' ratio, wall thickness) and natriuretic peptide levels (BNP/NT-proBNP). The pressure-volume loop remains the gold-standard conceptual tool for visualizing how each type of failure alters cardiac mechanics — a rightward-shifted, flattened ESPVR in systolic HF versus a steepened EDPVR in diastolic HF.