Assessment of myocardial mechanics in chronic rheumatic mitral regurgitation

A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, for the degree of Doctor of Philosophy Johannesburg 2016Chronic rheumatic mitral regurgitation (CRMR) is a commonly encountered lesion in the developing world, yet it remains an understudied disease in comparison to degenerative MR. There are several unresolved issues in CRMR ranging from limited data on the current demographic and clinical profile of the contemporary patient with CRMR, to the evaluation of this lesion with sophisticated techniques utilising strain (Ɛ), magnetic resonance imaging (MRI) and biomarkers. Furthermore, the role of medical therapy has been mainly restricted to studies pertaining to degenerative MR. Thus, in this thesis the aim was to address some of the aforementioned deficiencies in the field of CRMR. In the process of studying the atrioventricular functional parameters in CRMR, we established age and vendor-specific (Philips QLAB 9) normative data for left atrial (LA) functional and volumetric parameters in a normal black population. Eighty four subjects with CRMR were studied at Chris Hani Baragwanath Hospital (CHBAH) and compared with a prior landmark study by Marcus et al conducted at this institution. Mean age was 44.0±15.3 years, compared to 19 years in the study by Marcus et al. Acute rheumatic fever (ARF) was rare compared to the previous study. Hypertension and human immunodeficiency virus (HIV) were present in 52% and 26% respectively. Echocardiography showed leaflet thickening and calcification, restricted motion and sub-valvular disease, as opposed to pliable leaflets with predominant prolapse and chordal rupture in the study by Marcus et al. One hundred and twenty normal black subjects from 18 and 70 years of age were studied. Maximum LA volume indexed (LAVi) was 19.7±5.9 mL/m2. LA pump function increased with age (r=0.2, p=0.02), and the conduit function decreased with age (r=-0.3, p< 0.001). LA Ɛ in the reservoir phase was 39.0±8.3%. LA Ɛ in the reservoir phase declined with age (p<0.001). Two studies were conducted using speckle tracking in 77 patients with CRMR. The first study found that 86% had decreased LA peak reservoir Ɛ and 58% had depressed left ventricular (LV) peak systolic Ɛ. In the second study, right ventricle (RV) peak systolic Ɛ was lower in the MR group compared to controls (-16.8±4.5% vs -19.2±3.4%, p=0.003). LV peak systolic Ɛ was an independent predictor of RV peak systolic Ɛ (r=0.46, p<0.004). CRMR is a disease characterised by eccentric jets due to distorted leaflet architecture. Thus, the echocardiographic proximal isovelocity surface area (PISA) method, to assess MR severity, is suboptimal. In CRMR there may be involvement of the LV by the rheumatic process especially in the postero basal region. To study these issues, 22 patients without comorbidities underwent MRI. On comparison of MR severity assessment by echocardiography (using an integrated approach) and MRI, there was concordance between the two techniques in all but seven patients. Six patients were reclassified as severe MR after MRI and one patient was re-categorised as moderate MR. Only four patients had fibrosis on late gadolinium enhancement. No particular regional involvement was noted. We also studied markers of collagen degradation and synthesis in CRMR and their relation with MRI parameters. Matrix metalloproteinase-1 was increased compared to controls (log MMP-1 3.5±0.68 vs 2.7±0.9, p=0.02), implying increased collagen degradation rather than synthesis in CRMR. This supports the paucity of fibrosis found on MRI. Effects of combination medical therapy in heart failure (HF) secondary to severe CRMR in 31 patients was studied. On optimal therapy no HF-related admissions or deaths were noted. There was improvement in LA peak systolic strain. LV and RV functional indices remained unchanged on maximal therapy. In conclusion, the contemporary CRMR patients are older, have comorbidities and less ARF. Upper limits of maximum LAVi are lower in the black population compared to Caucasians, and age needs to be considered when interpreting abnormalities of LA function. LA dysfunction was noted with or without involvement of the LV, therefore perhaps in CRMR, LA dysfunction precedes LV dysfunction. RV peak systolic Ɛ was useful for assessment of subclinical RV dysfunction in CRMR, therefore quantitative measurement of RV systolic function should not rely solely on conventional indices. Cardiac MRI was a useful adjunctive tool for MR severity assessment in 32% of CRMR patients when echocardiography alone was insufficient. CRMR is characterised by predominant collagen degradation and is associated with low prevalence of fibrosis. Finally, there may be a role for combination anti-remodelling therapy in HF secondary to MR. Finally, we have provided normal reference ranges for LA volume and strain parameters that would serve as platform for future studies in this population. Our findings pertaining to imaging, biomarkers and role of combination anti-remodelling therapy in CRMR may aid in the clinical assessment and management of patients with CRMR, and serve as a base for further research in these fields.MT201

Rôles et mécanismes moléculaires de l'apoptose cardiovasculaire en réponse à des antihypertenseurs

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