7/25/2019

Ventricular

Erik Schelbert, MD MS Director, Cardiovascular Magnetic Resonance Heart & Vascular Institute University of Pittsburgh

Disclosure

• Gadolinium based contrast agents for cardiac purposes remains “off label”

• I believe cardiac MR is underutilized to the detriment of patient care

Conclusions

• CMR is a remarkably versatile tool for clinicians and researchers to ascertain risks of ventricular arrhythmias and sudden cardiac death (SCD)

• CMR can establish a wide variety of cardiovascular conditions and gauge disease severity

• LGE tissue characterization is especially important

• Trials of CMR guided care are underway to link therapeutics to diagnostics

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• Sustained ventricular (VT): regular wide QRS complex (≥120 milliseconds) tachycardia at a rate greater than 100 beats per minute, >30 sec

• Nonsustained (VT): <30 sec

• Ventricular (VF): most frequent cause of SCD. VF is a rapid, disorganized ventricular , resulting in hemodynamic collapse

Clinically…

• Most patients with VT or VF have underlying cardiac disease…

• …and remain at risk for sudden cardiac death (SCD)

• Note: when VT and VF occur in “normal” hearts, consider molecular derangements of cardiac ion channels or structural proteins where risk of SCD remains high

Our jobs ultimately are about people: Who has what disease and how severe? How to treat? Leverage CMR to exclude structural abnormalities and nonstructural disorders

http://static.guim.co.uk/sys-images/Guardian/Pix/pictures/2013/1/30/1359549064145/Crowd-of-people-008.jpg

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Main approach for VT/VF/SCD risk stratification

1. Accurately assess left ventricular ejection fraction

CMR is the gold standard (not MUGA in my opinion and many others)

2. Identify other substrates for sudden cardiac death including obstructive CAD

3. Correct substrates when able or consider ICD

Those at lowest apparent risk constitute the biggest fraction of SCD since denominator of those at less risk is huge

Huikuri HV, Castellanos A, Myerburg RJ. Engl J Med, Vol. 345, No. 20, p 1473 Nov 15, 2001

SCD-HeFT

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Same trend for ischemic and nonischemic CM

but more pronounced in ischemic CM

DANISH Trial

No all cause mortality benefit with ICD for primary prevention in DANISH Trail

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• Less power than SCD-HeFT

• Probably more heterogeneity in NICM with respect to LGE

• But significantly less SCD !

CMR is versatile (“table of truth”—almost) • Image characteristics on CMR exams with LGE do stratify risk of arrhythmia • Identification of severel substrates: – Focal (midwall) myocardial fibrosis (LGE) – Diffuse myocardial fibrosis (ECV) – Myocardial (1st pass perfusion) – Unrecognized (LGE) – Anomalous coronary arteries (noncontrast MRA) – Amyloidosis (LGE, ECV) – Hypertrophic (cines) – Arrhythmogenic right ventricular cardiomyopathy/dysplasia (cines) – Left dominant arrhythmogenic cardiomyopathy (LDAC) (cines and LGE) – Cardiac sarcoidosis (LGE) – (LGE)

What CMR cannot do

• While CMR can easily identify , cannot distinguish severe from moderate aortic stenosis (but CMR great for regurgitant valve disease)

• Quantify elevated PA pressures

• Long/short QT syndromes and Brugada syndrome

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) – exercise stress test with increasing PVC with increasing exercise or nonsustained/sustained VT

• Metabolic derangements

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Options for CMR Scan sequences

• Localizers • Cines • T1, T2, and T2* mapping (for edema, iron and Fabry) • Coronary, aortic MR angiography • Stress 1st pass myocardial perfusion • Aortic and pulmonary arterial flow quantification • Late gadolinium enhancement • Post contrast T1 mapping for extracellular volume

Coronary anomalies

• Anomalous aortic origin of a coronary artery is one of the leading causes sudden cardiac death in pediatric and young adult patients

• Easy to add on to routine CMR scans in those with palpitations/syncope/chest pain/arrhythmia

• No contrast needed!

• CMR not good for identifying myocardial bridges; CT better for coronary aneurysms with Kawasaki disease

Noel C. Cardiac stress MRI evaluation of anomalous aortic origin of a coronary artery. Congenital Heart Disease. 2017;12:627–629. https://doi.org/10.1111/chd.12501

Classic case series : 242 isolated coronary anomaly pts

• High risk anatomy involved abnormalities of the initial coronary artery segment or coursing of the anomalous artery between the pulmonary artery and aorta. • Younger patients (<30 years old) more likely than older patients to die suddenly (62% vs. 12%, p=0.001) or during exercise (40% vs. 2%. p= 0.00001) despite low frequency of CAD (1% vs. 40%, p = 0.00001).

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Coronaries through the “valley of death” • Anomalous right coronary artery (RCA = black arrow) arising from the left sinus of Valsalva and coursing interatrially between the aorta (AO) and the pulmonary artery (PA). • Oblique origin and intramural course within the aortic wall may impair coronary blood flow

CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=30975234 Shaalan A, El Wakee E, Alassal MA, Ebaid HH (2016) Rare unexpected anatomy of the coronary artery: combination of two coronary anomalies case reportJIntegrCardiol,2: DOI: 10.15761/JIC.1000158

Not all that common but they do occur

• Anomalous origin of the RCA from the left sinus – 0.92% incidence

• Anomalous origin of the left coronary artery from the right sinus – 0.15% incidence

• total incidence of 1.07% for anomalous coronaries from opposite sinus

Angelini P, Villason S, Chan AV, Diez JG. Normal and anomalous coronary arteries in humans. In: Angelini P, ed. Coronary Artery Anomalies: A Comprehensive Approach. Philadelphia: Lippincott Williams & Wilkins; 1999:27–150.

Local case: 31 year old woman with syncope, 1 mo postpartum, and recurrent wide complex tachycardia and required amiodarone and lidocaine infusions. Then noted to have an anomalous RCA from left cusp on CMR. She received reimplantation of the RCA

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Finally, CMR contributes to diagnosis of ARVD

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• LGE is a big deal, identifying:

–ventricular arrhythmia substrate

–stratifying risk of SCD

CMR with late gadolinium enhancement is very powerful

Normal Inferior transmural MI Some substrates for ventricular arrhythmia and sudden cardiac death…

Midwall fibrosis (trastuzumab) Cardiac amyloidosis

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Mechanism of LGE -relative volume of distribution of Gd -dead myocytes or protein deposition

Focal myocardial fibrosis

• Echo and nuclear techniques will never detect it

A model based on: -CMR-LVEF ≤35% plus late gadolinium enhancement (LGE) vs -TTE-LVEF

Net reclassification improvement of 0.468 (95% confidence interval, 0.283–0.654; P<0.001) for VT/SCD

NRI 0.413 (95% confidence interval, 0.23–0.63; P<0.001) for SCD alone, respectively.

CMR provides additional prognostic value over TTE

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Collagen (and amyloid) protein

• Ample experimental data show how disruption of the myocardial architecture (excess collagen, amyloid protein deposition) impairs electrical conduction and creates substrate for reentry

• Protein deposition in the myocardium always bad !

• Collagen blocks electric conduction

• Substrate for reentry

Focal fibrosis in nonischemic

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Midwall fibrosis in septum detected by CMR in DCM

472 patients

5.3 yr median follow-up

30% prevalence

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Multivariable modeling for Sudden Cardiac Death

In NICM, CRT-D better than CRT-P only if midwall fibrosis present

Median EF ~25%

Sudden cardiac death

Sudden cardiac death + Hospitalization for ventricular arrhythmia

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Midwall LGE and the primary composite outcome of SCD or aborted SCD in those with LVEF ≥40%

• prospective • prespecified endpoint • 399 consecutive pts with dilated cardiomyopathy • no preexisting indication for ICD !

Halliday BP, et al. Circulation. 2017;135:2106–2115. DOI: 10.1161/CIRCULATIONAHA.116.026910

Very strong signal for LGE despite relatively small sample with milder disease (LVEF ≥40% 57% NYHA class 1)

Halliday BP, et al. Circulation. 2017;135:2106–2115. DOI: 10.1161/CIRCULATIONAHA.116.026910

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Remarkable discrimination for LGE despite relatively small sample with milder disease (LVEF ≥40% 57% NYHA class 1)

Halliday BP, et al. Circulation. 2017;135:2106–2115. DOI: 10.1161/CIRCULATIONAHA.116.026910

Focal fibrosis in combined ischemic or nonischemic dilated cardiomyopathy populations

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More LGE in those with events for both ICM and DCM (does etiology matter much?)

LGE

Ischemic scar (i.e., MI) in 35%

Nonischemic scar in 43%

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ICD

5% threshold of LGE, above which Death/ICD Rx triples

Examples

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Conclusions: The presence and quantitative burden of Late Gadolinium Enhancement (LGE) in CMR provides important prognostic information regarding:

• all-cause mortality, • cardiovascular mortality, • ventricular arrhythmia and sudden death, and • major adverse cardiovascular events

Consideration should be given to the utilization of LGE-CMR in future trials of risk stratification in ICM and NICM patients.

Epicardial

• Does asymptomatic plaque rupture occur providing an additional mechanism of myocardial scar?

• Is unrecognized MI – Prevalent? – prognostically adverse?

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Pathology data: Sudden Cardiac Death victims without known CAD

• Subclinical coronary plaque rupture occurs frequently, particularly in diabetic individuals

• Latent phase of coronary atherosclerotic activity prior to clinical presentation

• ? high incidence of unrecognized MI ?

Burke AP, Kolodgie FD, Farb A, et al. Circulation 2001;103:934-40

Unrecognized MI postulates

Recognized MI

Unrecognized MI

Foot print of unstable coronary disease

Schelbert EB, et al JAMA 2012

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90 yr old participant has 2 UMI !

Prevalence: Unrecognized MI >> Recognized MI

Schelbert EB, et al JAMA 2012

Schelbert EB, et al JAMA 2012

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Low rates of statin use

These data may be the best rebuttal to the widely publicized concerns of Dr. Rita Redberg

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CMR UMI data

• Failure of MI prevention

• Failure of MI detection

• Apparent under utilization of statins

• Just how liberal with statins should we be?

• Integrating published data about LGE to date, unrecognized likely associates with SCD as well

• case-control ECG autopsy SCD study of UMI in a consecutive Finnish population cohort 1998-2017, n=5869

• Unrecognized MI was detected in 1322 individuals (42.4%) with SCD without • clinical CAD. – older than participants without MI – more often men – Higher heart weight was in – more often during physical activity – A prior ECG was abnormal in 125 of 187 (67%)

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Randomized trial of LGE- guided Rx in ischemic and nonischemic cardiomyopathy with LGE randomizing to ICD or loop recorder in those with -LGE -EF 36-50%

Conclusions

• CMR is a remarkably versatile tool for clinicians and researchers to stratify risks of ventricular arrhythmia and sudden death

• CMR can establish a wide variety of cardiovascular conditions linked to SCD and gauge disease severity

• LGE tissue characterization is especially important

• Trials of CMR guided care are underway to link therapeutics to diagnostics

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Thank you

23 7/25/2019

Diffuse myocardial fibrosis

ExtraCellular Volume fraction (ECV) measures myocardial interstitial expansion

=myocardial Gd uptake relative to plasma (not whole blood measured from images)

Schelbert EB, Fonarow GC, Bonow RO, Butler J, Gheorghiade M. JACC 2014

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Diffuse fibrosis important: SCD in isolated LVH associates with excess collagen

Pittsburgh cohort: ECV predicts serious ventricular arrhythmia (appropriate ICD shock)

ACC 2018 “Diffuse myocardial fibrosis measured by extracellular volume associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients more than focal fibrosis

Shock or anti-tachycardia pacing

ACC 2018 “Diffuse myocardial fibrosis measured by extracellular volume associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients more than focal fibrosis

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Diffuse myocardial fibrosis measured by extracellular volume associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients more than focal fibrosis • Background: Diffuse myocardial fibrosis (DMF) in non-infarcted myocardium may associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis since DMF may affect large amounts of myocardium. This distinction remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to medical therapy. • Methods and results: Among patients referred for cardiovascular magnetic resonance (CMR) evaluations without congenital heart disease, hypertrophic cardiomyopathy, or amyloidosis, we identified those (n=215) subsequently receiving implantable cardioverter defibrillators (ICD). We quantified DMF with extracellular (ECV) volume measures and examined time from ICD to 1) appropriate shock, or 2) shock or anti-tachycardia pacing therapy. Over a median follow-up of 2.9 years, 25 patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing therapy. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints in all models (e.g., HR 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, , and myocardial infarction). Other variables related to focal fibrosis or native T1 did not exhibit such associations. • Conclusions: DMF quantified by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose response fashion, even adjusting for potential confounding variables whereas native T1 and variables related to focal fibrosis do not. The ability of ECV to stratify risk and the suitability of DMF as a therapeutic target to prevent life threatening ventricular arrhythmia warrant further investigation. ACC 2018

Potential medical therapy for diffuse myocardial fibrosis

• Renin angiotensin aldosterone inhibitors • Other agents in development

Schelbert, EB, et al. Circ Cardiovasc Imaging. 2017;10:e005619. DOI: 10.1161/CIRCIMAGING.116.005619

Cardiac amyloidosis

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CMR with late gadolinium enhancement is very powerful

Normal Inferior transmural MI Some substrates for ventricular arrhythmia and sudden cardiac death…

Midwall fibrosis (trastuzumab) Cardiac amyloidosis

CMR may diagnose occult cardiac amyloidosis in patients incidentally

• The prevalence of coexisting CA (mostly ATTR) in patients with: – HFpEF1 – TAVR2 • approximates 15%.

1. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G et al. Wild-type transthyretin amyloidosis as a cause of with preserved ejection fraction. Eur Heart J 2015;36:2585-94.

2. Castano A, Narotsky DL, Hamid N et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter replacement. Eur Heart J 2017;38:2879-2887.

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Very high rates of ICD shock, death, or transplant

• Relentless clinical decline…competing adverse events

Myocarditis

• A 15-year-old male presented clinically with myocarditis. • CMR demonstrated a severely dilated impaired left ventricle • end diastolic volume index, 160 mL/m2; • ejection fraction, 42%, • normal proximal coronary arteries, • a pattern of late gadolinium enhancement (LGE) which indicated extensive • myocardial scarring as a result of myocarditis (Figure 2). • The patient remained asymptomatic. • Unfortunately, he died suddenly 2 years later.

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Cardiac Sarcoidosis

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Hypertrophic cardiomyopathy

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Coronary anomalies

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