Association of Left Ventricular Volume in Predicting Clinical Outcomes in Patients with Aortic Regurgitation.

BACKGROUND: Aortic regurgitation (AR) is a common valvular lesion associated with increased mortality once the left ventricle enlarges significantly or develops systolic dysfunction (ejection fraction < 50%). Valve guidelines recommend aortic valve repair or replacement (AVR) for left ventricular (LV) linear end-systolic dimension ≥ 50 mm or end-diastolic dimension ≥ 65 mm. However, chamber quantification guidelines recommend using LV volume for LV size determination because linear measurements may not accurately reflect LV remodeling. The aim of this study was to evaluate the correlation of LV volumes with linear dimensions, interobserver variability in the estimation of volumes, and the association of volumes with outcomes in patients with AR. METHODS: A total of 1,100 consecutive patients with chronic moderate to severe and severe AR on echocardiography between 2004 and 2019 were retrospectively analyzed. The modified Simpson disk summation method was used for LV volume estimation. The primary outcome was all-cause mortality; the secondary outcome was mortality censored at AVR. RESULTS: Patients' age was 60 ± 17 years, and 198 were women (18%). Volumes were measured using the biplane method in 939 patients (85%) and the monoplane method in 161 (15%); end-systolic volume was normal in 169 (11%). Correlations between volumes and linear dimensions were 0.5 for end-diastolic volume and 0.6 for end-systolic volume. At median follow-up of 5.4 years (interquartile range, 2.4-10.0 years), 216 patients had died and 539 had undergone AVR. Indexed LV end-systolic volume (iLVESV) and indexed left ventricular end-systolic dimension were both associated with mortality and symptoms, but the association of iLVESV was stronger. iLVESV, age, male gender, Charlson comorbidity index, New York Heart Association functional class III or IV, and time-dependent AVR were independently associated with all-cause mortality. Interobserver variability in the estimation of LV volumes in 200 patients included intraclass coefficients of 0.94 (95% CI, 0.92-0.95) for end-diastolic volume and 0.88 (95% CI, 0.78-0.93) for end-systolic volume. Patients with iLVESV ≥ 45 mL/m2 had lower survival and a higher prevalence of symptoms than those with volumes < 45 mL/m2. CONCLUSIONS: Echocardiographic LV volume assessment had good reproducibility in patients with moderate to severe and severe AR. The correlation between linear dimensions and volumes was limited. Both iLVESV and indexed left ventricular end-systolic dimension were associated with worse outcomes, but the association of iLVESV was stronger. iLVESV ≥ 45 mL/m2 was associated with worse outcomes.

Worsening Renal Function in Cardiac Mechanical Support.

BACKGROUND: Venous congestion in heart failure (HF) may lead to worsening renal failure (WRF). We hypothesised that WRF in patients hospitalised for left ventricular assist device (LVAD) implantation is associated with increased 1-year mortality. There is limited data regarding WRF in HF patients with mechanical support. The objective of this paper is to determine whether WRF in HF patients hospitalised for LVAD implantation is associated with increased 1-year mortality and to identify risk factors for WRF. METHODS: We performed a single centre retrospective chart analysis of 162 patients who received an LVAD between August 2006 and December 2014 with pre-LVAD right heart catheterisation data. We stratified patients to those who demonstrated WRF and the use of haemodialysis (HD) or ultrafiltration (UF). RESULTS: Patients with a higher central venous pressure (CVP) >16 mmHg (17-24 mmHg range) developed WRF (29.7% vs. 14.1%, p=0.019). A CVP ≥16 and glomerular filtration rate (GFR) <30 ml/min/1.74m2 increased the odds of WRF. Worsening renal failure and HD/UF use were associated with increased 1-year mortality. Furthermore GFR <30, atherosclerosis, and right ventricular failure were independent predictors for increased 1-year mortality. A GFR <30 increased the odds of developing WRF five-fold (OR 4.14, CI [1.95-8.78], p<0.0001), and GFR <30 and central venous pressure (CVP) >16 increased the odds of requiring HD/UF. CONCLUSIONS: Worsening renal failure is associated with a higher CVP at the time of LVAD implantation and increases the risk of 1-year mortality and the odds of requiring HD/UF. Careful evaluation of renal function and comorbid conditions during LVAD implantation is critical to reduce mortality and for risk stratification.

Celiac Crisis Associated with Herpes Simplex Virus Esophagitis.

Celiac crisis is a rare presentation of celiac disease that is characterized by life-threatening electrolyte abnormalities, vitamin and mineral deficiencies, and diarrhea. Triggers for celiac crisis include major surgeries, pancreatitis, and infections of cytomegalovirus, and salmonella. A 24-year-old woman presented with celiac crisis associated with severe herpes simplex virus (HSV) esophagitis. This case demonstrates that nutritional deficiencies seen in celiac disease can result in a relative immunodeficiency, which may lead to other infectious complications. Additionally, early recognition of celiac crisis is imperative as the metabolic derangements may be life-threatening, and therapy with gluten restriction and nutritional repletion is effective.

Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme.

Insulin degrading enzyme (IDE) utilizes a large catalytic chamber to selectively bind and degrade peptide substrates such as insulin and amyloid beta (Abeta). Tight interactions with substrates occur at an exosite located approximately 30 A away from the catalytic center that anchors the N-terminus of substrates to facilitate binding and subsequent cleavages at the catalytic site. However, IDE also degrades peptide substrates that are too short to occupy both the catalytic site and the exosite simultaneously. Here, we use kinins as a model system to address the kinetics and regulation of human IDE with short peptides. IDE specifically degrades bradykinin and kallidin at the Pro/Phe site. A 1.9 A crystal structure of bradykinin-bound IDE reveals the binding of bradykinin to the exosite and not to the catalytic site. In agreement with observed high K(m) values, this suggests low affinity of bradykinin for IDE. This structure also provides the molecular basis on how the binding of short peptides at the exosite could regulate substrate recognition. We also found that human IDE is potently inhibited by physiologically relevant concentrations of S-nitrosylation and oxidation agents. Cysteine-directed modifications play a key role, since an IDE mutant devoid of all 13 cysteines is insensitive to the inhibition by S-nitrosoglutathione, hydrogen peroxide, or N-ethylmaleimide. Specifically, cysteine 819 of human IDE is located inside the catalytic chamber pointing toward an extended hydrophobic pocket and is critical for the inactivation. Thiol-directed modification of this residue likely causes local structural perturbation to reduce substrate binding and catalysis.