Genetically Modified Porcine-to-Human Cardiac Xenotransplantation.

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).

Epigenetic age estimation of wild mice using faecal samples.

Age is a key parameter in population ecology, with a myriad of biological processes changing with age as organisms develop in early life then later senesce. As age is often hard to accurately measure with non-lethal methods, epigenetic methods of age estimation (epigenetic clocks) have become a popular tool in animal ecology and are often developed or calibrated using captive animals of known age. However, studies typically rely on invasive blood or tissue samples, which limit their application in more sensitive or elusive species. Moreover, few studies have directly assessed how methylation patterns and epigenetic age estimates compare across environmental contexts (e.g. captive or laboratory-based vs. wild animals). Here, we built a targeted epigenetic clock from laboratory house mice (strain C57BL/6, Mus musculus) using DNA from non-invasive faecal samples, and then used it to estimate age in a population of wild mice (Mus musculus domesticus) of unknown age. This laboratory mouse-derived epigenetic clock accurately predicted adult wild mice to be older than juveniles and showed that wild mice typically increased in epigenetic age over time, but with wide variation in epigenetic ageing rate among individuals. Our results also suggested that, for a given body mass, wild mice had higher methylation across targeted CpG sites than laboratory mice (and consistently higher epigenetic age estimates as a result), even among the smallest, juvenile mice. This suggests wild and laboratory mice may display different CpG methylation levels from very early in life and indicates caution is needed when developing epigenetic clocks on laboratory animals and applying them in the wild.

Sexual Quality of Life in Left Ventricular Assist Device Patients and Their Partners.

BACKGROUND: Living with a left ventricular assist device (LVAD) comes with potentially burdensome aspects posed by, for example, battery packs and device drivelines. We aim to describe the impact of living with a durable LVAD on sexual quality of life (QOL), depression, and anxiety in patients and their partners. METHODS AND RESULTS: In this single-center, prospective, observational study, patients ≥4 months after LVAD implantation and their partners completed the Sexual Activities in Left Ventricular Assist Device Patients or Partners questionnaire to assess their sexual QOL, the 8-item Patient Health Questionnaire (PHQ-8) to assess symptoms of depression and the 7-item Generalized Anxiety Disorder (GAD-7) to assess symptoms of anxiety. Sixty patients and 60 partners completed the questionnaires 2.3 ± 1.9 years after implantation. Eighty-seven percent of the patients and 13% of partners were male. The mean age of patients was 57.4 ± 13.3 years, with 90% living with their partner. Ten percent of patients and 18% of partners had a current diagnosis of a psychological condition, most frequently depression and/or anxiety. Overall, 49% of participants indicated the LVAD influenced their sexual activity (patients 53% vs partners 45%; P = .33). Disturbances from the driveline were the most common problem indicated. Twenty-four percent of participants had scored in the mild to moderate depression range on the PHQ-8 and 28% scored in the mild to severe anxiety range on the GAD-7. The median total GAD-7 (1 [interquartile range (IQR) 0-4.25] vs 2.5 [IQR 0-5]; P = .06) were comparable between patients and partners; whereas patients had a higher total PHQ-8 score (3 [IQR 0-5.25] vs 1 [IQR 0-3.25]; P = .02). A preference to receive information regarding sexuality while on LVAD support was indicated by 54% of participants and did not differ between patients and partners (P > .99). Written resources were the most commonly preferred source of information. CONCLUSIONS: LVADs severely affect the sexual QOL for patients and their partners. The presence of a driveline is a major cause for concern. Patients prefer receiving written information on how to improve their sexual QOL.

Mechanical circulatory support devices in adults with congenital heart disease.

PURPOSE OF REVIEW: Mechanical circulatory support is used frequently as a method of stabilizing patients with end stage heart failure who are unable to safely await allograft availability. While this technology has been fundamentally important in supporting patients with normal cardiac anatomy, it is still used infrequently in adult patients with congenital heart disease and end-stage heart failure. Here, we review the data on mechanical circulatory support technology in this small but growing population of patients with chronic heart disease prone to the development of circulatory failure. RECENT FINDINGS: Mechanical circulatory support (MCS) has been increasingly employed in adults with congenital heart disease (ACHD) as a bridge to transplant. The new United Network for Organ Sharing listing system favoring temporary MCS use with a higher listing status offers another tool to stabilize ACHD patients and potentially shorten wait times. Both temporary and Durable MCS could help improve transplant candidacy and posttransplant outcomes in select groups of ACHD patients. SUMMARY: Durable and temporary MCS have the potential to significantly improve access to transplant and overall transplant outcomes in ACHD patients.

Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine.

BACKGROUND: Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development. METHODS: The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors. RESULTS: We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients. CONCLUSION: This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.

Transcatheter Left Ventricular Restoration in Patients With Heart Failure.

BACKGROUND: Left ventricular (LV) volume reshaping reduces myocardial wall stress and may induce reverse remodeling in patients with heart failure with reduced ejection fraction. The AccuCinch Transcatheter Left Ventricular Restoration system consists of a series of anchors connected by a cable implanted along the LV base that is cinched to the basal free wall radius. We evaluated the echocardiographic and clinical outcomes following transcatheter left ventricular restoration. METHODS AND RESULTS: We analyzed 51 heart failure patients with a left ventricular ejection fraction between 20% and 40%, with no more than 2+ mitral regurgitation treated with optimal medical therapy, who subsequently underwent transcatheter left ventricular restoration. Serial echocardiograms, Kansas City Cardiomyopathy Questionnaire scores, and 6-minute walk test distances were measured at baseline through 12 months. Primary analysis end point was change in end-diastolic volume at 12 months compared with baseline. Patients (n = 51) were predominantly male (86%) with a mean age of 56.3 ± 13.1 years. Fluoroscopy showed LV free wall radius decreased by a median of 9.2 mm amounting to a 29.6% decrease in the free wall arc length. At 12 months, the LV end-diastolic volume decreased by 33.6 ± 34.8 mL (P < .01), with comparable decreases in the LV end-systolic volume. These decreases were associated with significant improvements in the overall Kansas City Cardiomyopathy Questionnaire score (16.4 ± 18.7 points; P < .01) and 6-minute hall walk test distance (45.9 ± 83.9 m; P < .01). There were no periprocedural deaths; through the 1-year follow-up, 1 patient died (day 280) and 1 patient received a left ventricular assist device (day 13). CONCLUSIONS: In patients with heart failure with reduced ejection fraction without significant mitral regurgitation receiving optimal medical therapy, the AccuCinch System resulted in decreases of LV volume, as well as improved quality of life and exercise endurance. A randomized trial is ongoing (NCT04331769).

Vaccines, Antibodies and Donors: Varying Attitudes and Policies Surrounding COVID-19 and Heart Transplantation.

INTRODUCTION: There are varied opinions in the United States regarding many aspects of care related to COVID-19. The purpose of this study was to examine the opinions of health care personnel and the policies of heart transplant centers concerning practices for the prevention and treatment of COVID-19 in donors and recipients of heart transplants. METHODS: Two anonymous, electronic web-based surveys were developed: 1 was administered to health care personnel through a mailing list maintained by the Heart Failure Society of America (HFSA); another was administered to U.S. medical adult and pediatric heart transplant (HT) program directors. Individual and group e-mails were sent with an embedded link to the respective surveys in February 2022. RESULTS: A total of 176 individuals (8.6%) responded to the survey administered through the HFSA. Of medical directors of transplant programs, 78 (54% response rate) completed a separate survey on their centers' policies. Although 95% (n = 167) of individuals indicated vaccination against COVID-19 should be required prior to HT, only 67% (n = 52) of centers mandated that practice. Similarly, 61% of individuals thought vaccination should be required prior to HT for caregivers, but only 13% of transplant centers mandated caregiver vaccination. Of the centers, 63% reported considering donors despite histories of recent COVID-19 infection (within 3 months), and 47% considered donors with current positive polymerase chain reaction tests. Regarding post-transplant care, only 22% of programs routinely measured antibodies to COVID-19, and 71% used tixagevimab/cilgavimab (Evusheld) for pre-exposure prophylaxis. CONCLUSIONS: There were significant differences between individual preferences and centers' practices with respect to COVID-19 management of candidates for and recipients of HT. Additionally, there was wide variation in policies among centers, reflecting the need for further study to inform consistent guidance and recommendations across centers to optimize equitable care for this high-risk patient population.

Urinary Cell-Cycle Arrest Biomarkers as Early Predictors of Acute Kidney Injury After Ventricular Assist Device Implantation or Cardiac Transplantation.

OBJECTIVES: Acute kidney injury (AKI) remains a leading source of morbidity and mortality after cardiothoracic surgery. Insulin-like growth factor-binding protein 7 (IGFBP7), and tissue inhibitor of metalloproteinases-2 (TIMP-2), are novel early-phase renal biomarkers that have been validated as sensitive predictors of AKI. Here the authors studied the efficacy of these biomarkers for predicting AKI after left ventricular assist device (LVAD) implantation and cardiac transplantation. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: This was a prospective study of 73 patients undergoing LVAD implantation (n = 37) or heart transplant (n = 36) from 2016 to 2017 at the authors' center. TIMP-2 and IGFBP7 were measured with the NephroCheck Test on urine samples before surgery and one-to-six hours after surgery. NephroCheck scores were assessed as predictors of moderate/severe AKI (Kidney Disease International Global Outcomes 2/3 creatinine criteria) within 48 hours of surgery, and the association with survival to one year was investigated. MEASUREMENTS AND MAIN RESULTS: The LVAD and transplant cohorts overall were similar in demographics and baseline creatinine (p > 0.05), with the exception of having more African-American patients in the LVAD arm (p = 0.003). Eleven (30%) LVAD and 16 (44%) transplant patients developed moderate/severe AKI. Overall, AKI was associated with postsurgery NephroCheck (odds ratio [95% confidence interval] for 0.1 mg/dL increase: 1.36 [1.04-1.79]; p = 0.03), but not with baseline NephroCheck (p = 0.92). When analyzed by cohort, this effect remained for LVAD (1.68 [1.05-2.71]; p = 0.03) but not for transplant (p = 0.15). Receiver operating characteristic analysis showed postoperative NephroCheck to be superior to baseline creatinine in LVAD (p = 0.046). Furthermore, an increase of 0.1 mg/dL in postoperative NephroCheck was associated with a 10% increase in the risk of mortality (adjusted hazard ratio: 1.11 [1.01-1.21]; p = 0.04) independent of age and body mass index. CONCLUSION: Assessment of TIMP-2 and IGFBP7 within six hours after surgery appeared effective at predicting AKI in patients with LVADs. Larger studies are warranted to validate these findings.

Frailty in heart transplantation: Report from the heart workgroup of a consensus conference on frailty.

A consensus conference on frailty in solid organ transplantation took place on February 11, 2018, to discuss the latest developments in frailty, adopt a standardized approach to assessment, and generate ideas for future research. The findings and consensus of the Frailty Heart Workgroup (American Society of Transplantation's Thoracic and Critical Care Community of Practice) are presented here. Frailty is defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. Frailty is increasingly recognized as a distinct biologic entity that can adversely affect outcomes before and after heart transplantation. A greater proportion of patients referred for heart transplantation are older and have more complex comorbidities. However, outcomes data in the pretransplant setting, particularly for younger patients, are limited. Therefore, there is a need to develop objective frailty assessment tools for risk stratification in patients with advanced heart disease. These tools will help to determine appropriate recipient selection for advanced heart disease therapies including heart transplantation and mechanical circulatory support, improve overall outcomes, and help distinguish frailty phenotypes amenable to intervention.

Microbial transitions from health to disease.

Recent advances in our understanding of the microbial populations that colonize the human mouth, their acquisition, interdependency, and coevolution with the host, bring a different perspective to the mechanisms underpinning the maintenance of periodontal health and the development of disease. In this work we suggest that our knowledge map of the etiology of periodontal health and disease can be viewed as a broad, highly connected, and integrated system that spans the entire spectrum of microbe/host/clinical interactions. The overall concept of present Periodontology 2000, that the microbial biofilm can be considered a human tissue of bacteriological origin, is entirely consistent with this integrated system view. The health-associated community structure of microbial biofilms can be considered a system that is normally resilient to perturbation. Equally, there is evidence to suggest that the dysbiotic community structure in disease may share similar resilience properties. In both instances, the resilience may be governed by the precise makeup of the acquired microbiome and by the genetics of the host. Understanding the mechanisms that enable the resistance to change of healthy and dysbiotic microbial populations may be important in the development of approaches to prevent the progression of disease and to restore health in diseased individuals.

Health-Related Quality of Life in Patients With a Left Ventricular Assist Device (QOLVAD) Questionnaire: Initial Psychometrics of a New Instrument.

BACKGROUND: Patients with a left ventricular assist device are a unique and growing population who deserve their own valid, reliable instrument for health-related quality of life. OBJECTIVE: We developed and tested the Health-Related Quality of Life with a Left Ventricular Assist Device (QOLVAD) questionnaire. METHODS: In a prospective, descriptive study, patients from 7 sites completed the QOLVAD and comparator questionnaires. Construct validity was tested using confirmatory factor analysis. Convergent validity was tested using correlations of QOLVAD scores to well-established measures of subjective health status, depression, anxiety, and meaning/faith. Reliability and test-retest reliability were quantified. RESULTS: Patients (n = 213) were 58.7 ± 13.9 years old; 81.0% were male, 73.7% were White, and 48.0% had bridge to transplant. Questionnaires were completed at a median time of 44 weeks post ventricular assist device. The 5 QOLVAD domains had acceptable construct validity (root mean square error of approximation = 0.064, comparative and Tucker-Lewis fit indices > 0.90, weighted root mean square residual = 0.95). The total score and domain-specific scores were significantly correlated with the instruments to which they were compared. Internal consistency reliability was acceptable for all subscales (α = .79-.83) except the cognitive domain (α = .66). Unidimensional reliability for the total score was acceptable (α = .93), as was factor determinacy for multidimensional reliability (0.95). Total test-retest reliability was 0.875 (P < .001). CONCLUSION: Our analysis provided initial support for validity and reliability of the QOLVAD for total score, physical, emotional, social, and meaning/spiritual domains. The QOLVAD has potential in research and clinical settings to guide decision making and referrals; further studies are needed.

Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore.

Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca2+-independent phospholipase A2γ (iPLA2γ) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear. Herein, we demonstrate that human heart failure activates specific myocardial mitochondrial phospholipases that increase Ca2+-dependent production of toxic hydroxyeicosatetraenoic acids (HETEs) and attenuate the activity of phospholipases that promote the synthesis of protective epoxyeicosatrienoic acids (EETs). Mechanistically, HETEs activated the Ca2+-induced opening of the mPTP in failing human myocardium, and the highly selective pharmacological blockade of either iPLA2γ or lipoxygenases attenuated mPTP opening in failing hearts. In contrast, pharmacological inhibition of cytochrome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria. Remarkably, the major mitochondrial phospholipase responsible for Ca2+-activated release of arachidonic acid (AA) in mitochondria from non-failing hearts was calcium-dependent phospholipase A2ζ (cPLA2ζ) identified by sequential column chromatographies and activity-based protein profiling. In contrast, iPLA2γ predominated in failing human myocardium. Stable isotope kinetics revealed that in non-failing human hearts, cPLA2ζ metabolically channels arachidonic acid into EETs, whereas in failing hearts, increased iPLA2γ activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. This remodeling metabolically channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading to further progression of heart failure.

Report from the American Society of Transplantation on frailty in solid organ transplantation.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Occurrence of disputed rpoB mutations among Mycobacterium tuberculosis isolates phenotypically susceptible to rifampicin in a country with a low incidence of multidrug-resistant tuberculosis.

BACKGROUND: Accurate drug susceptibility testing (DST) of Mycobacterium tuberculosis in clinical specimens and culture isolates to first-line drugs is crucial for diagnosis and management of multidrug-resistant tuberculosis (MDR-TB). Resistance of M. tuberculosis to rifampicin is mainly due to mutations in hot-spot region of rpoB gene (HSR-rpoB). The prevalence of disputed (generally missed by rapid phenotypic DST methods) rpoB mutations, which mainly include L511P, D516Y, H526N, H526L, H526S, and L533P in HSR-rpoB and I572F in cluster II region of rpoB gene, is largely unknown. This study determined the occurrence of all disputed mutations in HSR-rpoB and at rpoB codon 572 in M. tuberculosis strains phenotypically susceptible to rifampicin in Kuwait. METHODS: A total of 242 M. tuberculosis isolates phenotypically susceptible to rifampicin were used. The DST against first-line drugs was performed by Mycobacteria growth indicator tube (MGIT) 960 system. Mutations in HSR-rpoB (and katG codon 315 and inhA-regulatory region for isoniazid resistance) were detected by GenoType MDBDRplus assay. The I572F mutation in cluster II region of rpoB was detected by developing a multiplex allele-specific (MAS)-PCR assay. Results were confirmed by PCR-sequencing of respective loci. Molecular detection of resistance for ethambutol and pyrazinamide and fingerprinting by spoligotyping were also performed for isolates with an rpoB mutation. RESULTS: Among 242 rifampicin-susceptible isolates, 0 of 130 pansusceptible/monodrug-resistant isolates but 4 of 112 polydrug-resistant isolates contained a disputed rpoB mutation. All 4 isolates were also resistant to isoniazid and molecular screening identified additional resistance to pyrazinamide and ethambutol in one isolate each. In final analysis, 2 of 4 isolates were resistant to all 4 first-line drugs. Spoligotyping showed that the isolates belonged to different M. tuberculosis lineages. CONCLUSIONS: Four of 242 (1.7%) rifampicin-susceptible M. tuberculosis isolates contained a disputed rpoB mutation including 2 isolates resistant to all four first-line drugs. The occurrence of a disputed rpoB mutation in polydrug-resistant M. tuberculosis isolates resistant at least to isoniazid (MDR-TB) suggests that polydrug-resistant strains should be checked for genotypic rifampicin resistance for optimal patient management since the failure/relapse rates are nearly same in isolates with a canonical or disputed rpoB mutation.

Durable left ventricular assist device implantation in extremely obese heart failure patients.

Left ventricular assist devices (LVADs) have improved clinical outcomes and quality of life for those with end-stage heart failure. However, the costs and risks associated with these devices necessitate appropriate patient selection. LVAD candidates are becoming increasingly more obese and there are conflicting reports regarding obesity's effect on outcomes. Hence, we sought to evaluate the impact of extreme obesity on clinical outcomes after LVAD placement. Consecutive LVAD implantation patients at our center from June 2008 to May 2016 were studied retrospectively. We compared patients with a body mass index (BMI) ≥40 kg/m2 (extremely obese) to those with BMI < 40 kg/m2 with respect to patient characteristics and surgical outcomes, including survival. 252 patients were included in this analysis, 30 (11.9%) of whom met the definition of extreme obesity. We found that patients with extreme obesity were significantly younger (47[33, 57] vs. 60[52, 67] years, P < 0.001) with fewer prior sternotomies (16.7% vs. 36.0%, P = 0.04). They had higher rates of pump thrombosis (30% vs. 9.0%, P = 0.003) and stage 2/3 acute kidney injury (46.7% vs. 27.0%, P = 0.003), but there were no differences in 30-day or 1-year survival, even after adjusting for age and clinical factors. Extreme obesity does not appear to place LVAD implantation patients at a higher risk for mortality compared to those who are not extremely obese; however, extreme obesity was associated with an increased risk of pump thrombosis, suggesting that these patients may require additional care to reduce the need for urgent device exchange.

Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. METHODS: In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. CONCLUSIONS: Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Utilization of high donor sequence number grafts in cardiac transplantation.

Donor sequence number (DSN) represents the number of candidates to whom a graft was offered and declined prior to acceptance for transplantation. We sought to investigate the outcomes of patients receiving high DSN grafts. Consecutive isolated adult cardiac transplantations performed at a single-center were reviewed. Recipients were grouped into standard (≤75th percentile) DSN and high (>75th percentile) DSN. A previously validated donor risk index was used to quantify the risk associated with donor grafts, and recipient outcomes were assessed. Overall, 254 patients were included: 194 standard DSN (range 1-79) and 60 high DSN (range 82-1723). High DSN grafts were harvested at greater distance (P < .001) with increased ischemia time (P < .001), resulting in a modest increase in donor risk index (1 point median difference, P = .014). High DSN recipients were less frequently listed as UNOS status 1A (P < .001). Despite a nonsignificant trend toward increased in-hospital/30-day mortality in high DSN recipients, there were no differences in primary graft dysfunction or 1-year survival (high DSN 89% vs standard DSN 88%, P = .82). After adjustment for risk factors, high DSN was not associated with increased 1-year mortality (hazard ratio 1.18, 95%-CI 0.54-2.58, P = .68).

Rational Heart Transplant From a Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan Horse.

BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely used for orthotopic heart transplantation (HT) owing to post-transplantation risks. New highly effective HCV antivirals may alter the landscape. METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. On daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir (400 mg)-velpatasvir (100 mg) (Epclusa; Gilead) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy). RESULTS: We report the kinetics of acute hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidentally with successful cardiac transplantation to an HCV-negative recipient. Prompt resolution of viremia was noted by the 1st week of a 12 week course of antiviral therapy. Sustained virologic remission continued beyond 12 weeks after completion of HCV therapy (SVR-12). CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool.

Arrhythmogenic Right Ventricular Dysplasia: An Under-recognized Form of Inherited Cardiomyopathy.

We report a case of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in order to evaluate the course of an under-recognized form of cardiomyopathy with a vast array of clinical manifestations. The patient is a 49-year-old white woman transferred from an outside hospital due to dyspnea and persistent hypoxia. She had a pertinent family history that included a sister who died suddenly in her 30s from unexplained heart failure. Initial work-up for hypoxia was unrevealing. Transthoracic echocardiography revealed isolated right ventricular dysfunction with dilation and multiple trabeculations. Further investigation, including cardiac computed tomography and magnetic resonance imaging, revealed fatty infiltration into the right ventricular wall suggestive of ARVD.

An 18S rRNA Workflow for Characterizing Protists in Sewage, with a Focus on Zoonotic Trichomonads.

Microbial eukaryotes (protists) are important components of terrestrial and aquatic environments, as well as animal and human microbiomes. Their relationships with metazoa range from mutualistic to parasitic and zoonotic (i.e., transmissible between humans and animals). Despite their ecological importance, our knowledge of protists in urban environments lags behind that of bacteria, largely due to a lack of experimentally validated high-throughput protocols that produce accurate estimates of protist diversity while minimizing non-protist DNA representation. We optimized protocols for detecting zoonotic protists in raw sewage samples, with a focus on trichomonad taxa. First, we investigated the utility of two commonly used variable regions of the 18S rRNA marker gene, V4 and V9, by amplifying and Sanger sequencing 23 different eukaryotic species, including 16 protist species such as Cryptosporidium parvum, Giardia intestinalis, Toxoplasma gondii, and species of trichomonad. Next, we optimized wet-lab methods for sample processing and Illumina sequencing of both regions from raw sewage collected from a private apartment building in New York City. Our results show that both regions are effective at identifying several zoonotic protists that may be present in sewage. A combination of small extractions (1 mL volumes) performed on the same day as sample collection, and the incorporation of a vertebrate blocking primer, is ideal to detect protist taxa of interest and combat the effects of metazoan DNA. We expect that the robust, standardized methods presented in our workflow will be applicable to investigations of protists in other environmental samples, and will help facilitate large-scale investigations of protistan diversity.