Hypertension, smoking, and preexistence of multiple cardiac risk factors correlate with carfilzomib-induced cardiovascular adverse events in a racially diverse population.

Background: Use of the proteasome inhibitor carfilzomib has become a standard of care in patients with relapsed/refractory multiple myeloma. An association between carfilzomib and cardiovascular adverse events has been well documented, but this had not been investigated in a racially diverse population. Black patients in particular are underrepresented in the reported outcomes of treatment with carfilzomib. Objective: The purpose of this study was to identify risk factors for carfilzomib-associated cardiovascular events in a diverse, single-center population. Methods: We conducted a retrospective review of 161 patients with multiple myeloma treated with carfilzomib between 2011 and 2020 at the University of Maryland Medical Center. Over half (86) were Black patients, with the remainder (75) being White patients. We did a multivariate analysis to determine risk factors for developing cardiovascular events during treatment with carfilzomib. Results: There was no statistically significant association with cardiotoxicity and race, gender, or age at first dose of carfilzomib. In multivariable analysis, patients with history of hypertension had a higher risk of cardiotoxicity [adjusted odds ratio (OR): 2.5; 95% CI: 1.1-5.9; P = 0.03] as did those with a history of smoking [OR: 2.8; 95% CI: 1.3-6.4; P = 0.01]. Conclusions: Here we report the largest cohort of Black patients treated with carfilzomib as yet reported. The results of this single center retrospective study show history of hypertension and smoking are associated with carfilzomib associated cardiotoxicity in a diverse patient population. There is a need for well-designed prospective studies enrolling a diverse population to investigate potential interventions to prevent carfilzomib-associated cardiotoxicity.

Isolated Antineutrophil Cytoplasmic Antibody-Associated Coronary Vasculitis and Valvulitis.

A 30-year-old woman presented with angina pectoris. Coronary angiography revealed severe stenosis in the left main and right coronary arteries that did not improve with intracoronary nitroglycerin. Coronary computed tomography angiography and positron emission tomography revealed coronary ostia inflammation and aortic root fat stranding. She was diagnosed with vasculitis and valvulitis and received immunotherapy and coronary bypass. (Level of Difficulty: Advanced.).

Haemodynamically Derived Pulmonary Artery Pulsatility Index Predicts Mortality in Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary artery (PA) pulsitility index (PAPi) is a novel haemodynamic index shown to predict right ventricular failure in acute inferior myocardial infarction and post left ventricular assist device surgery. We hypothesised that PAPi calculated as [PA systolic pressure - PA diastolic pressure]/right atrial pressure (RAP) would be associated with mortality in the National Institutes of Health Registry for Primary Pulmonary Hypertension (NIH-RPPH). METHODS: The impact of PAPi, the Pulmonary Hypertension Connection (PHC) risk score, right ventricular stroke work, pulmonary artery capacitance (PAC), other haemodynamic indices, and demographic characteristics was evaluated in 272 NIH-RPPH patients using multivariable Cox proportional hazards (CPH) regression and receiver operating characteristic (ROC) analysis. RESULTS: In the 272 patients (median age 37.7+/-15.9years, 63% female), the median PAPi was 5.8 (IQR 3.7-9.2). During 5years of follow-up, 51.8% of the patients died. Survival was markedly lower (32.8% during the first 3years) in PAPi quartile 1 compared with the remaining patients (58.5% over 3years in quartiles 2-4; p<0.0001). The best multivariable CPH survival model included PAPi, the PHC-Risk score, PAC, and body mass index (BMI). In this model, the adjusted hazard ratio for death with increasing PAPi was 0.946 (95% CI 0.905-0.989). The independent ROC areas for 5-year survival based on bivariable logistic regression for PAPi, BMI, PHC Risk, and PAC were 0.63, 0.62, 0.64, and 0.65, respectively (p<0.01). The ROC area for 5-year survival for the multivariable logistic model with all four covariates was 0.77 (p<0.0001). CONCLUSIONS: Pulmonary artery pulsatility index was independently associated with survival in PAH, highlighting the utility of PAPi in combination with other key measures for risk stratification in this population.

Increased Pulmonary-Systemic Pulse Pressure Ratio Is Associated With Increased Mortality in Group 1 Pulmonary Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular (RV) failure. The failing RV, through interventricular uncoupling, deleteriously impacts the left ventricle and overall cardiac efficiency. We hypothesised that the ratio of the pulmonary artery pulse pressure to the systemic pulse pressure ("pulmonary-systemic pulse pressure ratio", or PS-PPR) would be associated with mortality in PAH. METHODS: We conducted a retrospective analysis of 262 patients in the National Institute of Health Primary Pulmonary Hypertension Registry (NIH-PPH). We evaluated the association between the PS-PPR and mortality after adjustment for the Pulmonary Hypertension Connection (PHC) risk equation. RESULTS: Among 262 patients (mean age 37.5±15.8years, 62.2% female), median PS-PPR was 1.04 (IQR 0.79-1.30). In the Cox proportional hazards regression model, each one unit increase in the PS-PPR was associated with more than a two-fold increase in mortality during follow-up (HR 2.06, 95% CI 1.40-3.02, p=0.0002), and this association of PS-PPR with mortality remained significant in the multivariable Cox model adjusted for the PHC risk equation, mean pulmonary artery pressure, and body mass index (BMI) (adjusted HR 1.81, 95% CI 1.13-2.88, p=0.01). Furthermore, PS-PPR in the upper quartile (>1.30) versus quartiles 1-3 was associated with a 68% increase in mortality after adjustment for these same covariates (adjusted HR 1.68, 95% CI 1.13-2.50, p=0.01). CONCLUSIONS: Pulmonary-systemic pulse pressure ratio, a marker of biventricular efficiency, is associated with survival in PAH even after adjustment for the PHC risk equation. Further studies are needed on the wider applications of PS-PPR in PAH patients.

Right atrial to left atrial volume index ratio is associated with increased mortality in patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance leading to right heart failure. Elevated right atrial (RA) pressure reflects right ventricular (RV) pressure overload and is an established risk factor for mortality in PH. We hypothesized that PH patients with an increased ratio of RA to LA volume index (RAVI/LAVI), would have increased mortality. METHODS: We evaluated the association of RAVI/LAVI with mortality in 124 patients seen at a single academic center's PH clinic after adjusting for the REVEAL risk score, an established risk score in PH. LA and RA volume indices were measured in the four-and two-chamber views by two independent researchers. Multivariable logistic regression was used to model the independent association of RAVI/LAVI with survival. RESULTS: Among 124 patients (mean age 62 ± 12.7 years, 68.6% female), each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.91, 95% CI: 1.20-3.04). In a multivariable logistic regression, each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.73, 95% CI: 1.003-2.998). Furthermore, RAVI/LAVI in the highest quartile (>1.42) was significantly associated with elevated right atrial pressure (RAP) to pulmonary artery wedge pressure ratio (RAP/PAWP) (0.76 ± 0.41, P = 0.02) compared with the lowest quartile (<0.77), suggesting an interaction between invasive hemodynamic data, atrial structural changes, and mortality in PH. CONCLUSIONS: Increased RAVI/LAVI in PH is associated with decreased survival and accounts for atrial structural remodeling related to invasive hemodynamics. These findings support further study of this index in predicting outcomes in PH.

The kinetics of dimethylhydroxypyridinone interactions with iron(iii) and the catalysis of iron(iii) ligand exchange reactions: implications for bacterial iron transport and combination chelation therapies.

Many microbes acquire environmental Fe by secreting organic chelators, siderophores, which possess the characteristics of a high and specific binding affinity for iron(iii) that results in the formation of thermodynamically stable, and kinetically inert iron(iii) complexes. Mechanisms to overcome the kinetic inertness include the labilization of iron(iii) by means of ternary complex formation with small chelators. This study describes a kinetic investigation of the labilization of iron(iii) between two stable binding sites, the prototypical siderophore ferrioxamine B and EDTA, by the bidentate siderophore mimic, 1,2-dimethyl-3-hydroxy-4-pyridinone (L1, H(DMHP)). The proposed mechanism is substantiated by investigating the iron(iii) exchange reaction between ferrioxamine B and H(DMHP) to form Fe(DMHP)3, as well as the iron(iii) exchange from Fe(DMHP)3 to EDTA. It is also shown that H(DMHP) is a more effective catalyst for the iron(iii) exchange reaction than bidentate hydroxamate chelators reported previously, supporting the hypothesis that chelator structure and iron(iii) affinity influence low denticity ligand facilitated catalysis of iron(iii) exchange reactions. The results are also discussed in the context of the design and use of combination chelator therapies in the treatment of Fe overload in humans.

Decreased pulmonary arterial proportional pulse pressure is associated with increased mortality in group 1 pulmonary hypertension.

BACKGROUND: This study evaluated the utility of a novel index, pulmonary arterial (PA) proportional pulse pressure (PAPP; range 0-1, defined as [PA systolic pressure - PA diastolic pressure] / PA systolic pressure), in predicting mortality in patients with World Health Organization group 1 pulmonary hypertension (PH). HYPOTHESIS: Low PAPP is associated with increased 5-year mortality independent of a validated contemporary risk-prediction equation (Pulmonary Hypertension Connection [PHC] equation). METHODS: In a group of 262 patients in the National Institutes of Health Primary Pulmonary Hypertension (NIH-PPH) Registry, PAPP and the PHC risk equation were used to predict mortality during 5 years of follow-up using Cox proportional hazards models. Kaplan-Meier survival curves were used to compare mortality among PAPP quartiles, and significance was tested using the log-rank test. RESULTS: Patients in the lowest quartile (PAPP ≤0.47) had a significantly higher 5-year mortality than did patients in higher quartiles (log-rank P = 0.016). In a Cox model adjusted for the PHC equation, PAPP remained significantly associated with 5-year mortality (hazard ratio: 0.74 per 0.10 increase in PAPP, 95% confidence interval: 0.61-0.90). The χ2 statistic for the single PAPP covariate in this model was 8.8 (P = 0.003), which compared favorably with the χ2 statistic of 15.2 (P < 0.0001) for the multivariable PHC equation. CONCLUSIONS: PAPP, an index of ventricular-arterial coupling, is independently associated with survival in World Health Organization group 1 PH. The use of this easily measurable index for guiding risk stratification needs further investigation.

Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis.

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.