Renal implications of pulmonary arterial capacitance in acute heart failure with preserved ejection fraction.

Worsening renal function in patients with heart failure with preserved ejection fraction is associated with poor outcomes. Pulmonary arterial capacitance is a novel right heart catheterization derived hemodynamic metric representing pulmonary arterial tree distensibility and right ventricle afterload. Given the strong association between heart failure, pulmonary hypertension, and kidney function, the goal of this study is to investigate the correlation between Pulmonary arterial capacitance and long-term renal function in patients with heart failure with preserved ejection fraction. In this retrospective single center study, data from 951 patients with the diagnosis of heart failure, who underwent right heart catheterization were analyzed. Eight hundred and one patients with reduced ejection fraction, end-stage kidney disease on hemodialysis, acute myocardial infarction, and severe structural valvular disorders, were excluded. Pulmonary arterial capacitance was calculated as the stroke volume divided by pulmonary artery pulse pressure (mL/mmHg). Hemodynamic and clinical variables including baseline renal function were obtained at the time of the right heart catheterization, and renal function was also obtained at 3-5 years after right heart catheterization. The final cohort consisted of 150 subjects with a mean age 68 ( ± 14.2) years, 93 (62%) were female. The mean value for Pulmonary arterial capacitance was 2.82 ( ± 2.22) mL/mm Hg and the mean Glomerular Filtration Rate was 60.32 mL/min/l.73 m² ( ± 28.36). After multivariate linear regression analysis (including baseline Estimated Glomerular Filtration Rate as one of the variates), only age and Pulmonary arterial capacitance greater than 2.22 mL/mm Hg were predictors of long term Glomerular Filtration Rate. Pulmonary arterial capacitance as a novel right heart catheterization index could be a predictor of long-term renal function in patients with heart failure with preserved ejection fraction.

Dynamics of Dystrophin's Actin-Binding Domain.

We have used pulsed electron paramagnetic resonance, calorimetry, and molecular dynamics simulations to examine the structural mechanism of binding for dystrophin's N-terminal actin-binding domain (ABD1) and compare it to utrophin's ABD1. Like other members of the spectrin superfamily, dystrophin's ABD1 consists of two calponin-homology (CH) domains, CH1 and CH2. Several mutations within dystrophin's ABD1 are associated with the development of severe degenerative muscle disorders Duchenne and Becker muscular dystrophies, highlighting the importance of understanding its structural biology. To investigate structural changes within dystrophin ABD1 upon binding to actin, we labeled the protein with spin probes and measured changes in inter-CH domain distance using double-electron electron resonance. Previous studies on the homologous protein utrophin showed that actin binding induces a complete structural opening of the CH domains, resulting in a highly ordered ABD1-actin complex. In this study, double-electron electron resonance shows that dystrophin ABD1 also undergoes a conformational opening upon binding F-actin, but this change is less complete and significantly more structurally disordered than observed for utrophin. Using molecular dynamics simulations, we identified a hinge in the linker region between the two CH domains that grants conformational flexibility to ABD1. The conformational dynamics of both dystrophin's and utrophin's ABD1 showed that compact conformations driven by hydrophobic interactions are preferred and that extended conformations are energetically accessible through a flat free-energy surface. Considering that the binding free energy of ABD1 to actin is on the order of 6-7 kcal/mole, our data are compatible with a mechanism in which binding to actin is largely dictated by specific interactions with CH1, but fine tuning of the binding affinity is achieved by the overlap between conformational ensembles of ABD1 free and bound to actin.

Oxidation increases the strength of the methionine-aromatic interaction.

Oxidation of methionine disrupts the structure and function of a range of proteins, but little is understood about the chemistry that underlies these perturbations. Using quantum mechanical calculations, we found that oxidation increased the strength of the methionine-aromatic interaction motif, a driving force for protein folding and protein-protein interaction, by 0.5-1.4 kcal/mol. We found that non-hydrogen-bonded interactions between dimethyl sulfoxide (a methionine analog) and aromatic groups were enriched in both the Protein Data Bank and Cambridge Structural Database. Thermal denaturation and NMR spectroscopy experiments on model peptides demonstrated that oxidation of methionine stabilized the interaction by 0.5-0.6 kcal/mol. We confirmed the biological relevance of these findings through a combination of cell biology, electron paramagnetic resonance spectroscopy and molecular dynamics simulations on (i) calmodulin structure and dynamics, and (ii) lymphotoxin-α binding toTNFR1. Thus, the methionine-aromatic motif was a determinant of protein structural and functional sensitivity to oxidative stress.

Blood stream infection is associated with cerebrovascular accident in patients with left ventricular assist device: a systematic review and meta-analysis.

Cerebrovascular accident (CVA) is one of the major complications and a leading cause of death in patients with a left ventricular assist device (LVAD). Multiple studies of have shown that patients with blood stream infection (BSI) are more likely to develop CVA compared to patients without BSI. However, there is no meta-analysis to confirm this association. Studies were systematically acquired from MEDLINE and EMBASE electronic databases. Included studies assessed patients with heart failure requiring LVAD and reported the number of patients who had BSI post LVAD, incidence of ischemic CVA, hemorrhagic CVA, or any CVA. Pooled effect size was calculated with a random-effect model, weighted for the inverse of variance. Heterogeneity was assessed with I2. Six studies were analyzed. Participants with LVAD who developed BSI were more likely to have a CVA compared to participants without BSI (RR 3.43, 95% CI 2.49-4.72, I2 = 0). In four studies, there was an association between BSI and increased incidence of hemorrhagic CVA post LVAD (RR 5.28, 95% CI 2.65-10.53) with minimal heterogeneity (I2 = 30%). In three studies, participants with BSI were more likely to develop ischemic CVA (RR 2.18, 95% CI 1.23-3.84) compared to patients without BSI. This meta-analysis suggested that there maybe an association between blood stream infection and cerebrovascular accident in patients with LVAD.

Synaptotagmin I's Intrinsically Disordered Region Interacts with Synaptic Vesicle Lipids and Exerts Allosteric Control over C2A.

Synaptotagmin I (Syt I) is a vesicle-localized integral membrane protein that senses the calcium ion (Ca(2+)) influx to trigger fast synchronous release of neurotransmitter. How the cytosolic domains of Syt I allosterically communicate to propagate the Ca(2+) binding signal throughout the protein is not well understood. In particular, it is unclear whether the intrinsically disordered region (IDR) between Syt I's transmembrane helix and first C2 domain (C2A) plays an important role in allosteric modulation of Ca(2+) binding. Moreover, the structural propensity of this IDR with respect to membrane lipid composition is unknown. Using differential scanning and isothermal titration calorimetry, we found that inclusion of the IDR does indeed allosterically modulate Ca(2+) binding within the first C2 domain. Additionally through application of nuclear magnetic resonance, we found that Syt I's IDR interacts with membranes whose lipid composition mimics that of a synaptic vesicle. These findings not only indicate that Syt I's IDR plays a role in regulating Syt I's Ca(2+) sensing but also indicate the IDR is exquisitely sensitive to the underlying membrane lipids. The latter observation suggests the IDR is a key route for communication of lipid organization to the adjacent C2 domains.

A near-miss diagnosis of necrotizing breast fasciitis complicated by atrial fibrillation secondary to septic focus: a case report and brief review of literature.

Necrotizing fasciitis of the breast is a rare, life-threatening entity characterized by a rapidly aggressive infection of the soft tissue. There are few literature reports on necrotizing fasciitis at the level of the breast tissue as the most common locations are within the abdominal wall or extremities, but this entity can lead to sepsis and systemic multiorgan failure if not adequately managed. Here, we report a case that highlights the course of a 68-year-old African American female with a past medical history of hypertension, hyperlipidemia, and poorly controlled diabetes mellitus, who presented with the complaint of a painful right breast abscess with intermittent, purulent drainage. An initial point-of-care ultrasound displayed an area of induration of the right breast as well as soft tissue edema with no identifiable fluid collection. A subsequent CT abdomen and pelvis was obtained given new onset abdominal pain, which demonstrated incidental findings of inflammatory changes and subcutaneous emphysema along with colonic diverticulosis. Surgical intervention was immediately sought for which she underwent debridement and exploration of the right breast with findings that were consistent with necrotizing transformation. The patient was sent back to the OR for an additional surgical debridement the next day. Of note, the patient had post-op atrial fibrillation with rapid ventricular response and had to be admitted to the ICU for conversion to sinus rhythm. She returned to sinus rhythm and was transferred back to medicine before application of a negative pressure wound dressing on discharge. The patient was transitioned from Enoxaparin to Apixaban for anticoagulation control in the setting of atrial fibrillation before being discharged to a Skilled Nursing Facility with long-term antibiotics. This case highlights the difficulty and significance in establishing a prompt diagnosis for necrotizing fasciitis.

A Case of Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis Post COVID-19 Vaccination.

In this report, we examine the case of a patient who developed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis after receiving the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine. This is a case of a 62-year-old female who received the first dose of COVID-19 vaccine in July 2021 before presenting a few weeks later with migrating polyarthralgia and hemoptysis. Autoimmune workup was positive for ANCA against proteinase 3 (PR3).

Retrospective Comparison of Patients ≥ 80 Years With Atrial Fibrillation Prescribed Either an FDA-Approved Reduced or Full Dose Direct-Acting Oral Anticoagulant.

Direct-acting oral anticoagulants (DOACs) represent the standard for preventing stroke and systemic embolization (SSE) in patients with atrial fibrillation (AF). There is limited information for patients ≥ 80 years. We report a retrospective analysis of AF patients ≥ 80 years prescribed either a US Food and Drug Administration (FDA)-approved reduced (n = 514) or full dose (n = 199) DOAC (Dabigatran, Rivaroxaban, or Apixaban) between January 1st, 2011 (first DOAC commercially available) and May 31st, 2017. The following multivariable differences in baseline characteristics were identified: patients prescribed a reduced dose DOAC were older (p < 0.001), had worse renal function (p = 0.001), were more often prescribed aspirin (p = 0.004) or aspirin and clopidogrel (p < 0.001), and more often had new-onset AF (p = 0.001). SSE and central nervous system (CNS) bleed rates were low and not different (1.02 vs 0 %/yr and 1.45 vs 0.44 %/yr) for the reduced and full dose groups, respectively. For non-CNS bleeds, rates were 10.89 vs 4.15 %/yr (p < 0.001, univariable) for the reduced and full doses, respectively. The mortality rate was 6.24 vs 1.75 %/yr (p = 0.001, univariable) for the reduced and full doses. Unlike the non-CNS bleed rate, mortality rate differences remained significant when adjusted for baseline characteristics. Thus, DOACs in patients ≥ 80 with AF effectively reduce SSE with a low risk of CNS bleeding, independent of DOAC dose. The higher non-CNS bleed rate and not the mortality rate is explained by the higher risk baseline characteristics in the reduced DOAC dose group. Further investigation of the etiology of non-CNS bleeds and mortality is warranted.

Exercise behavior of degenerative mitral stenosis.

Mitral annular calcification (MAC) is increasingly encountered, particularly among the elderly and those with chronic kidney disease, and is often associated with a transvalvular gradient. In contrast to rheumatic mitral stenosis relatively little is known about mitral stenosis due to MAC. We aimed to clarify whether exercise limitation in this group is primarily due to valvular obstruction or ventricular dysfunction resulting from multiple comorbidities. 20 patients with severe MAC (bulky calcium deposits which restricted leaflet motion) were submitted to supine bicycle exercise, measuring Doppler and echocardiographic parameters at baseline and during exercise. They were compared 1:1 to subjects matched for age, sex, and left ventricular wall thickness. At baseline MAC subjects had higher mean mitral valve gradients (MVG) than comparison subjects (7.5 ± 3.8 vs 1.6 ± 0.8 mm Hg, p < 0.0001), along with larger indexed left atrial volumes (54.4 ± 14.9 vs 34.0 ± 11.7 mL, p < 0.0001) and reduced left atrial strains (reservoir, conduit, and booster pump). With exercise MAC subjects reached higher levels of MVG (17.3 ± 8.4 vs 5.5 ± 2.5 mm Hg, p < 0.0001), and pulmonary artery systolic pressure (estimated from tricuspid regurgitant jet [TR] velocity) and displayed a moderate correlation between ΔMVG and ΔTR velocity (r2 = 0.57). MAC subjects whose exercise MVG was ≥ 15 mm Hg all had a peak pulmonary artery systolic pressure > 60 mm Hg. MAC subjects also had relative chronotropic incompetence. Patients with severe MAC and a transvalvular gradient experience large increases in MVG and pulmonary pressure with exercise, similar to what has been described in rheumatic mitral stenosis. MAC may be an under-recognized cause of dyspnea and exercise intolerance in older patients.

Acute Kidney Injury Post Cardiac Catheterization: Does Vascular Access Route Matter?

BACKGROUND: Acute Kidney Injury as a complication of cardiac catheterization is associated with increased length of hospital stay and mortality. In recent years, the use of the radial artery for cardiac catheterization is increasing in frequency. OBJECTIVE: The objective of this concise review was to evaluate the method of cardiac access site and its impact on Acute Kidney Injury following cardiac catheterization. METHODS: After a thorough search on Medline, Google Scholar and PubMed, we included all the literature relevant to Acute kidney injury following transradial and transfemoral cardiac catheterization. RESULTS: While acute kidney injury was caused due to a variety of reasons, it was important to consider each case on an individual basis. We found a trend towards increased use of transradial approach in patients at high risk of developing kidney injury. However, limitations such as operator experience, anatomical challenges and so on do exist with this approach. CONCLUSION: Transradial access offers several advantages to a patient at high risk of acute kidney injury undergoing cardiac catheterization. Further large studies are needed to establish this trend in the years ahead.

New-onset atrial fibrillation is associated with increased mortality in critically ill patients: a systematic review and meta-analysis.

INTRODUCTION: Atrial fibrillation (AF) is one of the most comorbid conditions in critically ill patients requiring intensive care unit (ICU). Multiple studies have suggested that there may be an association between new-onset AF and adverse outcome in critically ill patients. However, there are no meta-analyses to assess this association. METHODS: Studies were systematically searched from electronic databases. Studies that examined the relationship between new-onset AF and adverse outcomes including mortality and length of stay in ICU patients were included. Studies that included patients with prior AF were excluded. The pooled effect size was calculated with a random-effect model, weighted for the inverse of variance, to determine an association between new-onset AF and in-hospital mortality. Heterogeneity was assessed with I2. RESULTS: Twelve studies were included. Pooled analysis showed statistically significant difference rate of the hospital mortality between patients with and without new-onset AF (OR 2.70; 95% CI 2.43-3.00). Subgroup analysis of only patients with sepsis or septic shock showed a significant association between new-onset AF and in-hospital mortality (OR 2.32; 95% CI 1.88-2.87). No significant heterogeneity was observed (I2 = 0%) in both analyses. Pooled analysis of four studies also showed a significant association between new-onset AF and short-term mortality (OR 2.22; 95% CI 1.28-3.83) with moderate heterogeneity (I2 = 67%). CONCLUSIONS: New-onset AF is associated with worse outcome in critically ill patients. Further studies should be done to evaluate for causality and adjust for confounders.

Comparing outcomes after transcatheter aortic valve replacement in patients with stenotic bicuspid and tricuspid aortic valve: A systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an alternative treatment to surgery in patients with severe aortic stenosis. However, patients with bicuspid aortic stenosis (BAV) are usually excluded from major TAVR studies. The aim of this study is to reexamine current evidence of TAVR in patients with severe aortic stenosis and BAV compared with tricuspid aortic valve (TAV). HYPOTHESIS: There might be differences in outcomes post TAVR between patients with BAV comparing to TAV. METHOD: Databases were systematically searched for relevant articles featuring cohort studies that included patients with BAV and TAV who underwent TAVR studies, of which reported outcomes of interest included mortality and complications in both groups. Pooled effect size was calculated with a random-effect model and weighted for the inverse of variance, to compare outcomes post-TAVR between BAV and TAV. RESULTS: Nine studies were included in the meta-analysis. There was no difference in 30-day mortality rate in patients with BAV compared with TAV (OR: 1.27, 95% CI: 0.84-1.93, I2 = 0). Patients with BAV were more likely to have a moderate to severe paravalvular leak (9 studies; OR: 1.42, 95% CI: 1.08-1.87, I2 = 0) and conversion to surgery (5 studies; OR: 5.48, 95% CI: 1.74-17.27, I2 = 0), and less likely to have device success compared with patients with TAV (5 studies; OR: 0.57, 95% CI: 0.40-0.81, I2 = 0%). CONCLUSIONS: There was no difference in mortality post-TAVR in patients with BAV compared with TAV. Further randomized studies should be done in newer-generation prostheses to assess this association.