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• This study included 216 patients taking tacrolimus after heart transplantation, 81 of whom were switched from mycophenolate to sirolimus after 1 year. • Treatment with sirolimus was associated with a reduction in intimal thickness on serial IVUS studies, driven by patients diagnosed with rapidly progressive CAV. • However, the transition to sirolimus was not associated with cardiovascular events after a median follow-up of 8.6 years. Inhibition of the mammalian target of rapamycin (mTor) pathway after heart transplantation has been associated with reduced progression of coronary allograft vasculopathy (CAV). The application of low-dose mTOR inhibition in the setting of modern immunosuppression, including tacrolimus, remains an area of limited exploration. This retrospective study included patients who received heart transplantation between January 2009 and January 2019 and had baseline, 1-year and 2–3-year coronary angiography with intravascular ultrasound (IVUS). Intimal thickness in 5 segments along the left anterior descending artery was compared across imaging time points in patients who were transitioned to low-dose mTOR inhibitor (sirolimus) vs standard treatment with mycophenolate on a background of tacrolimus. Long-term adverse cardiovascular outcomes (revascularization, severe CAV, retransplant, and cardiovascular death) were also assessed. Among 216 patients (mean age 51.5 ± 11.9 years, 77.8% men, 80.1% white), 81 individuals (37.5%) were switched to mTOR inhibition. mTOR inhibition was associated with a reduction in intimal thickness by 0.05 mm (95% CI 0.02–0.07; P < 0.001). This reduction was driven by patients who met the criteria for rapidly progressive CAV 1-year post-transplant (0.12 mm; P = 0.016 for interaction). After a median follow-up of 8.6 (IQR 6.6–11) years, 40 patients had major adverse cardiovascular outcomes. The use of mTOR inhibitors was not significantly associated with cardiovascular outcomes (P = 0.669). Transitioning patients after heart transplantation to an immunosuppression regimen composed of low-dose mTOR inhibition and tacrolimus was associated with a lack of progression of CAV, particularly in those with rapidly progressive CAV at 1 year, but not with long-term cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE‐HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin‐treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin‐treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits. [ABSTRACT FROM AUTHOR]

Background: Gene expression profiling (GEP) and donor‐derived cell‐free DNA (dd‐cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single‐center experience of combined GEP and dd‐cfDNA testing for AR surveillance. Methods: GEP and dd‐cfDNA are tested together starting at 2 months post‐OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd‐cfDNA. This approach was compared to using a GEP‐only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd‐cfDNA usage. Results: A total of 153 OHT patients over a 13‐month period underwent 495 combined GEP/dd‐cfDNA tests. 82.2% of dd‐cfDNA tests were below threshold. Above threshold results identified high‐risk patients who developed AR. 378 combined tests ≥6 months post‐OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody‐mediated rejection episodes, and no significant AR ≥6 months. Conclusion: Routine dd‐cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re‐classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd‐cfDNA identified patients at higher risk for AR. [ABSTRACT FROM AUTHOR]

Posttraumatic activation of the catabolic cascade plays a major role in degradation of cartilage. Interleukin-1β (IL-1β), a primary instigator in the catabolic axis, is upregulated in chondrocytes following injury. IL-1β activates key degradative enzymes, including MMPs and aggrecanases, and other proinflammatory mediators such as PGE2 which contribute to ECM breakdown. Posttranscriptional silencing of IL-1β by RNA interference (RNAi) may drive a reduction in IL-1β. We hypothesized that transduction of chondrocytes using rAAV2 expressing a short hairpin RNAi motif targeting IL-1β (shIL-1β) would significantly decrease IL-1β expression and, in turn, decrease expression of other catabolic enzymes. Chondrocyte cultures were transduced with rAAV2-tdT-shIL-1β in serum-free media. The fluorescent protein, tdTomato, was used to determine transduction efficiency via flow cytometry and fluorescent microscopy. Cells were stimulated with lipopolysaccharide (LPS) 48 hours following transduction. After 24-hour stimulation, supernatants were collected for cytokine analysis, and cells lysed for gene expression analysis. IL-1β knockdown led to significantly decreased expression of IL-1β, TNF-α, and ADAMTS5. PGE2 synthesis was also significantly downregulated. Overall, effective silencing of IL-1β using rAAV2 vector expressing a short hairpin IL-1β knockdown sequence was shown. Additionally, significant downstream effects were evident, including decreased expression of TNF-α and ADAMTS5. Targeted silencing of catabolic cytokines may provide a promising treatment avenue for osteoarthritic (OA) joints. [ABSTRACT FROM AUTHOR]

Objectives: We sought to assess the diagnostic accuracy and incremental prognostic value of delayed hyper-enhancement cardiac magnetic resonance (DHE-CMR) compared with electrocardiographic and transthoracic echocardiographic (TTE) parameters in such patients. Background: Utility of DHE-CMR in the diagnosis of patients with suspected cardiac amyloidosis (CA) has recently been demonstrated, but its incremental prognostic utility is unclear. Methods: Forty-seven consecutive patients (mean age 63 years, 70% men, 55% New York Heart Association functional class >II) with suspected CA who underwent electrocardiography (ECG), TTE, DHE-CMR, and biopsy (38 endomyocardial, 9 extracardiac) were studied. Low voltage on ECG was defined as S-wave in lead V1 + R-wave in lead V5 or V6 <15 mm. TTE parameters, including deceleration time, E/E′ ratio, and diastolic grade were recorded. CMR was considered positive with diffuse DHE of the subendocardium extending to adjacent myocardium. All-cause mortality was ascertained. Results: In the study population, 59% had low voltage on ECG, 30% had abnormal deceleration time ≤150 ms, 38% had E/E′ ratio >15, and 47% had advanced (pseudonormal or restrictive) diastology. The diagnostic accuracy of DHE-CMR in patients undergoing endomyocardial biopsy was as follows: sensitivity 88%, specificity 90%, positive predictive value 88%, and negative predictive value 90%. On multivariable logistic regression testing of the diagnostic ability of various noninvasive imaging parameters, only DHE-CMR was significant (Wald chi-square statistic 9.6, p < 0.01). At 1-year post-biopsy, there were 9 (19%) deaths. On Cox proportional hazards analysis, only positive DHE-CMR was a predictor of 1-year mortality (Wald chi-square statistic 4.91, p = 0.03). Conclusions: A characteristic DHE-CMR pattern is more accurate for diagnosis and is a stronger predictor of 1-year mortality in patients with suspected CA as compared with other noninvasive parameters. [Copyright &y& Elsevier]

Background: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) with the MitraClip rapidly improved health status and reduced the long-term risks for death and heart failure (HF) hospitalization in patients with HF and severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT).Objectives: The aim of this study was to examine if early health status changes were associated with long-term clinical outcomes in the COAPT population.Methods: The association between change in health status (Kansas City Cardiomyopathy Questionnaire overall summary score [KCCQ-OS]) from baseline to 1 month and the composite rate of death or HF hospitalization between 1 month and 2 years in the COAPT trial were evaluated, and whether treatment (TMVr or GDMT alone) modified this association was tested.Results: Among 551 patients with HF and severe secondary mitral regurgitation who were alive at 1 month, those randomized to TMVr were more likely than those randomized to GDMT alone to achieve a ≥10-point improvement in KCCQ-OS from baseline to 1 month (TMVr, 58%; GDMT alone, 26%). Early improvement in KCCQ-OS was inversely associated with the risk for death or HF hospitalization between 1 month and 2 years (p < 0.001). When analyzed as a continuous variable, a 10-point increase in KCCQ-OS was associated with a 14% lower risk for death or HF hospitalization (hazard ratio: 0.86; 95% confidence interval: 0.81 to 0.92; p < 0.001), with no significant interaction with treatment group (pinteraction = 0.17). After adjusting for demographic and clinical factors, the association between change in KCCQ-OS and outcomes was strengthened (hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p < 0.001).Conclusions: In patients with HF and severe secondary mitral regurgitation, a short-term change in disease-specific health status was strongly associated with the subsequent long-term risk for death or HF hospitalization. These findings reinforce the prognostic utility of serial KCCQ-OS assessments to identify patients at risk for poor long-term clinical outcomes in this population. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079). [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) and preserved ejection fraction (EF) have been shown to have high mortality rates, comparable to those with reduced EF. Thus, long-term survivors of HF, regardless of ejection fraction, are a select group. Little is known about disease-related quality of life (QOL) and health status in these patients., Hypothesis: Preserved EF in patients with heart failure independently predicts long-term survival, health related quality of life (QOL), or functional status., Methods: The study followed a cohort of 413 patients consecutively hospitalized for HF between March 1996 and September 1998. In July 2005, information was collected about their mortality, health related QOL as defined by disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and functional decline as defined by limitations in Activities of Daily Living (ADL) scores., Results: The primary outcomes were mortality, QOL, and functional decline. At follow-up, 8.1 years after enrollment, overall mortality was 76% (314/413). Adjusted for age, gender, renal insufficiency, diabetes mellitus, hypertension, HF, and respiratory disease, those with decreased ejection fraction (EF < 40%) had higher mortality compared with those with preserved ejection fraction (hazard ratio [HR] 1.42; confidence interval [CI] = 1.13, 1.80, p = 0.003). The KCCQ scores, including Clinical Summary Scores and Symptom Limitation Scores, as well as ADL limitations, were not significantly different in the survivors with preserved or decreased EF., Conclusions: Heart failure patients with preserved EF have a modest survival advantage compared with those with decreased EF, but health related QOL scores and functional decline in survivors are similar regardless of systolic function.