Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy

Cardiomyopathy

1. Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 75, NO. 10, 2020

2. Dilated cardiomyopathy (DCM) is common, estimated prevalence of up to 1 in 250 of the population . Mortality rates remain high and is the leading cause of heart transplantation. INTRODUCTION Male patients, the incidence of death is 3.6 per 100 patient-years, whereas in women it is 2.3 per 100 patient-years. Death occurs from cardiovascular causes, such as heart failure progression (pump failure) or sudden cardiac death (SCD) and noncardiac causes.

3. AIM Review study focuses on predicting outcomes in idiopathic and genetic DCM, as inflammatory DCM has been reviewed recently elsewhere

4. DCM results from a diverse range of etiologies including complex interactions between the environment and genetic predisposition. Familial, representing genetic basis and >50 genes have been associated with the condition Inflammatory DCM occurs from abnormal responses to pathogens and a result of autoimmune disease, also occur from exogenous insults such as alcohol and chemotherapy PATHOPHYSIOLOGY Common sequelae of different etiologies is adverse remodeling of the left ventricle with progressive dilatation and impairment of mechanical function with accompanying myocardial fibrosis. Fibrosis can occur as focal replacement (scar) tissue, interstitial fibrosis, and perivascular fibrosis, become a substrate for life-threatening arrhythmia, further impairment of mechanical function

5. CURRENT RISK PREDICTION METHODS IN SUDDEN CARDIAC DEATH American Heart Association and European Society of Cardiology guidelines recommend implantable cardioverter-defibrillator (ICD) implantation in DCM patients who are in New York Heart Association functional class II to III heart failure with left ventricular ejection fraction (LVEF) <35% DANISH (defibrillator implantation in patients with nonischemic systolic heart failure) trial assessed the efficacy of primary prevention with ICD. all-cause mortality was not significantly improved, subgroup analysis did show benefit in patients age <58 years, patients who experience SCD with heart failure have an LVEF >30%underlining the need to identify those who are at risk with LVEF >35%. Multiple risk prediction models have been created to predict risk of SCD, none have made the international guidelines

6. CURRENT RISK PREDICTION METHODS FOR HEART FAILURE DEATH When assessing prognosis to assist referral for advanced heart failure treatment, decisions are often made on clinical grounds with information supplemented by cardiopulmonary exercise testing (CPEX) and heart catheterization Several multiparametric risk prediction models incorporating clinical, cardiopulmonary variables, and laboratory blood tests have been created and have been incorporated into international guidelines performance is questionable with wide variations in discrimination and are outperformed by the newer metabolic exercise test data combined with cardiac and kidney indexes score; however, none of these are specific to DCM

7. Risk Assessment in Nonischemic Dilated Cardiomyopathy

8. Risk Assessment in Nonischemic Dilated Cardiomyopathy

9. CARDIAC MAGNETIC RESONANCE IMAGING Echocardiography is the first line investigation for heart failure, with its high accessibility, excellent assessment of hemodynamics and valvular abnormalities, and relatively low cost. decisions are often made on clinical grounds with information supplemented by cardiopulmonary exercise testing (CPEX) and heart catheterization CMR is the gold standard technique for the quantification of volumes and ejection fraction, with better accuracy and reproducibility than echocardiography CMR used to identify or exclude ischemic etiology in the work-up of DCM and to act as a gatekeeper for coronary angiography Provides value_Inflammatory cardiomyopathies, sarcoid and myocarditis through distinctive patterns of late gadolinium enhancement (LGE), and directs further investigations and cause-specific treatment

10. ASSESSMENT OF REMODELING IN DCM DCM, cardiac chambers undergo remodeling, which is characterized by dilatation and impairment of systolic function in the left and often right ventricle. Remodeling is dynamic and improvement is known as left ventricular reverse remodeling patients who demonstrate this phenomenon have good prognosis, with transplant-free survival of 95% versus 71% in those who do not at 180-month followup

11. ASSESSMENT OF REMODELING IN DCM DCM, remodeling of the right ventricle and atria as a result of primary myocardial disease or secondary hemodynamic consequences of left ventricular dysfunction. Right ventricular dysfunction is supported by a DANISH CMR substudy in which patients with right ventricular ejection fraction <45% benefited from ICD therapy. Increased left atrial volume indexed for body surface area by CMR is predictive of all-cause mortality and transplantation. studies highlight the importance of changes in cardiac chambers other than the LV, which are easier to quantify with CMR than echocardiography.

12. Familial Dilated cardiomyopathy is defined as an individual diagnosed with DCM with >1 relative diagnosed with DCM or 1 first-degree relative with unexplained SCD age <35 years. In familial DCM, around 40% have an identifiable genetic cause, with >50 genes identified that overlap with other cardiomyopathies ETIOLOGY OF DCM (Dilated cardiomyopathy)

13. IMAGING IN THE DETECTION OF FIBROSIS CMR is the ability to characterize tissue and detect fibrosis. LGE is a post-contrast CMR technique that detects focal fibrosis and correlates with Native T1 mapping and extracellular volume assessment (with post-contrast T1 imaging) have been shown to correlate with interstitial fibrosis on histology and enable identification of diffuse fibrosis not seen with LGE

14. (A) Nonischemic midwall fibrosis (black arrows). (B) Cardiac sarcoid with distinctive patchy midwall and epicardial late gadolinium enhancement (LGE) (white arrows). (C) Dilated cardiomyopathy with subendocardial LGE (yellow arrows) suggesting ischemic cause. (D) Native T1 mapping with increased T1 time in septum. (E) Same patient with no LGE present. (F) Same patient with increased septal extracellular volume 2 CMR in the Assessment of Fibrosis in DCM

15. LATE GADOLINIUM ENHANCEMENT LGE has also been shown to predict a composite outcome of SCD and aborted SCD in patients with LVEF >40%, suggesting it may be helpful in selecting patients for defibrillator therapy who do not meet the criteria in current guideline. LGE is in 30% of patients with DCM, typically in a midwall pattern CMR-GUIDE (Cardiac Magnetic Resonance GUIDEd Management of Mild-moderate Left Ventricular Systolic Dysfunction) trial is currently recruiting and assesses whether ICD implantation improves outcomes in a population with ischemic or nonischemic cardiomyopathy (LVEF 36% to 50%) with >2 segments of LGE.

16. T1 MAPPING AND EXTRACELLULAR VOLUME QUANTIFICATION Native T1 mapping time has been shown to predict outcome in the largest study, the average ejection fraction was relatively preserved, questioning its validity in patients with severe disease Later studies are less convincing for native T1 mapping, demonstrating only trends toward adverse outcome. ECV quantification, appears to be more consistent in predicting outcome and is of incremental benefit to LVEF

17. Studies Examining T1 Mapping and ECV Quantification in DCM CI_confidence interval; ECV_ extracellular volume; LVEF_ left ventricular ejection fraction; MACE_major adverse cardiac events; NYHA_New York Heart Association; RVEF_right ventricular ejection fraction.

18. MYOCARDIAL DEFORMATION IMAGING IN DCM Myocardial strain is expressed as the percentage change in myocardial length Strain is quantified using algorithms of echocardiography (speckle tracking) and CMR (tissue or feature tracking) and allows comprehensive assessment ventricular function Myocardial deformation can detect subtle abnormalities in relatives of patients who carry sarcomeric mutations but have normal LVEF and volumes relation between myocardial strain and prognosis has been reported in 4 studies in DCM populations

19. Functional Assessment of Dilated Cardiomyopathy (A) Assessment of left ventricular and right ventricular volumes and ejection fraction. (B to D) Assessment of global longitudinal strain in a patient with dilated cardiomyopathy (DCM) and ejection fraction 40%; overall global longitudinal strain 7.4%. (B) Four-chamber assessment of global longitudinal strain. (C) Threechamber assessment of global longitudinal strain. (D) Two-chamber assessment of global longitudinal strain

20. Studies Relating Strain to Prognosis in DCM BNP_brain natriuretic peptide; BSA_body surface area; CHF_congestive heart failure; DCM_dilated cardiomyopathy; GCS_global circumferential strain; GLS_global longitudinal strain; GRS_global radial strain; IDCM_ischemic dilated cardiomyopathy; IHD_ischemic heart disease; LAS_ong-axis strain; LVEDV_ left ventricular end-diastolic volume; MCS_mean circumferential strain; MLS_mean longitudinal strain; MRS_mean radial strain; Naþ_serum sodium;

21. CIRCULATING BIOMARKERS TO PREDICT PROGNOSIS IN DCM NATRIURETIC PEPTIDES AND TROPONIN Brain natriuretic peptide, N-terminal pro-brain natriuretic peptide (NT-proBNP) have been found to be related to all-cause mortality in multiple studies. NT-proBNP_ role in predicting those most likely to die from pump failure, will not benefit from ICD implantation. A cut off for troponin T of >18 ng/l was found to be predictive of all-cause mortality in nonischemic heart failure after adjustment for covariables.

22. CIRCULATING BIO-MAKERS OF FIBROSIS: SOLUBLE SUPPRESSION OF TUMEROGENICITY (sST)FACTOR 2 AND GALECTIN-3 MARKERS TO PREDICT PROGNOSIS IN DCM sST-2 is a member of the interleukin family released by fibroblasts and cardiomyocytes in heart failure and is associated with fibrosis and adverse LV remodeling Galectin 3 is a protein that is present as a result of tissue stress in many organs, including the heart, and its release results in myofibroblast activation sST-2 and galectin-3 have both been found to predict all cause mortality in heart failure of mixed etiology in a meta-analysis subgroup analysis revealed that sST-2 remained predictive in idiopathic and inflammatory DCM but not familial DCM, whereas galectin-3 appeared to be predictive in the inflammatory DCM

23. MULTIMARKER STRATEGY prospective study of 864 outpatients patients with chronic heart failure (48% nonischemic) examined the effect of adding NT-proBNP, hs troponin T, and ST2 to the Barcelona Bio-HF risk score all 3 biomarkers increased discrimination, which was significantly better than adding 1 biomarker to the model pathophysiological processes linked to the relevant biomarker and point toward more sophisticated multiparametric models.

24. GENETICS DCM has substantially increased, enabled largely through next-generation sequencing and genome-wide association studies genetics of DCM is complex and characterized by incomplete penetrance, variable expressivity, unclear association between genotypes, and DCM-specific phenotypes pathophysiological processes linked to the relevant biomarker and point toward more sophisticated multiparametric models.

25. TITIN Titin truncating variants that disrupt 1 copy of the titin gene are observed in up to 25% of familial and 15% of sporadic cases of DCM Titin variants have also been associated with alcoholic, chemotherapy, and peripartum cardiomyopathies conflicting evidence_titin truncating variants confer a higher risk of receiving appropriate ICD therapy, increased with midwall fibrosis

26. LAMIN A/C Mutations are found in around 6% of DCM patients (enriched in younger cases) and confer a worse prognosis with respect to SCD, response to treatment, death, and transplantation LMNA mutations found a risk prediction in sex, atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction. 5-year risk of life-threatening ventricular arrhythmia ≥7% predicted 96.2% of life-threatening ventricular arrhythmias and was able to reclassify 28.8% of these patients from guideline (ESC/AHA)-directed care

27. OTHER NOTABLE GENOTYPES Filamin C (FLNC) gene mutations in DCM are linked to high rates of ventricular arrhythmias, cardiac arrest, heart transplantation, and left ventricular fibrosis at premature age RBM20 mutations have recently found to have high penetrance and produce an arrhythmogenic phenotype Mutations in the BAG-3 have recently been found to cause a DCM with high penetrance (80% over 40 years) Associated with increased incidence of death and cardiac transplantation but not arrhythmic events Suggesting it has a role in predicting who may need advanced heart failure treatment

28. EXERCISE TESTING CPEX quantifies oxygen consumption (VO2), CO2 produced, and ventilation integrates with hemodynamic and electrocardiographic monitoring. Ventilatory efficiency (VE/VCO2), predicted VO2, exercise oscillatory ventilation, and oxygen uptake efficiency slope reflect the pathophysiological changes seen in heart failure and predict poor outcome Peak VO2 provide incremental benefit to LVEF, LGE, and natriuretic peptides in the DCM population, underlining its potential utility in multiparametric models

29. CPEX TO GUIDE CLINICAL MANAGEMENT CPEX_used in the assessment & prognostication of ambulatory DCM patients who are being considered for advanced heart failure treatment Peak VO2 and VE/VCO2 are recommended in the international society for heart and lung transplantation guidelines for selection for transplantation patients with borderline peak VO2, the heart failure survival score in the high/medium risk range should be considered for listing (Class IIb) A Seattle Heart Failure Model 1 year survival of <80% with appropriate peak VO2 is an indication (Class IIb),scores were derived from older cohorts and may not reflect the modern heart failure population.

30. GENETICS DCM has substantially increased, enabled largely through next-generation sequencing and genome-wide association studies genetics of DCM is complex and characterized by incomplete penetrance, variable expressivity, unclear association between genotypes, and DCM-specific phenotypes 40% of familial DCM cases, a likely diseasecausing genetic variant is found, with lesser yield in nonfamilial DCM

31. Genes in Dilated Cardiomyopathy Associated With Adverse Outcome AHA_American Heart Association; ARVC_arrhythmogenic right ventricular cardiomyopathy; DCM_dilated cardiomyopathy; EF_ejection fraction; ESC_European Society of Cardiology; ICD_implantable cardioverter-defibrillator; LGE_late gadolinium enhancement; NA_ not available; SCD_sudden cardiac death; TTN_ titin; TTNtv_titin truncation

32. TITIN Titin truncating variants that disrupt 1 copy of the titin gene are observed in up to 25% of familial and 15% of sporadic cases of DCM. Titin truncations appear to be associated with good prognosis and good response to therapy, which may be useful in prognostic modeling titin truncating variants confer a higher risk of receiving appropriate ICD therapy, which is increased with midwall fibrosis

33. LAMIN A/C Mutations are found in around 6% of DCM patients (enriched in younger cases) and confer a worse prognosis with respect to SCD, response to treatment, death, and transplantation ( LMNA mutations found a risk prediction model including sex, atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction was predictive of lifethreatening ventricular tachyarrhythmia in 839 patients The 5-year risk of life-threatening ventricular arrhythmia $7% predicted 96.2% of life-threatening ventricular arrhythmias and was able to reclassify 28.8% of these patients from guideline (European Society of Cardiology/American Heart Association)-directed care

34. Genes in Dilated Cardiomyopathy Associated With Adverse Outcome Ambulatory patients achieve maximal volitional effort, peak oxygen consumption VO2 is recommended variable for selection, cut-off dependent on beta-blocker therapy. If the score is uncertain or intermediate, the heart failure survival score can be used to supplement the decision (Class IIb). In younger, obese, and female patients, peak VO2 should be adjusted for body weight and quoted as percentage predicted peak VO2. If exercise testing is submaximal, use VE/VCO2 (Class IIb).

35. CONCLUSIONS Pathophysiology is different to ischemic cardiomyopathy, ICD implantation is clearly of benefit in patients with low LVEF. Advances in genetic sequencing and cardiac imaging, have allowed the identification of patients with DCM at higher risk of both SCD and pump failure. Future holds great promise in improving risk stratification by incorporation of genetic, imaging, and circulating biomarkers in combined scores with clinical and CPEX variables . Before such risk scores can be used in clinical practice, they will require extensive validation in large and specific DCM cohorts.