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CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Loie Farina (Northwestern University CardioNerds Ambassador), Dr. Josh Cheema, and Dr. Graham Peigh from Northwestern University for drinks along the shores of Lake Michigan at North Avenue Beach. They discuss a case of a 52-year-old woman with limited cutaneous systemic sclerosis who presents with progressive symptoms of heart failure and is found to have a severe, non-ischemic cardiomyopathy. The etiology of her cardiomyopathy is not clear until her untimely death. She is ultimately diagnosed with cardiac AL amyloidosis with isolated vascular involvement a real occam’s razor or hickam’s dictum conundrum. We discuss the work-up and management of her condition including a detailed discussion of the differential diagnosis, the underlying features of systemic sclerosis with cardiac involvement as well as cardiac amyloidosis, the role of a shock team in managing cardiogenic shock, and how to identify those with advanced or stage D heart failure. Advanced heart failure expert Dr. Yasmin Raza (Northwestern University) provides the ECPR segment. Episode introduction by CardioNerds Clinical Trialist Dr. Liane Arcinas. Audio editing by CardioNerds Academy Intern, Christian Faaborg-Andersen.

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Disclosures: None
Jump to: Pearls – Notes – References

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Case Summary – Occam’s Razor or Hickam’s Dictum?

This is a case of a 52-year-old woman with limited cutaneous systemic sclerosis who presented with progressive dyspnea on exertion and weight loss over the course of 1 year. Her initial work-up was notable for abnormal PFTs and finding of interstitial pneumonia on high-resolution CT, an ECG with frequent PVCs and normal voltage, a transthoracic echocardiogram with a mildly reduced ejection fraction of 40%, and a right/left heart catheterization with normal coronary arteries, filling pressures, and cardiac output. Scleroderma-related cardiac involvement is suspected. She is placed on GDMT, but her condition worsens over the next several months, and repeat echocardiogram shows severely reduced biventricular function, reduced LV global longitudinal strain (GLS) with apical preservation of strain, severely reduced mitral annular tissue Doppler velocities, and a normal left ventricular wall thickness. Scleroderma-related cardiac involvement remains highest on the differential, but because of some findings on the echo that are concerning for cardiac amyloidosis, an endomyocardial biopsy was obtained. It showed vascular amyloid deposition without interstitial involvement. The diagnosis of cardiac amyloid was discussed but deemed unlikely due to lack of interstitial involvement. However, a serologic work-up soon revealed a monoclonal serum lambda light chain and a follow-up bone marrow biopsy showed 20% plasma cells. She was discharged with very near-term follow-up in oncology clinic with a presumptive diagnosis of AL amyloidosis, but she unfortunately returned in shock and suffered a cardiac arrest. She initially survived and underwent emergent veno-arterial extracorporeal membrane oxygenation (VA ECMO) cannulation with subsequent left ventricular assist device placement (LVAD). However, she passed away due to post-operative hemorrhage. Autopsy was consistent with a final diagnosis of cardiac AL amyloidosis with isolated vascular involvement. 

Case Media – Occam’s Razor or Hickam’s Dictum?

Episode Teaching -Occam’s Razor or Hickam’s Dictum?

Pearls

1. Scleroderma causes repeated focal ischemia-reperfusion injuries which result in patchy myocardial fibrosis. Cardiac involvement in scleroderma is frequent but often not clinically evident; when symptomatic, it is associated with a poor prognosis. 

2. Myocardial dysfunction in cardiac AL amyloidosis can result from myocardial infiltration, vascular deposition causing microvascular dysfunction and ischemia, and direct cardiotoxicity from circulating light chains. 

3. While isolated vascular amyloid is very rare, it can occur and can be seen without key characteristics of interstitial amyloid deposition, namely left ventricular hypertrophy and low voltage on an ECG.  

4. Cardiogenic shock outcomes are improved by multi-disciplinary discussions, commonly referred to as a “shock team call.”  

5. Heart failure is a progressive, morbid, and potentially fatal condition. LVADs and heart transplantation improve life expectancy and decrease morbidity among patients with stage D heart failure. Identification of patients with advanced heart failure can be challenging – a helpful mnemonic is “I NEED HELP 

Notes – Occam’s Razor or Hickam’s Dictum?

1. How does scleroderma affect the heart? 

• Scleroderma is a connective tissue disorder characterized by extracellular matrix deposition, with widespread fibrosis of the skin and visceral organs, microvascular injury, and evidence of immune system activation.  
• Cardiac involvement is common, although likely underestimated as it is often subclinical, and the estimated prevalence varies widely. Myocardial involvement is identified in up to 80% of patients in histological studies and clinical myocardial dysfunction is recognized in 15-25%. When clinically evident, cardiac involvement portends a poor prognosis, with up to a 70% mortality at 5 years. Approximately 25% of scleroderma-related deaths are due to cardiac causes. 
• Primary involvement is thought to be mediated by repeated focal ischemic-reperfusion injury, impaired microcirculation, inflammation, and eventual focal irreversible fibrosis leading to heart failure and arrhythmias. 
• Cardiac involvement can also occur secondary to lung or renal disease, pulmonary arterial hypertension, or other cardiovascular risk factors.  
• Cardiac manifestations: 
  • Myocardial failure: diastolic dysfunction is frequently reported but less commonly associated with diastolic heart failure. Systolic dysfunction can also occur, but severe systolic dysfunction is rare.  
  • Electrical failure: arrhythmias and conduction disorders 
  • Pericardial failure: pericarditis and pericardial effusion 
  • Coronary failure: coronary microvascular dysfunction 
  • Valvular failure: valvular involvement (uncommon)  

2. What is cardiac amyloidosis (CA) and what is the pathophysiology?  

• For an in-depth review of Cardiac Amyloidosis, enjoy the CardioNerds Cardiac Amyloid Series! 
• Amyloidosis is a process in which proteins misfold, aggregate, and form amyloid fibrils that deposit in various organs, thereby causing tissue injury and organ malfunction. The most common types of cardiac amyloidosis are AL (light chain) and TTR (transthyretin).  
• AL amyloidosis is a hematologic disorder of clonal plasma cells that overproduce light chains, which may deposit in any organ sparing the central nervous system, and commonly deposit in the heart and kidneys.  
• Delayed diagnoses are common, with an estimated one-third of patients visiting five or more physicians before receiving the diagnosis. Cardiac involvement with heart failure portends a particularly poor prognosis, with a median survival from onset of heart failure of less than six months without treatment. Stem cell transplantation has been shown to improve survival if performed prior to the diagnosis of advanced heart failure. Unfortunately, about 80% of patients are not candidates for aggressive therapy due to advanced stage of disease. 
• In CA, amyloid deposits infiltrate and expand the extracellular space which results in increased ventricular wall thickness and classically manifests as a restrictive cardiomyopathy with relatively preserved EF; however, a subset of patients may present with reduced LVEF and minimal or no ventricular wall thickening.  
• Patients with AL cardiac amyloidosis tend to have greater severity of heart failure than TTR despite less morphological involvement (in terms of LV wall thickness), felt due to the toxic effect of light chain amyloid fibrils on the tissue resulting in a toxic-infiltrative cardiomyopathy.  
• Additional mechanisms thought to play a major contributing role in cardiac AL amyloidosis: 
  • Circulating light chains cause direct cardiotoxicity through cardiomyocyte oxidant stress and abnormal vascular reactivity, impairing vasodilation  
  • Vascular amyloid deposition in the small intramural coronary vessels results in microvascular dysfunction and global myocardial ischemia. Vascular involvement is common in AL cardiac amyloidosis (much more common than in TTR cardiac amyloid). A pathology study demonstrated obstructive intramural coronary amyloidosis in 63 of 96 patients (66%) and 86% of these patients had microscopic evidence of myocardial ischemia. Isolated vascular involvement, however, is rare – 97% of patients in this study had interstitial involvement.  
  • Coronary microvascular dysfunction occurs via 3 major mechanisms:  
    • Structural – with amyloid deposition in the vessel wall causing wall thickening and luminal stenosis 
    • Extravascular – through extrinsic compression of the microvasculature from perivascular and interstitial amyloid deposits and decreased diastolic perfusion 
    • Functional – through autonomic and endothelial dysfunction 

3. What are common cardiac MRI (CMR) findings in scleroderma heart disease and cardiac amyloidosis? 

• First, a review of a few key concepts in CMR (also, enjoy Episode #33. Cardiac MRI with Dr. Deborah Kwon): 
  • Native T1 signals are increased by edema (e.g. acute infarction) and an increase in interstitial space (e.g. fibrosis, amyloidosis). T1 signals are decreased by lipid and iron overload.  
  • Gadolinium contrast agents are distributed throughout the extracellular space and shorten the T1 relaxation times of myocardium in proportion to local concentrations of gadolinium – areas of fibrosis/scar will exhibit shorter T1 relaxation times (due to higher gadolinium proportion). 
  • Extracellular volume fraction is calculated using myocardial and blood T1 before and after contrast is administered. It serves as a marker of myocardial tissue remodeling; ECV is increased in amyloid and excessive collagen deposition and serves as a robust marker of myocardial fibrosis. 
  • Late gadolinium enhancement (LGE) – depicts relative difference in the T1 recovery times between enhancing areas of fibrosis or scar (T1 shortened due to accumulation of extracellular gadolinium contrast agent) and normal nulled myocardium (longer T1 as gadolinium contrast agent is more rapidly washed out). 
  • T2 weighted imaging – sensitive to regional or global increases in myocardial water content (i.e. edema). 
• Scleroderma CMR findings:  
  • Perfusion defects – predominantly stress perfusion abnormalities, less common at rest 
  • Increased signal intensity on T2-weighted sequences 
  • Increase in ECV 
  • Delayed enhancement – mainly linear and typically mid-wall (spares the endocardium)  
  • Accurate assessment of RV function, which is particularly important given risk of PAH in these patients 
• Amyloid CMR findings: 
  • T1 signal abnormalities 
  • Increase in ECV 
  • Classically, causes global subendocardial LGE in a noncoronary distribution; however, LGE can also be diffuse and transmural or more localized and patchy 
  • Difficulty nulling the myocardium (the myocardium appears similar to the blood pool) 
    • Myocardial nulling” refers to an inversion recovery pulse sequence that is used to null the signal from a desired tissue to accentuate surrounding pathology.  
    • Normally, the blood pool nulls before the myocardium but in amyloid myocardium nulls simultaneously or before the blood pool 

4. How do we identify if someone has Stage D or advanced heart failure? 

• A topic of critical importance is identifying which patients have advanced or Stage D heart failure, those that are so sick that GDMT alone or interventions including cardiac resynchronization therapy, implantable pulmonary artery pressure monitor, or percutaneous mitral valve repair are unlikely to prolong life and prevent suffering. These patients benefit from timely evaluation for advanced heart failure therapies: left ventricular assist device (LVAD) or orthotopic heart transplant (OHT).  
• Heart failure is a progressive condition. A study in JACC HF in 2017 with Dr. Javed Butler as the senior author showed that in a cohort of outpatients with Stage C HF, 25% progressed to Stage D or died within a 3-year span. They estimated that 100,000 patients a year progress from Stage C to Stage D.  
• Unfortunately, it is not always clear who has made this transition until it is too late. This was reinforced by a study published in 2021 in the Journal of Cardiac Failure. This was a multi-center retrospective analysis of referral patterns for LVAD/transplant, and they showed that 40% of the 515 patients studied were deemed to be too sick to qualify for an advanced therapy, and 60% of the referrals coming from the inpatient setting, clearly too late in the disease course. 

• So how do we identify patients with advanced HF? In addition to the guideline document mentioned, there is a popular mnemonic that can help you remember red flags. 

The mnemonic is “I NEED HELP.” 

I	Inotropes
N	NYHA class III or IV
E	End organ damage
E	Very low EF, <20%
D	Defibrillator shocks
H	Hospitalization, >1 in last 12 months
E	Edema with escalating diuretic doses
L	Low blood pressure
P	Progressive intolerance of GDMT

This identification schema is not perfect, and neither are our definitions for staging patients with heart failure. This is an area in need of active research.  

5. What is a “shock team” and what is its role in the management of cardiogenic shock?  

• In cardiogenic shock, diminished cardiac output leads to systemic hypoperfusion and resultant ischemia, inflammation, vasoconstriction, and salt/fluid retention with volume overload. The short-term mortality in CS is >40%. 
• A multidisciplinary shock team, composed of advanced heart failure, cardiac surgery, interventional cardiology, and critical care facilitates timely consultation and decision making. Observational studies suggest that a shock team approach may improve CS outcomes. A 2019 study published in JACC evaluated the impact of a standardized team-based approach in 204 consecutive patients with CS. 204 consecutive patients with CS were enrolled. They found that 30-day survival in 2017 and 2018 was 57.9% and 76.6%, respectively compared with a 30-day survival of 47% in 2016 (P<0.01).  
• For more on this, enjoy Episode #168. Cardiogenic Shock – Initial Assessment and The Shock Team Call with Dr. Anu Lala as part of the CardioNerds Cardiac Critical Care Series. 

References

1. Bissell LA, Anderson M, Burgess M, et al. Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis. Rheumatology (Oxford). 2017;56(6):912-921. https://pubmed.ncbi.nlm.nih.gov/28160468/ 

2. Bissell LA, Md Yusof MY, Buch MH. Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group. Rheumatology (Oxford). 2017;56(6):882-895. https://pubmed.ncbi.nlm.nih.gov/27940590/ 

3. Tehrani BN, Truesdell AG, Sherwood MW, et al. Standardized Team-Based Care for Cardiogenic Shock. Journal of the American College of Cardiology. 2019;73(13):1659-1669. https://pubmed.ncbi.nlm.nih.gov/30947919/ 

4. Haaf P, Garg P, Messroghli DR, Broadbent DA, Greenwood JP, Plein S. Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review. Journal of Cardiovascular Magnetic Resonance. 2016;18(1):89. https://pubmed.ncbi.nlm.nih.gov/27899132/ 

5. Hachulla A-L, Launay D, Gaxotte V, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Annals of the Rheumatic Diseases. 2009;68(12):1878-1884. https://pubmed.ncbi.nlm.nih.gov/19054830/ 

6. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. 2017;135(14):1357-1377. https://pubmed.ncbi.nlm.nih.gov/28373528/ 

7. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol. 2016;68(12):1323-1341. https://pubmed.ncbi.nlm.nih.gov/27634125/ 

8. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. https://pubmed.ncbi.nlm.nih.gov/19752327/ 

9. Kalogeropoulos AP, Samman-Tahhan A, Hedley JS, et al. Progression to Stage D Heart Failure Among Outpatients With Stage C Heart Failure and Reduced Ejection Fraction. JACC Heart Fail. 2017;5(7):528-537. https://pubmed.ncbi.nlm.nih.gov/28624484/ 

10. Fang JC, Ewald GA, Allen LA, et al. Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee. J Card Fail. 2015;21(6):519-534. https://pubmed.ncbi.nlm.nih.gov/25953697/ 

11. Herr JJ, Ravichandran A, Sheikh FH, et al. Practices of Referring Patients to Advanced Heart Failure Centers. J Card Fail. https://pubmed.ncbi.nlm.nih.gov/34146684/ 

12. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-1443. https://pubmed.ncbi.nlm.nih.gov/11794191/ 

13. Alanna A. MorrisMD, MSc, FAHA, Chair, Prateeti Khazanie, MD, MPH, Vice Chair, Mark H. Drazner, MD, MSc, Vice Chair, Nancy M. Albert, PhD, Khadijah Breathett, MD, MS, FAHA, Lauren B. Cooper, MD, MHS, Howard J. Eisen, MD, Patrick O’Gara, MD, Stuart D. Russell, MD, on behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Hypertension. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001016 

CardioNerds Case Report Production Team