Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

Clinician Response to Pharmacogenetic Clinical Decision Support Alerts.

The objective of this study was to characterize clinician response following standardization of pharmacogenetic (PGx) clinical decision support alerts at University of Florida (UF) Health. A retrospective analysis of all PGx alerts that fired at a tertiary academic medical center from August 2020 through May 2022 was performed. Alert acceptance rate was calculated and compared across six gene-drug pairs, patient care setting, and clinician specialty. The disposition of the triggering medication was compared with the alert response and evaluated for congruence. There were a total of 818 alerts included for analysis of alert response, 557 alerts included in acceptance rate calculations, and 392 alerts with sufficient information to assess clinical response. The overall acceptance rate was 63%. The alert response and clinical response were congruent for 47% of alerts. Alert response was influenced by the triggering gene-drug pair, clinician specialty, patient care setting, and specialty of the provider who initially ordered the PGx test. Clinical response was mostly incongruent with alert response. Alert acceptance is influenced by the triggering gene-drug pair, clinician specialty, and care setting. Alert response is not a reliable surrogate marker for clinical action. Any future research into the impact of clinical decision support (CDS) alerts should focus on clinical response rather than alert response. Given the reliance on CDS alerts to enhance uptake of PGx, it is worthwhile to further investigate their impact on prescribing and patient outcomes.

Reimbursement of pharmacogenetic tests at a tertiary academic medical center in the United States.

Introduction: Pharmacogenetics (PGx) has the potential to improve health outcomes but cost of testing is a barrier for equitable access. Reimbursement by insurance providers may lessen the financial burden for patients, but the extent to which PGx claims are covered in clinical practice has not been well-characterized in the literature. Methods: A retrospective analysis of outpatient claims submitted to payers for PGx tests from 1/1/2019 through 12/31/2021 was performed. A reimbursement rate was calculated and compared across specific test types (e.g., single genes, panel), payers, indication, and the year the claim was submitted. Results: A total of 1,039 outpatient claims for PGx testing were analyzed. The overall reimbursement rate was 46% and ranged from 36%-48% across payers. PGx panels were reimbursed at a significantly higher rate than single gene tests (74% vs. 43%, p < 0.001). Discussion: Reimbursement of claims for PGx testing is variable based on the test type, indication, year the claim was submitted, number of diagnosis codes submitted, and number of unique diagnosis codes submitted. Due to the highly variable nature of reimbursement, cost and affordability should be discussed with each patient.

Retrospective Analysis of Wastewater-Based Epidemiology of SARS-CoV-2 in Residences on a Large College Campus: Relationships between Wastewater Outcomes and COVID-19 Cases across Two Semesters with Different COVID-19 Mitigation Policies.

Wastewater-based epidemiology (WBE) has been utilized for outbreak monitoring and response efforts in university settings during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies examined the impact of university policies on the effectiveness of WBE to identify cases and mitigate transmission. The objective of this study was to retrospectively assess relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wastewater outcomes and COVID-19 cases in residential buildings of a large university campus across two academic semesters (August 2020-May 2021) under different COVID-19 mitigation policies. Clinical case surveillance data of student residents were obtained from the university COVID-19 response program. We collected and processed building-level wastewater for detection and quantification of SARS-CoV-2 RNA by RT-qPCR. The odds of obtaining a positive wastewater sample increased with COVID-19 clinical cases in the fall semester (OR = 1.50, P value = 0.02), with higher odds in the spring semester (OR = 2.63, P value < 0.0001). We observed linear associations between SARS-CoV-2 wastewater concentrations and COVID-19 clinical cases (parameter estimate = 1.2, P value = 0.006). Our study demonstrated the effectiveness of WBE in the university setting, though it may be limited under different COVID-19 mitigation policies. As a complementary surveillance tool, WBE should be accompanied by robust administrative and clinical testing efforts for the COVID-19 pandemic response.

Neurite Outgrowth and Gene Expression Profile Correlate with Efficacy of Human Induced Pluripotent Stem Cell-Derived Dopamine Neuron Grafts.

Transplantation of human induced pluripotent stem cell-derived dopaminergic (iPSC-DA) neurons is a promising therapeutic strategy for Parkinson's disease (PD). To assess optimal cell characteristics and reproducibility, we evaluated the efficacy of iPSC-DA neuron precursors from two individuals with sporadic PD by transplantation into a hemiparkinsonian rat model after differentiation for either 18 (d18) or 25 days (d25). We found similar graft size and dopamine (DA) neuron content in both groups, but only the d18 cells resulted in recovery of motor impairments. In contrast, we report that d25 grafts survived equally as well and produced grafts rich in tyrosine hydroxylase-positive neurons, but were incapable of alleviating any motor deficits. We identified the mechanism of action as the extent of neurite outgrowth into the host brain, with d18 grafts supporting significantly more neurite outgrowth than nonfunctional d25 grafts. RNAseq analysis of the cell preparation suggests that graft efficacy may be enhanced by repression of differentiation-associated genes by REST, defining the optimal predifferentiation state for transplantation. This study demonstrates for the first time that DA neuron grafts can survive well in vivo while completely lacking the capacity to induce recovery from motor dysfunction. In contrast to other recent studies, we demonstrate that neurite outgrowth is the key factor determining graft efficacy and our gene expression profiling revealed characteristics of the cells that may predict their efficacy. These data have implication for the generation of DA neuron grafts for clinical application.

A Bioinformatic Algorithm based on Pulmonary Endoarterial Biopsy for Targeted Pulmonary Arterial Hypertension Therapy.

Background: Optimal pharmacological therapy for pulmonary arterial hypertension (PAH) remains unclear, as pathophysiological heterogeneity may affect therapeutic outcomes. A ranking methodology based on pulmonary vascular genetic expression analysis could assist in medication selection and potentially lead to improved prognosis. Objective: To describe a bioinformatics approach for ranking currently approved pulmonary arterial antihypertensive agents based on gene expression data derived from percutaneous endoarterial biopsies in an animal model of pulmonary hypertension. Methods: We created a chronic PAH model in Micro Yucatan female swine by surgical anastomosis of the left pulmonary artery to the descending aorta. A baseline catheterization, angiography and pulmonary endoarterial biopsy were performed. We obtained pulmonary vascular biopsy samples by passing a biopsy catheter through a long 8 French sheath, introduced via the carotid artery, into 2- to 3-mm peripheral pulmonary arteries. Serial procedures were performed on days 7, 21, 60, and 180 after surgical anastomosis. RNA microarray studies were performed on the biopsy samples. Results: Utilizing the medical literature, we developed a list of PAH therapeutic agents, along with a tabulation of genes affected by these agents. The effect on gene expression from pharmacogenomic interactions was used to rank PAH medications at each time point. The ranking process allowed the identification of a theoretical optimum three-medication regimen. Conclusion: We describe a new potential paradigm in the therapy for PAH, which would include endoarterial biopsy, molecular analysis and tailored pharmacological therapy for patients with PAH.

Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

IMPORTANCE: Sepsis and septic shock are major healthcare problems that need early and appropriate management. OBJECTIVES: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement. DESIGN SETTING AND PARTICIPANTS: This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes. MAIN OUTCOMES AND MEASURES: Change in daily SOFA score and vasopressors requirement. RESULTS: A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T>MIC) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score. CONCLUSIONS AND RELEVANCE: Achieving 100% T>MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score.

Medication-Related Osteonecrosis of the Jaw in Cancer Patients: Result from the OneFlorida Clinical Research Consortium.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severely debilitating drug-induced bone disorder in the jawbone region. The first MRONJ was reported in 2003 after bisphosphonate (BP) exposure. Recently, other drugs, such as receptor activator of NF-κB ligand (RANKL) inhibitor denosumab and antiangiogenic agents, were also associated with MRONJ. The purpose of this study was to evaluate the incidence and risk factors for MRONJ related to BPs or denosumab in cancer patients in real-world clinical settings using data from the OneFlorida Clinical Research Consortium. We queried the electronic health records of participants with prescriptions of intravenous (IV) BPs or denosumab between January 1, 2012, and September 1, 2021, in the OneFlorida Consortium. Time to MRONJ diagnosis was evaluated using the Kaplan-Meier method, and Cox regression analysis was performed to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for MRONJ. A total of 5689 participants had one or more prescriptions of IV BP or denosumab within this study period and were included in this study. Among these participants, 52 (0.9%) had a diagnosis of MRONJ. The overall rate of MRONJ was 0.73%, 0.86%, and 3.50% in the cancer patients treated with IV BPs, denosumab, and sequential IV BPs and denosumab, respectively. The risk of MRONJ was similar in participants treated with denosumab alone compared to those treated with IV BPs alone (HR: 1.25, 95% CI: 0.66-2.34, p = .49). Patients with sequential prescription of IV BP and denosumab were at much higher risk for MRONJ, with an adjusted HR of 4.49, 95% CI of 1.96-10.28, p = .0004. In conclusion, in real-world clinical settings, the rates of MRONJ associated with IV BPs and denosumab were similar, while the sequential treatment of these two drug classes was associated with a much higher risk of MRONJ. © 2022 American Society for Bone and Mineral Research (ASBMR).

Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance.

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two Zn2C6 transcription factors YRR1 and YRM1 (p < 1 × 10-100). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency.

Robotic-assisted lobectomy for malignant lung tumors.

Objectives: For patients with lung cancer, surgical resection remains the best curative option and is associated with the longest disease-free survival. We present our institutional outcomes treating pulmonary malignancy with robotic lobectomy over the course of 1 year. Methods: A retrospective review was conducted on patients who underwent robotic pulmonary lobectomy for malignancy at a single institution in 2018. Results: Over the course of 1 year, 166 patients underwent robotic lobectomy for pulmonary neoplasm. The mean age of the patients was 75 years; 73% were current or prior smokers and 52% of the patients were male. The mean body mass index was 28 kg/m2. Conversion to open thoracotomy occurred in 7% of patients. The mean total hospital length of stay (LOS) was 3 days. Histopathological examination revealed a mean tumour size of 2.7 cm with 11 lymph nodes harvested. Left-sided tumours had a significantly higher number of lymph nodes harvested when compared to right-sided tumours (11.6 vs. 9.8, P = 0.01), despite sampling the recommended minimum of three N2 stations. The most common pathology was adenocarcinoma (65%), followed by squamous cell carcinoma (17%) The 30-day operative mortality was 0.6%. Conclusions: Robotic video-assisted thoracoscopic surgery is a safe, feasible and oncologically adequate procedure for lung malignancies. Comparison of our outcomes to previously reported national averages suggests a similar hospital LOS, lymph node harvest, conversion rate to open thoracotomy and 30-day mortality rate. We acknowledge the limitations of this non-randomised, retrospective study. Future research on robotic lobectomies is encouraged.

Endoluminal management of benign bronchoesophageal fistula.

The ideal management of bronchoesophageal fistulas is a debated topic. While open surgical repair remains the most definitive treatment, not all patients are fit for surgery. In this communication, we present a patient who developed a bronchoesophageal fistula 1 year after an Ivor Lewis esophagectomy that involved the native oesophagus and right mainstem bronchus. Endoluminal vacuum therapy was successful at closing this benign bronchoesophageal fistula.

Lessons Learned From Miami-Dade County's COVID-19 Epidemic: Making Surveillance Data Accessible for Policy Makers.

INTRODUCTION: COVID-19 represents an unprecedented challenge to policy makers as well as those entrusted with capturing, monitoring, and analyzing COVID-19 data. Effective public policy is data-informed policy. This requires a liaison between public health scientists and public officials. OBJECTIVE: This article details the experience, challenges, and lessons learned advising public officials in a large metropolitan area from March to October 2020. METHODS: To effectively do this, an R Markdown report was created to iteratively monitor the number of COVID-19 tests performed, positive tests obtained, COVID-19 hospitalization census, intensive care unit census, the number of patients with COVID-19 on ventilators, and the number of deaths due to COVID-19. RESULTS: These reports were presented and discussed at meetings with policy makers to further comprehension. DISCUSSION: To facilitate the fullest understanding by both the general public and policy makers alike, we advocate for greater centralization of public health surveillance data, objective operational definitions of metrics, and greater interagency communication to best guide and inform policy makers. Through consistent data reporting methods, parsimonious and consistent analytic methods, a clear line of communication with policy makers, transparency, and the ability to navigate unforeseen externalities such as "data dumps" and reporting delays, scientists can use information to best support policy makers in times of crises.

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Lactobacilli spp.: real-time evaluation of biofilm growth.

BACKGROUND: Biofilm is a fundamental bacterial survival mode which proceeds through three main generalized phases: adhesion, maturation, and dispersion. Lactobacilli spp. (LB) are critical components of gut and reproductive health and are widely used probiotics. Evaluation of time-dependent mechanisms of biofilm formation is important for understanding of host-microbial interaction and development of therapeutic interventions. Time-dependent LB biofilm growth was studied in two systems: large biofilm output in continuous flow system (microfermenter (M), Institute Pasteur, France) and electrical impedance-based real time label-free cell analyzer (C) (xCELLigence, ACEA Bioscience Inc., San Diego, CA). L. plantarum biofilm growth in M system was video-recorded, followed by analyses using IMARIS software (Bitplane, Oxford Instrument Company, Concord, MA, USA). Additionally, whole genome expression and analyses of attached (A) and dispersed (D) biofilm phases at 24 and 48 h were performed. RESULTS: The dynamic of biofilm growth of L. plantarum was similar in both systems except for D phases. Comparison of the transcriptome of A and D phases revealed, that 121 transcripts differ between two phases at 24 h. and 35 transcripts - at 48 h. of M growth. The main pathways, down-regulated in A compared to D phases after 24 h. were transcriptional regulation, purine nucleotide biosynthesis, and L-aspartate biosynthesis, and the upregulated pathways were fatty acid and phospholipid metabolism as well as ABC transporters and purine nucleotide biosynthesis. Four LB species differed in the duration and amplitude of attachment phases, while growth phases were similar. CONCLUSION: LB spp. biofilm growth and propagation area dynamic, time-dependent processes with species-specific and time specific characteristics. The dynamic of LB biofilm growth agrees with published pathophysiological data and points out that real time evaluation is an important tool in understanding growth of microbial communities.

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

Robotic video-assisted thoracoscopy: minimally invasive approach for management of mediastinal tumors.

In spite of difficult anatomic access for tumors of mediastinum, surgical resection remains the best diagnostic and therapeutic approach. Widespread acceptance of video-assisted thoracoscopy (VATS) is restricted by the limiting nature of instruments and suboptimal visualization. Robotic assisted minimally invasive surgery seems to hold most promise in remote, narrow anatomical regions. After obtaining approval from Institutional Review Board (IRB), a retrospective review of prospectively collected database on patients that underwent Robotic VATS between 2009 and 2013 was conducted. Forty-eight patients underwent RVATS resection of mediastinal tumor. One procedure (2.1%) was converted to open. The size of the mass ranged from 0.6 to 12.5 cm in greatest dimension (mean 5.16 cm). The mean duration of procedure was 127.96 min (60-240 min). Five patients (10.4%) had early postoperative complications including chylothorax (1 patient), new onset atrial fibrillation (1 patient), pleural effusion (1 patient), empyema (1 patient), and bleeding (1 patient). Mean follow-up time was 186 days (10-1300 days). Two patients (4%) with invasive thymoma developed local recurrence. The present study documents the feasibility of RVATS in the management of mediastinal tumors irrespective of the location in various mediastinal compartments. The role for careful and complete excision of the tumor, and surveillance afterward on invasive thymoma, was noted in our study, as in literature.

Isolated and concomitant minimally invasive minithoracotomy aortic valve surgery.

OBJECTIVE: To evaluate whether the outcomes of minimally invasive aortic valve surgery were similar in younger versus older patient groups, as well as whether concomitant minimally invasive aortic valve replacement (AVR) surgeries added significant risks in these populations. METHODS: We performed a single-institution retrospective analysis of 1018 patients undergoing isolated AVR and 378 patients undergoing concomitant AVR procedures over a 6-year period. All surgeries were via a right minithoracotomy approach, and patients who underwent reoperation were excluded. RESULTS: Mortality was 1.3% in the isolated AVR group and 3.2% in the concomitant AVR group. The incidence of permanent stroke was low in both the isolated and concomitant AVR groups (0.8% and 1.1%, respectively). In both groups, femoral cannulation was associated with equally low stroke rates (0.8% and 0.6%, respectively). When analyzing operative outcomes by age, mortality was similar for the isolated AVR group (age <80 vs ≥80 years, 0.9% vs 2.2%; P = .07) and the concomitant AVR group (<80 vs ≥80 years, 3.2% vs 3.2%; P = .99), whereas transfusion requirements, intensive care unit and hospital lengths of stay, and atrial fibrillation rates were greater in the older subsets of both AVR groups. CONCLUSIONS: Minimally invasive right thoracotomy AVR surgery was associated with low stroke and mortality rates in all age groups within 30 days of surgery. Similarly, minithoracotomy concomitant AVR surgery demonstrated excellent results and is deemed feasible in patients with multiple pathologies.

Mitral Valve and Subvalvular Repair for Secondary Mitral Regurgitation: Rationale and Clinical Outcomes of the Papillary Muscle Sling.

Secondary mitral regurgitation (MR) is a common finding in patients with dilated cardiomyopathy, and it is associated with poor outcomes. It is the result of incomplete systolic closure of the mitral valve (MV) as a consequence of left ventricular dilatation, papillary muscle displacement with impaired systolic shortening, and mitral leaflet tethering. MV surgery may be performed in cases of significant secondary MR despite guideline-directed medical therapy. However, MV repair, which is most commonly performed with an undersized ring annuloplasty, is associated with a 30-60% recurrence of moderate or greater MR at mid-term follow-up. To improve MV repair durability, several adjunctive subvalvular procedures have been proposed, one of which is the addition of papillary muscle approximation utilizing a papillary muscle sling. Recent studies comparing the outcomes of a conventional undersized ring annuloplasty with a MV repair utilizing a papillary muscle sling have reported a significant reduction in recurrent moderate or severe MR, greater left ventricular reverse remodeling, and improved MV apparatus geometry with the addition of the papillary muscle sling. We present a comprehensive review of the pathophysiology of secondary MR, and the rationale and clinical outcomes of MV repair with papillary muscle sling placement for the treatment of secondary MR.

Staged percutaneous coronary intervention followed by minimally invasive mitral valve surgery versus combined coronary artery bypass graft and mitral valve surgery for two-vessel coronary artery disease and moderate to severe ischemic mitral regurgitation.

BACKGROUND: The optimal treatment for concomitant two-vessel coronary artery disease (CAD) and moderate to severe ischemic mitral regurgitation (IMR) remains unclear. We compared the results of a staged percutaneous coronary intervention followed by minimally invasive mitral valve surgery (PCI+MIVS) versus combined coronary artery bypass graft and mitral valve surgery (CABG+MVS) in this population. METHODS: All consecutive patients with two-vessel CAD and moderate to severe IMR, who underwent PCI+MIVS or CABG+MVS at our institution between February 2009 and April 2014, were retrospectively evaluated. RESULTS: There were nine patients identified who underwent PCI+MIVS, and 15 who underwent CABG+MVS, with a mean age of 71±7, and 70±7 years, respectively (P=0.86). The remaining baseline characteristics were similar between both groups, with the exception of a higher prevalence of pre-operative clopidogrel administration (78% versus 27%, P=0.03) and left anterior descending plus left circumflex CAD (78% versus 27%, P=0.03), in those who underwent PCI+MIVS. The PCI+MIVS approach was associated with decreased mean cardiopulmonary bypass (111±41 versus 167±49 min, P=0.01) and aortic cross-clamp (79±32 versus 129±35 min, P=0.003) times, and less median number of intraoperative packed red blood transfusions {2 [interquartile range (IQR), 0-2] versus 3 units (IQR, 1-4), P=0.05}, when compared with CABG+MVS. The rate of mitral valve repair, postoperative complications, 30-day mortality, and 1-year survival did not differ between the surgical approaches. CONCLUSIONS: PCI+MIVS for two-vessel CAD and moderate to severe IMR is feasible, and associated with satisfactory outcomes, as compared with CABG+MVS.