Background HIV is associated with elevated risk of heart failure ( HF ). Despite poor agreement between automated, administrative code–based HF definitions and physician‐adjudicated HF , no studies have evaluated incident adjudicated HF for people living with HIV ( PLWH ). Methods and Results We analyzed PLWH and uninfected controls receiving care in an urban medical system from January 1, 2000, to July 12, 2016. Physicians reviewed data from medical records to adjudicate HF diagnoses. We used multivariable‐adjusted Cox models to analyze incident HF for PLWH versus controls and HIV ‐related factors associated with incident HF . We also analyzed the performance of automated versus physician‐adjudicated HF definitions. Incident adjudicated HF occurred in 97 of 4640 PLWH (2.1%; mean: 6.8 years to HF ) and 55 of 4250 controls (1.3%; mean: 6.7 years to HF ; multivariable‐adjusted hazard ratio: 2.10; 95% confidence interval, 1.38–3.21). Among PLWH , higher HIV viral load ( hazard ratio per log 10 higher time‐updated viral load: 1.22; 95% confidence interval, 1.11–1.33) was associated with greater HF risk and higher CD 4+ T cell count was associated with lower HF risk ( hazard ratio per 100 cells/mm 3 higher time‐updated CD 4 count: 0.80; 95% confidence interval, 0.69–0.92). In exploratory analyses, the most accurate automated HF definitions had sensitivities of 67% to 75% and positive predictive values of 54% to 60%. Conclusions In a cohort with rigorous HF adjudication, PLWH had greater risks of HF than uninfected people after adjustment for demographics and cardiovascular risk factors. Higher HIV viral load and lower CD 4+ T cell count were associated with higher HF risk among PLWH . Automated methods of HF ascertainment exhibited poor accuracy for PLWH and uninfected people.

BackgroundHuman Immunodeficiency Virus-Infected (HIV+) persons have elevated risks for various manifestations of cardiovascular disease (CVD). No studies to our knowledge have compared atrial fibrillation (AF) and atrial flutter (AFL) prevalence and associated characteristics for HIV+ persons and matched uninfected controls.Methods and findingsPersons with diagnoses of HIV receiving care at a large urban academic medical center were frequency-matched 1:2 on age, sex, race, zip code, and clinic location with uninfected persons. Possible AF/AFL was screened for using administrative codes and diagnoses of AF/AFL were subsequently adjudicated using electrocardiography and physician notes; adjudication was performed given the inconsistent validity of administrative code-derived AF diagnoses found in previous studies. There were 101 confirmed AF/AFL cases (2.00%) among 5,052 HIV+ patients and 159 confirmed AF/AFL cases (1.57%) among 10,121 uninfected controls [Odds Ratio (OR) 1.27, 95% Confidence Interval (CI) 0.99–1.64; p = 0.056]. The association between HIV serostatus and AF/AFL was attenuated after adjustment for demographics and CVD risk factors. Among HIV+ persons, nadir CD4+ T cell count <200 cells/mm3 was associated with approximately twofold elevated odds of AF/AFL even after adjustment for demographics and CVD risk factors (Multivariable-adjusted OR 1.98, 95% CI 1.21–3.25). There was no significant association between log10 of peak HIV viral load and AF/AFL (Multivariable-adjusted OR 1.03, 95% CI 0.86–1.24). Older age, diabetes, hypertension, and chronic obstructive pulmonary disease were associated with similarly elevated odds of AF/AFL for HIV+ persons and uninfected controls.ConclusionHIV-related immunosuppression (nadir CD4 T cell count <200 cells/mm3) and traditional CVD risk factors are associated with significantly elevated odds of AF/AFL among HIV+ persons. Although atrial fibrillation and flutter was more common among HIV+ versus uninfected persons in this cohort, this difference was attenuated by adjustment for demographics and CVD risk factors.

Aims HIV-infected persons may have elevated risks for heart failure, but factors associated with heart failure in the modern era of HIV therapy are insufficiently understood. Despite substantial disagreement between physician-adjudicated heart failure and heart failure diagnosis codes, few studies of HIV cohorts have evaluated adjudicated heart failure. We evaluated associations of HIV viremia, immunosuppression, and cardiovascular risk factors with physician-adjudicated heart failure. Methods and results We analyzed clinical characteristics associated with heart failure in a cohort of 5041 HIV-infected patients receiving care at an urban hospital system between 2000 and 2016. We also evaluated characteristics of HIV-infected patients who screened negative for heart failure, screened positive for possible heart failure but did not have heart failure after adjudication, and had adjudicated heart failure. HIV-infected patients with heart failure (N = 216) were older and more likely to be black, hypertensive, and have diabetes than HIV-infected patients without heart failure; heart failure with reduced ejection fraction was more common than heart failure with preserved ejection fraction. In our primary analyses restricted to HIV-infected patients whose heart failure diagnoses did not precede their HIV diagnoses (N = 149), peak HIV viral load ≥100,000 copies/mL (odds ratio (OR) 2.12, 1.28–3.52) and nadir CD4 T-cell count <200 cells/mm3 (OR 2.35, 1.04–5.31) were associated with significantly elevated odds of heart failure. Overall, 30.6% of patients with any diagnosis code of heart failure had adjudicated heart failure. Conclusion Higher peak HIV viremia and lower CD4 cell nadir are associated with significantly elevated odds of heart failure for HIV-infected persons. Physician adjudication of heart failure may be helpful in HIV cohorts.

To penetrate host tissues, histotoxic clostridia secrete virulence factors including enzymes to hydrolyze extracellular matrix. Clostridium histolyticum, recently renamed as Hathewaya histolytica, produces two classes of collagenase (ColG and ColH). The high-speed AFM study showed that ColG collagenase moves unidirectionally to plane collagen fibril and re-bundles fibril when stalled [1]. The structural explanation of the roles for the tandem collagen-binding segment (CBDs) is illuminated by its calcium-bound crystal structure at 1.9 Å resolution (Rwork=15.0%; Rfree=19.6%). Activation may involve calcium-dependent domain rearrangement supported by both small angle X-ray scattering and size exclusion chromatography. At pCa≥5 (pCa=-log[Ca2+]), the tandem CBD adopts an extended conformation that may facilitate secretion from the bacterium. At pCa≤4, the compact structure seen in the crystal structure is adopted. This arrangement positions the two binding surfaces ~55 Å apart, and possibly ushers ColG along tropocollagen molecules that allow for unidirectional movement. A sequential binding mode where tighter binding CBD2 binds first could aid in processivity as well. Switch from processive collagenolysis to fibril rearrangement could be concentration dependent. Collagen fibril formation is retarded at 1:1 molar ratio of tandem CBD to collagen. Tandem CBD may help isolate a tropocollagen molecule from a fibril at this ratio. At 0.1:1 to 0.5:1 molar ratios fibril self-assembly was accelerated. Gain of function as a result of gene duplication of CBD for the M9B enzymes is speculated. The binding and activation modes described here will aid in drug delivery design.

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.