Executive Summary
Key Points
- EF is a fraction (SV/EDV), not a measure of cardiac output — a "normal" EF can mask cardiogenic shock
- An EF of 45–55% producing a CI <2.0 L/min/m² is the hemodynamic signature of infiltrative cardiomyopathy
- Tissue Doppler (e’ velocity) and E/e’ ratio are more reliable than the E/A ratio for assessing diastolic function in amyloidosis
- Global longitudinal strain with apical sparing ("bull’s-eye" pattern) has >80% sensitivity and specificity for cardiac amyloidosis
- Echo cannot measure cardiac output, cannot differentiate ATTR from AL, and cannot assess hemodynamic severity — RHC is required when clinical severity exceeds echo findings
- CI <2.2 L/min/m² defines low-output heart failure; CI <1.8 defines cardiogenic shock range
1. EF Is a Fraction, Not Output
Ejection fraction measures what percentage of end-diastolic volume is ejected, not how much blood the heart delivers to the body. In a normal heart, the two correlate well. In an infiltrative cardiomyopathy, they dissociate dramatically because the stiff ventricle cannot fill adequately — EDV is reduced, making the ratio appear acceptable while absolute SV is critically low.
1.1 EF-CO Dissociation: Three Clinical Scenarios
| Parameter | Normal Heart | Dilated CM (EF 25%) | Amyloid Heart (EF 55%) |
|---|---|---|---|
| EDV | 120 mL | 300 mL | 50 mL |
| SV | 72 mL | 75 mL | 28 mL |
| EF | 60% | 25% | 55% |
| HR | 70 bpm | 90 bpm | 85 bpm |
| CO | 5.0 L/min | 6.8 L/min | 2.4 L/min |
| CI (BSA 2.0) | 2.5 | 3.4 | 1.2 |
| SVI | 36 mL/m² | 38 mL/m² | 14 mL/m² |
| Clinical | Normal | Compensated HF | Cardiogenic shock |
The Diagnostic Trap
The dilated cardiomyopathy with EF 25% has better cardiac output than the amyloid heart with EF 55%. A clinician who relies on EF alone will reassure themselves about the amyloid patient ("preserved EF, mild disease") while the patient is in hemodynamic extremis. SV and SVI, not EF, determine organ perfusion.
1.2 When EF and Hemodynamics Don’t Match
An EF of 45% that produces a CI of 1.75 L/min/m² represents a hemodynamic-EF mismatch. In dilated cardiomyopathy with EF 45%, cardiac output is typically far better maintained because the ventricle fills to a larger EDV. The "preserved EF with low output" pattern has a short differential:
- Cardiac amyloidosis (AL or ATTR)
- Hypertrophic cardiomyopathy with obstruction
- Cardiac sarcoidosis
- Fabry disease
- Advanced aortic stenosis with small cavity
2. Diastolic Parameters: The Real Story
Standard E/A ratio assessment frequently underestimates diastolic severity in amyloidosis due to pseudonormalization. Tissue Doppler provides load-independent assessment:
2.1 Key Parameters
| Parameter | What It Measures | Normal | Amyloid Typical | Clinical Meaning |
|---|---|---|---|---|
| e’ septal | Intrinsic myocardial relaxation velocity | >7 cm/s | 3–5 cm/s | Direct measure of myocardial stiffness; load-independent |
| E/e’ | Estimated filling pressure (correlates with PCWP) | <14 | 20–40+ | E/e’ >14 predicts PCWP >15 mmHg |
| MV E velocity | Early filling velocity (load-dependent) | 0.6–1.0 m/s | Often elevated | Reflects LA driving pressure |
| E/A ratio | Filling pattern | 1–2 | Variable | Can be "pseudonormalized" — misleading |
| Deceleration time | Rate of E-wave decline | 160–240 ms | <150 ms (restrictive) | Short DT = high LA pressure, restrictive physiology |
Clinical Pearl
An e’ velocity of 4 cm/s means the myocardium is relaxing at less than half the normal rate — it is functionally a brick. An E/e’ of 37 with e’ of 4 represents at minimum Grade II, likely transitional to Grade III diastolic dysfunction. If the echo report says "impaired relaxation" (Grade I) based solely on the E/A ratio while e’ is <5 and E/e’ is >20, the echocardiographer has underread the study. Always check tissue Doppler before accepting an E/A-based diastolic assessment.
2.2 The Pseudonormalization Trap
The E/A ratio can be "pseudonormalized" when elevated LA pressure pushes the E wave back up despite impaired relaxation. The pattern:
- Normal: E/A 1–2, e’ >7 — Normal filling
- Grade I (Impaired Relaxation): E/A <1, e’ <7 — True impaired relaxation
- Grade II (Pseudonormal): E/A 1–2, e’ <7 — Looks normal but e’ exposes the lie
- Grade III (Restrictive): E/A >2, DT <150 ms, e’ very low — Severe restriction
3. Global Longitudinal Strain and Apical Sparing
Global longitudinal strain (GLS) with an apical sparing pattern — the "cherry on top" or "bull’s-eye" pattern — is the most sensitive echocardiographic indicator of cardiac amyloidosis, with sensitivity and specificity both exceeding 80%.
In cardiac amyloidosis, amyloid fibrils deposit preferentially in the basal and mid-wall segments while the apex is relatively spared. This produces a characteristic pattern where basal GLS is severely reduced while apical GLS is preserved — visible as a red apex surrounded by blue/purple base and mid-segments on the bull’s-eye map.
Why EF Varies by Echo View in Amyloid
| Method | EF | Explanation |
|---|---|---|
| A4C (4-chamber) | 59% | Weights apical function — which is preserved in amyloid |
| A2C (2-chamber) | 42% | Weights basal function — which is impaired |
| Biplane (Simpson’s) | 52% | Averages — masks the regional variation |
| Visual estimate | 31% | Often underestimates when texture is abnormal |
| Fractional shortening | 31% | Linear measure through basal segments |
Clinical Pearl
A wide spread in EF across methods (31–59%) is itself abnormal and suggests regional variation in function — the hallmark of infiltrative disease with apical sparing. If you see a >15-point spread between A4C EF and A2C EF, request GLS with a bull’s-eye map.
4. What Echo Cannot Tell You
| Question | Can Echo Answer It? | What Can |
|---|---|---|
| What is the cardiac output? | No — estimated, not measured | RHC (thermodilution or Fick) |
| What is the true PCWP? | Estimated via E/e’ (imprecise) | RHC (direct measurement) |
| Is this ATTR or AL? | No — both look identical on echo | PYP scan + monoclonal screen; mass spectrometry amyloid typing |
| Is this restrictive or constrictive? | Suggestive but not definitive | RHC (respirophasic ventricular interdependence) |
| Will diuresis cause hemodynamic collapse? | No — cannot predict preload sensitivity | RHC (Forrester classification; CI response to volume removal) |
| What is the RA pressure? | Estimated via IVC diameter/collapse | RHC (direct measurement) |
| Is there a pre-capillary component to PH? | No | RHC (PVR, TPG, DPG) |
5. When RHC Is Mandatory
Indications for RHC in Suspected or Confirmed Cardiac Amyloidosis
- Clinical severity exceeds echo findings: Diuretic resistance, hypotension, AKI, vasopressor dependence with "preserved" EF
- Volume management uncertainty: Defining safe operating filling pressures for the stiff ventricle
- Restrictive vs. constrictive differentiation: When the hemodynamic pattern is ambiguous
- Transplant evaluation: PVR assessment for cardiac or combined heart-liver transplant candidacy
- Cardiogenic shock assessment: CI <2.2 suspected but echo cannot confirm
CI Thresholds and Their Clinical Meaning
| CI (L/min/m²) | Clinical Status | Management Implication |
|---|---|---|
| 2.5–4.0 | Normal | Standard care |
| 2.0–2.5 | Low-output heart failure | Cautious diuresis; monitor for AKI |
| 1.8–2.0 | Pre-shock | ICU monitoring; vasopressor availability |
| <1.8 | Cardiogenic shock | Vasopressors, inotropes, or mechanical support; diuresis may be contraindicated without vasopressor support |
Clinical Pearl
The hallmark teaching point: in any patient where diuresis causes hemodynamic collapse despite only mildly reduced EF, think infiltrative disease. The heart that "should" tolerate diuresis but does not is a heart that is stiffer than its EF suggests. The Frank-Starling curve is flat — output is already maximized at a fixed, small stroke volume, and any preload reduction drops output precipitously.
6. Additional Echo Findings in Amyloidosis
- Multi-valve mild regurgitation: Mild regurgitation across all four valves is common from amyloid infiltration of valve leaflets and annulus
- Thickened interatrial septum: Often >6 mm; a specific marker when combined with biventricular hypertrophy
- Pericardial effusion: Small effusions are common but not universal
- Left atrial dilation: Severe LA enlargement from chronic elevation of filling pressures
- Small pericardial effusion + thick walls + biatrial enlargement: This triad should trigger amyloid evaluation
References
- Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: AHA scientific statement. Circulation. 2020;142(1):e7-e22. PubMed
- Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC review. J Am Coll Cardiol. 2019;73(22):2872-2891. PubMed
- Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of LV diastolic function by echocardiography: ASE/EACVI update. J Am Soc Echocardiogr. 2016;29(4):277-314. PubMed
- Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC expert consensus on cardiac amyloidosis. J Am Coll Cardiol. 2023;81(11):1076-1126. PubMed
- Ladefoged B, Dybro A, Povlsen JA, et al. Diagnostic delay in ATTRwt cardiac amyloidosis. Int J Cardiol. 2020;304:138-143. PubMed
- Quarta CC, et al. AL amyloidosis for cardiologists. JACC CardioOncol. 2022;4(4):427-441. PubMed
- Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using 2D speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. PubMed
- Rangaswami J, Bhalla V, Blair JEA, et al. Cardiorenal syndrome: AHA scientific statement. Circulation. 2019;139(4):e52-e154. PubMed
Amyloid Series Navigation
© Urine Nephrology Now | Amyloid Series
Andrew Bland, MD, MBA, MS