A roadmap for modelling radiation-induced cardiac disease.

Cardiac risk mitigation is a major priority in improving outcomes for cancer survivors as advances in cancer screening and treatments continue to decrease cancer mortality. More than half of adult cancer patients will be treated with radiotherapy (RT); therefore it is crucial to develop a framework for how to assess and predict radiation-induced cardiac disease (RICD). Historically, RICD was modelled solely using whole heart metrics such as mean heart dose. However, data over the past decade has identified cardiac substructures which outperform whole heart metrics in predicting for significant cardiac events. Additionally, non-RT factors such as pre-existing cardiovascular risk factors and toxicity from other therapies contribute to risk of future cardiac events. In this review, we aim to discuss the current evidence and knowledge gaps in predicting RICD and provide a roadmap for the development of comprehensive models based on three interrelated components, (1) baseline CV risk assessment, (2) cardiac substructure radiation dosimetry linked with cardiac-specific outcomes and (3) novel biomarker development.

A practical guide for assessing and managing cardiovascular risk during androgen-deprivation therapy in patients with prostate cancer.

Prostate cancer is the most common malignancy among men worldwide, and androgen-deprivation therapy (ADT) is a mainstay of treatment. There are observational data demonstrating an increased risk of cardiovascular events in patients who receive ADT, particularly those who have an elevated baseline cardiovascular risk. Because, for most patients with prostate cancer, death is predominantly from noncancer-related causes, cardiovascular disease and its risk factors should be optimized during cancer treatment. This review provides an overview of the landscape of ADT treatment and serves as a guide for appropriate cardiovascular screening and risk-mitigation strategies. The authors emphasize the importance of shared communication between the multidisciplinary cancer team and primary care to improve baseline cardiovascular screening and treatment of modifiable risk factors within this higher risk population.

Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

Donor-specific antibodies in heart transplantation: can we afford the price or is it too steep to pay?

PURPOSE OF REVIEW: One-third of patients awaiting heart transplant are sensitized and 25-35% of heart allograft recipients develop de novo DSAs. Solid phase assays for DSA measurement have facilitated wider use of antibody monitoring and as such, our experience with DSAs is continuously evolving. RECENT FINDINGS: DSAs continue to exhibit poor correlation with biopsy-proven rejection. Novel molecular technologies, such as cell-free DNA and the molecular microscope (MMDx, which detects rejection-associated intragraft mRNA transcripts), are emerging as more sensitive methods to capture subclinical graft injury. High-resolution typing techniques are providing insight into the differential immunogenicity of HLA classes through epitope and eplet analysis. As sensitization of the transplant population is continuing to rise, our repertoire of desensitization strategies is also expanding. However, there is an acute need of predictive algorithms to help forecast the responders and the durability of desensitization. Novel immunomodulatory therapies have allowed safely transplanting across a positive crossmatch with good short-term survival but reported greater degree of rejection and lower long-term graft survival. SUMMARY: Our experience of outcomes as pertaining to DSAs still originates primarily from single-center studies. Our field is confronted with the challenge to establish common practice algorithms for the monitoring and treatment of DSAs.

cBIN1 Score (CS) Identifies Ambulatory HFrEF Patients and Predicts Cardiovascular Events.

BACKGROUND: Cardiac Bridging Integrator 1 (cBIN1) is a membrane deformation protein that generates calcium microdomains at cardiomyocyte t-tubules, whose transcription is reduced in heart failure, and is released into blood. cBIN1 score (CS), an inverse index of plasma cBIN1, measures cellular myocardial remodeling. In patients with heart failure with preserved ejection fraction (HFpEF), CS diagnoses ambulatory heart failure and prognosticates hospitalization. The performance of CS has not been tested in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: CS was determined from plasma of patients recruited in a prospective study. Two comparative cohorts consisted of 158 ambulatory HFrEF patients (left ventricular ejection fraction (LVEF) ≤ 40%, 57 ± 10 years, 80% men) and 115 age and sex matched volunteers with no known history of HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were also analyzed for comparison. CS follows a normal distribution with a median of 0 in the controls, which increases to a median of 1.9 (p < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class (p = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, p = 0.01, hazard ratio 1.9). Compared to a model with demographics, clinical risk factors, and NT-proBNP, adding CS to the model improved the overall continuous net reclassification improvement (NRI 0.64; 95% CI 0.18-1.10; p = 0.006). Although performance for diagnosis and prognosis was similar to CS, NT-proBNP did not prognosticate between patients whose NT-proBNP values were > 400 pg/ml. CONCLUSION: CS, which is mechanistically distinct from NT-proBNP, successfully differentiates myocardial health between patients with HFrEF and matched controls. A high CS reflects advanced NYHA stage, pathologic cardiac muscle remodeling, and predicts 1-year risk of cardiovascular events in ambulatory HFrEF patients. CS is a marker of myocardial remodeling in HFrEF patients, independent of volume status.

Cardiac Allograft Vasculopathy: The Enduring Enemy of Cardiac Transplantation.

Cardiac allograft vasculopathy remains a major limiting factor in the long-term survival of the heart transplant recipient. Our understanding of its pathogenesis is continuously evolving as advances in imaging modalities have allowed a direct window into the natural history of the disease. Innovation in diagnostic modalities has spurred the proliferation of prognostic tools and biomarkers. And in parallel, pharmacological advances have emerged that have helped ameliorate the disease's progressive course.

Association of a Novel Diagnostic Biomarker, the Plasma Cardiac Bridging Integrator 1 Score, With Heart Failure With Preserved Ejection Fraction and Cardiovascular Hospitalization.

Importance: Transverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease. Objective: To determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF). Design, Setting, and Participants: In this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017. Main Outcomes and Measures: The analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations. Results: A total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P < .001). For patients with HFpEF, the CS outperforms NT-proBNP when the comparator group was either healthy control participants (CS: area under curve [AUC], 0.98 [95% CI, 0.96-1.00]; NT-proBNP level: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001) or those with risk factors (CS: AUC, 0.98 [95% CI, 0.97-1.00]; NT-proBNP: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001). Kaplan-Meier analysis of 1-year cardiovascular hospitalizations adjusted for age, sex, body mass index, and NT-proBNP levels reveals that patients with HFpEF with CS greater than or equal to 1.80 have a hazard ratio of 3.8 (95% CI, 1.3-11.2; P = .02) for hospitalizations compared with those with scores less than 1.80. Conclusions and Relevance: If further validated, the plasma CS, a marker of transverse tubule dysfunction, may serve as a biomarker of cardiomyocyte remodeling that has the potential to aide in the diagnosis of HFpEF.

A role for glutamine 183 in the folate oxidative half-reaction of methylenetetrahydrofolate reductase from Escherichia coli.

The flavoprotein methylenetetrahydrofolate reductase (MTHFR) from Escherichia coli catalyzes a ping-pong reaction with NADH and 5,10-methylenetetrahydrofolate (CH2-H4folate) to produce NAD+ and 5-methyltetrahydrofolate (CH3-H4folate). This work focuses on the function of the invariant, active-site aminoacyl residue Gln183. X-ray structures of the enzyme complexes Ered(wild-type)•NADH and Eox(Glu28Gln)•CH3-H4folate indicate that Gln183 makes key hydrogen-bonding interactions with both NADH and folate in their respective half-reactions, suggesting roles in binding each substrate. We propose that the polarity of Gln183 may also aid in stabilizing the proposed 5-iminium cation intermediate during catalysis in the oxidative half-reaction with folate. We have prepared mutants Gln183Ala and Gln183Glu, which we hypothesize to have altered charge/polarity and hydrogen bonding properties. We have examined the enzymes by steady-state and stopped-flow kinetics and by measurement of the flavin redox potentials. In the reductive half-reaction, NADH binding affinity and the rate of flavin reduction have not been hindered by either mutation. By contrast, our results support a minor role for Gln183 in the oxidative half-reaction. The Gln183Ala variant exhibited a 6-10 fold lower rate of folate reduction and bound CH2-H4folate with 7-fold lower affinity, whereas the Gln183Glu mutant displayed catalytic constants within 3-fold of the wild-type enzyme.

Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium.

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here, we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways, such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF.

Functional role for the conformationally mobile phenylalanine 223 in the reaction of methylenetetrahydrofolate reductase from Escherichia coli.

The flavoprotein methylenetetrahydrofolate reductase from Escherichia coli catalyzes the reduction of 5,10-methylenetetrahydrofolate (CH(2)-H(4)folate) by NADH via a ping-pong reaction mechanism. Structures of the reduced enzyme in complex with NADH and of the oxidized Glu28Gln enzyme in complex with CH(3)-H(4)folate [Pejchal, R., Sargeant, R., and Ludwig, M. L. (2005) Biochemistry 44, 11447-11457] have revealed Phe223 as a conformationally mobile active site residue. In the NADH complex, the NADH adopts an unusual hairpin conformation and is wedged between the isoalloxazine ring of the FAD and the side chain of Phe223. In the folate complex, Phe223 swings out from its position in the NADH complex to stack against the p-aminobenzoate ring of the folate. Although Phe223 contacts each substrate in E. coli MTHFR, this residue is not invariant; for example, a leucine occurs at this site in the human enzyme. To examine the role of Phe223 in substrate binding and catalysis, we have constructed mutants Phe223Ala and Phe223Leu. As predicted, our results indicate that Phe223 participates in the binding of both substrates. The Phe223Ala mutation impairs NADH and CH(2)-H(4)folate binding each 40-fold yet slows catalysis of both half-reactions less than 2-fold. Affinity for CH(2)-H(4)folate is unaffected by the Phe223Leu mutation, and the variant catalyzes the oxidative half-reaction 3-fold faster than the wild-type enzyme. Structures of ligand-free Phe223Leu and Phe223Leu/Glu28Gln MTHFR in complex with CH(3)-H(4)folate have been determined at 1.65 and 1.70 A resolution, respectively. The structures show that the folate is bound in a catalytically competent conformation, and Leu223 undergoes a conformational change similar to that observed for Phe223 in the Glu28Gln-CH(3)-H(4)folate structure. Taken together, our results suggest that Leu may be a suitable replacement for Phe223 in the oxidative half-reaction of E. coli MTHFR.