Impact of Myocardial Viability Assessed by Delayed Enhancement Cardiovascular Magnetic Resonance on Clinical Outcomes in Real World Practice

Background: Delayed enhancement cardiovascular magnetic resonance imaging (DeCMRI) has become the preferred method for viability assessment. It is well established that viable dysfunctional myocardium has the potential for functional recovery after revascularization. Objective: Our objective is to evaluate whether viability assessment by DeCMRI affects clinical outcome in daily clinical practice. Methodology:We retrospectively studied 132 consecutive patients (114 male, mean age 59 ± 10 years) with ischaemic cardiomyopathy (Mean LVEF: 29.1 ± 14%) who underwent CMRI viability testing from 1st Jan-31st Dec 2015 in our centre. Patientswere divided into 3 groups: Group A: Viable myocardium- optimal medical therapy only (38.6%); B: Viable myocardium- revascularization done (29.5%); and C: Nonviable myocardium (29.5%). Results: Mean age for groups A, B and C were 61.2, 58.3, 56.2 years respectively, p=0.048. The proportion of triple vessel disease in each of the groups were 56.1%, 54.5% and 38.5% (p=0.44); whereas left main involvement was 31.7%, 21.2% and 19.2% respectively (p=0.43). Majority of group C patients did not undergo revascularisation (90%). Group B had statistically significant EF improvement (5.5%, SD 11.9) compared to Group A (-0.6%, SD 6.7) and Group C (-1.2%, SD 9.8), p value 0.014. Mortality at 1 year was significantly higher in Group A compared to Group Band C (31.4%, 7.7% and 12.8% respectively, p=0.009). MACE rates were also increased in Group A compared to the other two groups (41.2%, 20.5% and 27.0%, p=0.09). Odds Ratio for MACE was 3.01 (95% Cl 1.22 - 7.45) for Group A vs B and 2.8 (95% Cl 1.1 - 6.9) for Group A vs C. Conclusion: Patients with viable myocardium who did not undergo revascularization (group A) had the worst prognosis, even when compared to those with non-viable myocardium; with significantly higher 1-year mortality. Although not statistically significant, there was also a trend towards higher MACE in these patients. These findings emphasize that patients with poor LV function but viable myocardium need to undergo revascularisation and that optimal medical therapy alone is not sufficient

The role of extracellular volume fraction in predicting left ventricular reverse remodelling and adverse outcomes in patients with non-ischemic cardiomyopathy and reduced left ventricular ejection fraction

Cardiac magnetic resonance (CMR) permits the quantification of extracellular volume fraction (ECV) which is a surrogate marker of myocardial interstitial fibrosis. ECV has been shown to predict heart failure (HF) events. Conversely, left ventricular reverse remodelling (LVRR) defined as decrease in chamber volumes and improvement in function, has a positive impact on prognosis. In patients with non-ischemic cardiomyopathy (NICM), the role of ECV in LVRR is not established

Echocardiographic improvement of left atrial booster pump and reservoir function observed in heart failure with improved ejection fraction and its prognostication

The novel subgroup of Heart Failure with improved ejection fraction(HFimpEF) is focused on improving left ventricle systolic function, but there is sparse data on left atrial(LA) recovery. Recent studies observed reversal remodelling of LA echocardiographic volume indices in HFimpEF. However, there is a lack of data on the echocardiographic description of volumetric LA functions, such as booster pump and reservoir dysfunction, in patients with HFimpEF

Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003. Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys, 120 girls; mean age: 11.9+/-2.8 years). About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients. Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean+/-SD: 5.76+/-3.61 years). During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections). Four patients had endstage renal failure (ESRF) (one died during a lupus flare). All deaths and end-stage renal failure occurred in the Class IV nephritis group. Chronic organ damage was infrequent in the survivors. The actuarial patient survival rates at 5, 10 and 15 years of age were 95.3, 91.8, and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies.postprin

Human SCARB2-Mediated Entry and Endocytosis of EV71

Enterovirus (EV) 71 infection is known to cause hand-foot-and-mouth disease (HFMD) and in severe cases, induces neurological disorders culminating in fatality. An outbreak of EV71 in South East Asia in 1997 affected over 120,000 people and caused neurological disorders in a few individuals. The control of EV71 infection through public health interventions remains minimal and treatments are only symptomatic. Recently, human scavenger receptor class B, member 2 (SCARB2) has been reported to be a cellular receptor of EV71. We expressed human SCARB2 gene in NIH3T3 cells (3T3-SCARB2) to study the mechanisms of EV71 entry and infection. We demonstrated that human SCARB2 serves as a cellular receptor for EV71 entry. Disruption of expression of SCARB2 using siRNAs can interfere EV71 infection and subsequent inhibit the expression of viral capsid proteins in RD and 3T3-SCARB2 but not Vero cells. SiRNAs specific to clathrin or dynamin or chemical inhibitor of clathrin-mediated endocytosis were all capable of interfering with the entry of EV71 into 3T3-SCARB2 cells. On the other hand, caveolin specific siRNA or inhibitors of caveolae-mediated endocytosis had no effect, confirming that only clathrin-mediated pathway was involved in EV71 infection. Endocytosis of EV71 was also found to be pH-dependent requiring endosomal acidification and also required intact membrane cholesterol. In summary, the mechanism of EV71 entry through SCARB2 as the receptor for attachment, and its cellular entry is through a clathrin-mediated and pH-dependent endocytic pathway. This study on the receptor and endocytic mechanisms of EV71 infection is useful for the development of effective medications and prophylactic treatment against the enterovirus

T Cell-Dependence of Lassa Fever Pathogenesis

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development

Impact of total ischemic time (TIT) on 1-month clinical outcomes at a tertiary cardiology centre (TCC) with a limited primary percutaneous coronary intervention (LPPCI) service in the management of ST-elevation myocardial infarction (STEMI)

PPCI is the recommended treatment strategy over fibrinolytic for treatment of STEMI. However, majority of hospitals offer only a LPPCI service or fibrinolytic strategy for STEMI. TIT is associated with clinical outcomes for both treatment strategies. At a single public access tertiary cardiology centre (SPATCC) covering a large geographical area, a LPPCI service is provided

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors