# Misleading Echocardiographic Findings in Infiltrative Cardiomyopathy

Andrew Bland, MD, FACP, FAAP

[← Amyloid Series Index](https://urinenephrology.org/mastery/amyloid-series/index.html)

## 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

**EF = SV / EDV**     where     **CO = HR × SV**     and     **CI = CO / BSA**

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:

1.  **Normal:** E/A 1–2, e’ \>7 — Normal filling
2.  **Grade I (Impaired Relaxation):** E/A \<1, e’ \<7 — True impaired relaxation
3.  **Grade II (Pseudonormal):** E/A 1–2, e’ \<7 — **Looks normal but e’ exposes the lie**
4.  **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

1.  Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: AHA scientific statement. *Circulation*. 2020;142(1):e7-e22. [PubMed](https://pubmed.ncbi.nlm.nih.gov/32476490/)
2.  Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC review. *J Am Coll Cardiol*. 2019;73(22):2872-2891. [PubMed](https://pubmed.ncbi.nlm.nih.gov/31171094/)
3.  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](https://pubmed.ncbi.nlm.nih.gov/27037982/)
4.  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](https://pubmed.ncbi.nlm.nih.gov/36697326/)
5.  Ladefoged B, Dybro A, Povlsen JA, et al. Diagnostic delay in ATTRwt cardiac amyloidosis. *Int J Cardiol*. 2020;304:138-143. [PubMed](https://pubmed.ncbi.nlm.nih.gov/32033783/)
6.  Wechalekar AD, Fontana M, Quarta CC, et al. AL amyloidosis for cardiologists. *JACC CardioOncol*. 2022;4(4):427-441. [PubMed](https://pubmed.ncbi.nlm.nih.gov/36444232/)
7.  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](https://pubmed.ncbi.nlm.nih.gov/22865865/)
8.  Rangaswami J, Bhalla V, Blair JEA, et al. Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the AHA. *Circulation*. 2019;139(16):e840-e878. [PubMed](https://pubmed.ncbi.nlm.nih.gov/30852913/)

## Amyloid Series Navigation

© Urine Nephrology Now \| Amyloid Series\
Andrew Bland, MD, FACP, FAAP


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