Extracellular volume is an independent predictor of arrhythmic burden in dilated cardiomyopathy

The current stratification of arrhythmic risk in dilated cardiomyopathy (DCM) is sub-optimal. Cardiac fibrosis is involved in the pathology of arrhythmias; however, the relationship between cardiovascular magnetic resonance (CMR) derived extracellular volume (ECV) and arrhythmic burden (AB) in DCM is unknown. This study sought to evaluate the presence and extent of replacement and interstitial fibrosis in DCM and to compare the degree of fibrosis between DCM patients with and without AB. This is a prospective, single-center, observational study. Between May 2019 and September 2020, 102 DCM patients underwent CMR T1 mapping. 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) composed study population. AB was defined as the presence of VT or a high burden of PVCs. There were 41 (41.4%) patients with AB and 58 (58.6%) without AB. Replacement fibrosis was assessed with late gadolinium enhancement (LGE), whereas interstitial fibrosis with ECV. Overall, LGE was identified in 41% of patients. There was a similar distribution of LGE (without AB 50% vs. with AB 53.7%; p = 0.8) and LGE extent (without AB 4.36 ± 5.77% vs. with AB 4.68 ± 3.98%; p = 0.27) in both groups. ECV at nearly all myocardial segments and a global ECV were higher in patients with AB (global ECV: 27.9 ± 4.9 vs. 30.3 ± 4.2; p < 0.02). Only indexed left ventricular end-diastolic diameter (HR 1.1, 95%CI 1.0–1.2; p < 0.02) and global ECV (HR 1.12, 95%CI 1.0–1.25; p < 0.02) were independently associated with AB. The global ECV cut-off value of 31.05% differentiated both groups (AUC 0.713; 95%CI 0.598–0.827; p < 0.001). Neither qualitative nor quantitative LGE-based assessment of replacement fibrosis allowed for the stratification of DCM patients into low or high AB. Interstitial fibrosis, expressed as ECV, was an independent predictor of AB in DCM. Incorporation of CMR parametric indices into decision-making processes may improve arrhythmic risk stratification in DCM.

Electrophysiological Consequences of Cardiac Fibrosis

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.

Echocardiographic global longitudinal strain as a marker of myocardial fibrosis predicts outcomes in aortic stenosis

Background Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) reflects intrinsic myocardial function, influenced by interstitial abnormalities. Cardiovascular magnetic resonance (CMR) detects myocardial fibrosis non-invasively, but it is limited for widespread use. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on CMR and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57±10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR for replacement myocardial fibrosis. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71±12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, myocardial infarction and cerebrovascular events. Results In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74; 95% confidence interval: 0.66–0.83; P&lt;0.001) and calibration (Hosmer-Lemeshow X2=6.37; P=0.605) for replacement fibrosis. In the outcome cohort, 52 events occurred over 16 [3.1, 42.0] months of follow-up. Patients with LV-GLS &gt;−15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS &lt;−21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between −21.0 and −15.0% (log-rank P&lt;0.001; Figure 1). Furthermore, LV-GLS offered independent prognostic value over clinical variables, AS severity, echocardiographic LVEF and E/e' (hazard ratio 1.18; 95% confidence interval: 1.07 to 1.30; P=0.001). Conclusions LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF (Figure 2). FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Medical Research Council Figure 1 Figure 2

Cardiovascular Magnetic Resonance as Pathophysiologic Tool in Diabetes Mellitus

Diabetes mellitus can independently contribute to cardiovascular disease and represents a severe risk factor for premature development of cardiovascular disease. A three-fold higher mortality than the general population has been observed in type 1 diabetes mellitus whereas a two- to four-fold increased probability to develop cardiovascular disease has been observed in type 2 diabetes mellitus. Cardiovascular magnetic resonance, a non-radiative modality, is superior to all other modalities in detecting myocardial infarction. The main cardiovascular magnetic resonance sequences used include a) balanced steady-state free precession (bSSFP) for function evaluation; b) T2-W for oedema detection; c) T1 W for ischemia detection during adenosine stress; and d) late gadolinium enhanced T1-W images (LGE), evaluated 15 min after injection of paramagnetic contrast agent gadolinium, which permit the diagnosis of replacement fibrosis, which appears white in the middle of suppressed, nulled myocardium. Although LGE is the technique of choice for diagnosis of replacement fibrosis, it cannot assess diffuse myocardial fibrosis. The application of T1 mapping (native or pre contrast and post contrast) allows identification of diffuse myocardial fibrosis, which is not detectable my other means. Native T1 and Contrast-enhanced T1 mapping are involved in the extracellular volume fraction (ECV) calculation. Recently, 1H-cardiovascular magnetic resonance spectroscopy has been applied to calculate the amount of myocardial triglycerides, but at the moment it is not part of the routine assessment of diabetes mellitus. The multifaceted nature of cardiovascular magnetic resonance has the great potential of concurrent evaluation of function and myocardial ischemia/fibrosis in the same examination and represents an indispensable tool for accurate diagnosis of cardiovascular disease in diabetes mellitus.

Myocardial extracellular volume by T1 mapping: a new marker of arrhythmia in mitral valve prolapse

Funding Acknowledgements Type of funding sources: None. Background In MVP, MAD has been associated with myocardial replacement fibrosis and arrhythmia, but the importance of interstitial fibrosis remains unknown. We aimed to evaluate the relationship between mitral annular disjunction (MAD) severity and myocardial interstitial fibrosis at the left ventricular (LV) base in patients with mitral valve prolapse (MVP), and to assess the association between severity of interstitial fibrosis and the occurrence of ventricular arrhythmic events Methods Thirty patients with MVP and MAD (MVP-MAD) underwent Cardiac Magnetic Resonance (CMR) with assessment of MAD length, late gadolinium enhancement (LGE), and basal segments myocardial extracellular volume (ECV). The control group included 14 patients with mitral regurgitation but no MAD (MR-NoMAD) and 10 patients with normal CMR (NoMR-NoMAD). Fifteen MVP-MAD patients underwent 24h-Holter monitoring. Results LGE was observed in 47% of MVP-MAD patients and absent in controls. ECV was higher in MVP-MAD (30 ± 3% vs 24 ± 3% MR-NoMAD, p &lt; 0.0001 and vs 24 ± 2% NoMR-NoMAD, p &lt; 0.0001), even in MVP-MAD patients without LGE (29 ± 3% vs 24 ± 3%, p &lt; 0.0001 and vs 24 ± 2%, p &lt; 0.0001, respectively), Fig.1. MAD length was correlated with ECV (rho = 0.61, p = 0.0003), but not with LGE extent. Four patients had history of OHCA; LGE and ECV were equally performant to identify those high-risk patients (area under the ROC curve 0.81 vs 0.83, p = 0.84). Among patients with Holter, 87% had complex ventricular arrhythmia. ECV was above the cut-off value in all while only 53% had LGE. Conclusion Increase in ECV, a marker of interstitial fibrosis, occurs in MVP-MAD even in the absence of LGE, and was correlated with MAD length and OHCA. ECV should be part of the CMR examination of MVP patients in an effort to better assess fibrous remodelling as it may provide additional value beyond the assessment of LGE in the arrhythmic risk stratification.

Lack of Relationship between Fibrosis-Related Biomarkers and Cardiac Magnetic Resonance-Assessed Replacement and Interstitial Fibrosis in Dilated Cardiomyopathy

The relationship between circulating fibrosis-related molecules and magnetic resonance-assessed cardiac fibrosis in dilated cardiomyopathy (DCM) is poorly understood. To compare circulating biomarkers between DCM patients with high and low fibrosis burdens, we performed a prospective, single-center, observational study. The study population was composed of 100 DCM patients (87 male, mean age 45.2 ± 11.8 years, mean ejection fraction 29.7% ± 10.1%). Replacement fibrosis was quantified by means of late gadolinium enhancement (LGE), whereas interstitial fibrosis was assessed via extracellular volume (ECV). Plasma concentrations of cardiotrophin-1, growth differentiation factor-15, platelet-derived growth factor, procollagen I C-terminal propeptide, procollagen III N-terminal propeptide, and C-terminal telopeptide of type I collagen were measured. There were 44% patients with LGE and the median ECV was 27.7%. None of analyzed fibrosis serum biomarkers were associated with the LGE or ECV, whereas NT-proBNP was independently associated with both LGE and ECV, and troponin T was associated with ECV. None of the circulating fibrosis markers differentiated between DCM patients with and without replacement fibrosis, or patients stratified according to median ECV. However, cardiac-specific markers, such as NT-proBNP and hs-TnT, were associated with fibrosis. Levels of circulating markers of fibrosis seem to have no utility in the diagnosis and monitoring of cardiac fibrosis in DCM.

Cardiac Imaging for Risk Assessment of Malignant Ventricular Arrhythmias in Patients With Mitral Valve Prolapse

Recent studies have described the occurrence of complex ventricular arrhythmias and sudden cardiac death among patients with mitral valve prolapse (MVP). The reported incidence rate of sudden cardiac death or ventricular tachycardia is about 1–1.5% among patients with MVP. Various imaging markers have been associated with this increased risk, including mitral annular disjunction, replacement fibrosis by late gadolinium enhancement, and mechanical dispersion. In this review, we briefly discuss how multimodality cardiac imaging can be applied to identify MVP patients with high risk of sudden cardiac death and complex ventricular arrhythmias.

Can shear wave imaging distinguish between diffuse interstitial and replacement myocardial fibrosis?

Funding Acknowledgements Type of funding sources: None. Background Diffuse interstitial or myocardial replacement fibrosis are common features of a large variety of cardiomyopathies. These alterations contribute to functional changes, particularly to an increased myocardial stiffness (MS). Histological examination is the gold standard for myocardial fibrosis quantification, however, it requires endomyocardial biopsy which is invasive and not without risks. Cardiac magnetic resonance (CMR) can characterize the extent of both diffuse and replacement fibrosis and may have prognostic value in various cardiomyopathies. Echocardiographic shear wave (SW) elastography is an emerging approach for measuring MS in vivo. SWs occur after mechanical excitation of the myocardium, e.g. after mitral valve closure (MVC), and their propagation velocity is directly related to MS, thus providing an opportunity to assess stiffness at end-diastole. Purpose The aim was to investigate if velocities of natural SW can distinguish between interstitial and replacement fibrosis. Methods We prospectively enrolled 47 patients (22 patients after heart transplant [54.2 ± 15.8 years, 82.6% male] and 25 patients with established hypertrophic cardiomyopathy [54.0 ± 13.5 years, 80.0% male]) undergoing CMR during their check-up. We performed SW elastography in parasternal long axis views of the LV using a fully programmable experimental scanner (HD-PULSE) equipped with a clinical phased array transducer (Samsung Medison P2-5AC) at 1100 ± 250 frames per second. Tissue acceleration maps were extracted from an anatomical M-mode line along the midline of the LV septum. The SW propagation velocity at MVC was measured as the slope in the M-mode image. All patients underwent T1 mapping as well as late gadolinium enhancement (LGE) cardiac magnetic resonance at 1.5 T to assess the presence of diffuse or replacement fibrosis (Figure A). Therefore, patients were divided in three groups: no fibrosis, diffuse fibrosis and replacement fibrosis. Results Mechanical SW’s were observed in 46 subjects starting immediately after MVC and propagating from the LV base to the apex. SW propagation velocity at MVC correlated well with native myocardial T1 values (r = 0.65, p &lt; 0.0001) and differed significantly among groups (p &lt; 0.0001), with a significant post-test between any pair of groups (Figure B). SW velocities below a cut-off of 6.01 m/s showed the highest accuracy to identify patients without any type of fibrosis (sensitivity 88 %, specificity 89%, area under the curve = 0.93) (Figure C). A cut-off of 8.11 m/s could distinguish replacement fibrosis from diffuse fibrosis with a sensitivity and specificity of 59% and 92 %, respectively (area under the curve = 0.80) (Figure D). Conclusions Shear wave velocities after mitral valve closure can distinguish between normal and pathological myocardium and can detect differences between diffuse and replacement fibrosis. Abstract Figure.