Seventeen years since rimonabant's downfall: reassessing its suicidality risk profile.

Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.

Evaluating the Abuse Potential of Lenabasum, a Selective CB2 Cannabinoid Receptor Agonist.

Background: Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. Methods: This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n=56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120mg) were compared to placebo, and nabilone (3 and 6mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Results: Lenabasum was safe and well tolerated. Compared to placebo, a 20mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3mg and 6mg, which is a currently FDA-approved medication. Conclusions: At a target therapeutic dose (20mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120mg) did elicit subjective ratings of Drug Liking compared to placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared to 3mg and 6mg of nabilone, suggesting that lenabasum does have abuse potential and should be used cautiously in clinical settings. Significance Statement This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well-tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

Novel cannabinoid receptor 1 inverse agonist CRB-913 enhances efficacy of tirzepatide, semaglutide, and liraglutidein the diet-induced obesity mouse model.

OBJECTIVE: Incretin receptor agonists are now standard of care in treating obesity. Their efficacy and tolerability might be further improved by combining them with compounds that offer orthogonal mechanisms of action. The cannabinoid type 1 receptor (CB1R) is a clinically validated therapeutic target in obesity, and several experimental CB1R inverse agonists have been shown to induce weight loss. METHODS: This study characterizes a novel CB1R inverse agonist (CRB-913) with similar preclinical potency to rimonabant but markedly reduced brain penetration. CRB-913 was tested as monotherapy and in combination with tirzepatide, semaglutide, or liraglutide in the diet-induced obesity (DIO) mouse model for body weight reduction. RESULTS: CRB-913 demonstrated enhanced plasma exposure (3.8-fold larger area under the curvelast ) and reduced brain levels (9.5-fold lower area under the curvelast ) than rimonabant. CRB-913 monotherapy yielded a dose-dependent decrease in body weight in DIO mice reaching -22% within 18 days. In further DIO studies in combination with tirzepatide, semaglutide, or liraglutide, CRB-913 (2.5 mg/kg) resulted in -32.6%, -28.8%, and -16.8% decreases in body weight on Day 18, respectively, with concomitant improvements in body fat content, liver triglycerides, and liver fat deposits. CONCLUSIONS: CRB-913 in combination with incretin analogues could deliver meaningful improvements over current standards of care for obesity and related conditions.

Covid-19 positive donor utilization for heart transplantation: The new frontier for donor pool expansion.

BACKGROUND: Hearts from COVID-19 positive donors (CPD) are being utilized for heart transplantation by some centers; however, this is in the setting of the lack of guidelines or robust evidence. The paucity of evidence is reflected in the recent Organ Procurement and Transplantation Network (OPTN) communication describing CPD utilization as an "unknown risk." METHODS AND RESULTS: We analyzed the UNOS database for adult heart transplants performed between January 2021 to December 2022, and CPD comprised of a significant percentage of donors, being used in >10% of recipients in some UNOS regions. Between July 2022 and December 2022, 7.9% of heart transplants were with CPD, and in the same period Hepatitis C positive donors accounted for 7.1% and donation after circulatory death (DCD) accounted for 10.3%. CONCLUSION: If the transplant community comes up with a standardized approach and guidance in using CPD hearts, this could provide an effective donor pool expansion strategy.

Bedside ultrasound of the internal jugular vein to assess fluid status and right ventricular function: The POCUS-JVD study.

BACKGROUND: Accurate estimation of fluid status is important in the management of heart failure patients, however, the current methods for bedside assessment can be unreliable or impractical for daily use. METHODS: Non-ventilated patients were enrolled immediately prior to scheduled right heart catheterization (RHC). Using M-mode, IJV maximum (Dmax) and minimum (Dmin) anteroposterior diameters were measured during normal breathing, while supine. Respiratory variation in diameter (RVD) was calculated as [(Dmax - Dmin)/Dmax] in percentage. Collapsibility with sniff maneuver (COS) was assessed. Lastly, inferior vena cava (IVC) was assessed. Pulmonary artery pulsatility index (PAPi) was calculated. Data was obtained by five investigators. RESULTS: Total 176 patients were enrolled. Mean BMI was 30.5 kg/m2, LVEF 14-69% (range), 38% with LVEF ≤35%. The POCUS of IJV could be performed in all patients in <5 min. Increasing RAP demonstrated progressive increase in IJV and IVC diameters. For high filling pressure (RAP ≥10 mmHg), an IJV Dmax ≥1.2 cm or IJV-RVD < 30% had specificity >70%. Combining the POCUS of IJV to physical examination improved the combined specificity to 97% for RAP ≥10 mmHg. Conversely, a finding of IJV-COS was 88% specific for normal RAP (<10 mmHg). An IJV-RVD <15% is suggested as a cutoff for RAP ≥15 mmHg. The performance of IJV POCUS was comparable to IVC. For RV function assessment, IJV-RVD < 30% had 76% sensitivity and 73% specificity for PAPi <3, while IJV-COS was 80% specific for PAPi ≥3. CONCLUSION: POCUS of IJV is an easy to perform, specific and reliable method for volume status estimation in daily practice. An IJV-RVD < 30% is suggested for estimation of RAP ≥10 mmHg and PAPi <3.

Evaluation of adjusted international normalized ratio goal in patients with HeartMate 3 left ventricular assist devices.

BACKGROUND: The HeartMate3 left ventricular assist device (HM3 LVAD) has shown a low incidence of thrombosis, but bleeding risk is as high as 43%. We aim to describe the impact of lower international normalization ratio (INR) goal on clinical outcomes. METHODS: In February 2019, our tertiary care institution lowered INR goal in HM3 patients from manufacturer recommendations to 1.8-2.2 and retrospectively analyzed the data. Two cohorts were compared: patients with lower INR goal upon implant (De novo) and those with subsequently lowered INR goal (Adjusted). The Adjusted group also served as its own historical control. Both groups continued aspirin 81 milligrams daily per manufacturer recommendations. The primary outcomes were incidences of bleed and thrombosis events within 12 months. Secondary outcomes included survival free of disabling stroke or reoperation to remove or replace the device and Rosendaal time in therapeutic range (TTR) over 12 months. RESULTS: Thirty-one patients were evaluated for inclusion with 26 meeting criteria. Within 12 months, incidence of bleeding events was 25% and 28.6% in the De novo and Adjusted groups, respectively. Incidence of thrombotic events within 12 months was 0% in the De novo group and 7.1% in the Adjusted group. Twelve-month survival free of disabling stroke or reoperation to remove or replace the device was higher over 12 months for patients in the De novo group (91.7% vs. 78.6%). Median 12-month TTR was 36%, which was primarily attributable to subtherapeutic deviations. CONCLUSIONS: A lower INR goal may be safe when initiated De novo following implantation of the HM3. This study informs the need for larger prospective studies.

Patterns and outcomes of COVID-19 donor utilization for heart transplant.

BACKGROUND: The outcomes following COVID-19 positive donor (CPD) utilization for heart transplant are unknown. METHODS: UNOS database was analyzed for heart transplants performed from the declaration of COVID-19 pandemic until September 30, 2022. RESULT: Since the onset of pandemic, there were 9876 heart transplants reported. COVID-19 antigen or NAT results were available in 7698 adult donors within 14 days of donation, of which 177 (2.3%) were positive. There was no difference in recipient demographics, including age (COVID positive donor vs. negative: 55 vs. 56 years, p = .2) and BMI. Listing status 1 and 2 were similar in both groups (7% vs. 10% and 48% vs. 49% respectively, p = .4). Durable and temporary mechanical support were similar in both groups pre-transplant (both groups 33%, p = .9). There was no difference in days on the waitlist (median 31 days, p = .9). Simultaneous renal transplant rates were similar (11% vs. 10%, p = .9). CPD utilization has increased since the onset of the pandemic, and the adoption is present across most UNOS regions. Post-transplant, there was no difference in length of stay (median 16 vs. 17 days, p = .9) and acute rejection episodes prior to discharge (3% vs. 8%, p = .1). In survival analysis of 90-day follow up, number of deaths reported were comparable (5% in both groups, p = .9) Follow-up LVEF was comparable (62% vs. 60%, p = .4). CONCLUSION: Active COVID-19 infection in donors did not affect survival or rejection rates in the short-term post-heart transplant.

Long-Term Surveillance of Coronary Artery Dissection in an Orthotopic Heart Transplant Recipient.

We describe a case of an orthotopic heart transplant recipient who presented with chest pain related to blunt chest trauma 3 weeks post-transplantation. Electrocardiogram showed anterior ST-segment elevation. Coronary angiography revealed a dissection of the mid-distal left anterior descending artery with preserved antegrade flow. Conservative management of the coronary artery dissection was pursued. While the patient had a favorable long-term clinical outcome, the coronary dissection persisted on 1- and 2-year follow-up coronary angiography.

Outcomes of Heart Failure in COVID-19 Patients: An Appalachian Experience.

Background: The Southeastern rural areas of the USA have a higher prevalence of heart failure (HF). Coronavirus disease 2019 (COVID-19) infection is associated with poor outcomes in patients with HF. Our study aimed to compare the outcomes of hospitalized HF patients with and without COVID-19 infection specifically in rural parts of the USA. Methods: We conducted a retrospective cohort study of HF patients with and without COVID-19 hospitalized in Southeastern rural parts of the USA by using the Appalachian Regional Healthcare System. Analyses were stratified by waves from April 1, 2020 to May 31, 2021, and from June 1, 2021 to October 19, 2021. Results: Of the 14,379 patients hospitalized with HF, 6% had concomitant COVID-19 infection. We found that HF patients with COVID-19 had higher mortality rate compared to those without COVID-19 (21.8% versus 3.8%, respectively, P < 0.01). Additionally, hospital resource utilization was significantly higher in HF patients with COVID-19 compared to HF patients without COVID-19 with intensive care unit (ICU) utilization of 21.6% versus 13.8%, P < 0.01, mechanical ventilation use of 17.3% versus 6.2%, P < 0.01, and vasopressor/inotrope use of 16.8% versus 7.9%, P < 0.01. A lower percentage of those with COVID-19 were discharged home compared to those without a COVID-19 diagnosis (63.4% versus 72.0%, respectively). There was a six-fold greater odds of dying in the first wave and seven-fold greater odds of dying in the second wave. Conclusions: Our study confirms previous findings of poor outcome in HF patients with COVID-19. There is a need for review of healthcare resources in rural hospitals which already face numerous healthcare challenges.

Retrospective review of secondary prevention strategies for gastrointestinal bleeding and associated clinical outcomes in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is one of the most common bleeding complications associated with left ventricular assist devices (LVAD). Currently, there is no strong evidence or clear guidance for which secondary GIB prophylaxis strategy should be implemented after the discontinuation of aspirin. METHODS: Our single-center study describes the outcomes of 26 LVAD patients who experienced a total of 49 GIB events: these individuals were either in Group-1 (lower INR target range) or Group-2 (lower INR target plus a hemostatic agent) as the secondary prophylaxis strategy. Each GIB event was considered an independent event. Outcomes assessed were bleeding reoccurrence rates, time to next GIB, acute GIB strategies, GIB-free days, thromboembolic events, survival, coagulation, and hematologic parameters. RESULTS: GIB reoccurrence rates were not statistically different: Group-1, 9 (40.9%), versus Group-2, 15 (55.6%); p = 0.308. Danazol was utilized 81.5% of the time as the designated hemostatic agent. Additionally, no significant differences were observed with all of our secondary outcome measures for bleeding, ischemic events, or survival. CONCLUSION: While our study was not powered to assess the clinical outcomes related to survival and thromboembolic events, no discernable increased risk for ischemic events including pump thrombosis were observed. Our data suggest that a lower INR target range plus danazol does not confer any additional benefit over a lower INR target range only approach. The results of this report are hypothesis-generating and additional studies are warranted to elucidate the optimal antithrombotic strategy and role of hemostatic agents in reducing the risk of recurrent GIB events.

Lenabasum Reduces Porphyromonas gingivalis-Driven Inflammation.

The aim of this study was to evaluate the potential anti-inflammatory and anti-resorptive effects of lenabasum in the context of Porphyromonas gingivalis (Pg)-induced inflammation. Lenabasum or ajulemic acid (1',1'-dimethylheptyl-THC-11-oic-acid), a synthetic analog of THC-11-oic acid, has already demonstrated anti-inflammatory properties for the treatment of several inflammatory diseases. In vitro, the cytocompatibility of lenabasum was evaluated in human oral epithelial cells (EC), oral fibroblasts and osteoblasts by metabolic activity assay. The effect of lenabasum (5 µM) treatment of Pg-LPS- and P. gingivalis-infected EC on the pro- and anti-inflammatory markers was studied through RTqPCR. In vivo, lenabasum was injected subcutaneously in a P. gingivalis-induced calvarial abscess mouse model to assess its pro-healing effect. Concentrations of lenabasum up to 5 µM were cytocompatible in all cell types. Treatment of Pg-LPS and Pg-infected EC with lenabasum (5 µM; 6 h) reduced the gene expression of TNF-α, COX-2, NF-κB, and RANKL, whereas it increased the expression of IL-10 and resolvin E1 receptor respectively (p < 0.05). In vivo, the Pg-elicited inflammatory lesions' clinical size was significantly reduced by lenabasum injection (30 µM) vs untreated controls (45%) (p < 0.05). Histomorphometric analysis exhibited improved quantity and quality of bone (with reduced lacunae) and significantly reduced calvarial soft tissue inflammatory score in mice treated with lenabasum (p < 0.05). Tartrate-resistant acid phosphatase activity assay (TRAP) also demonstrated decreased osteoclastic activity in the treatment group compared to that in the controls. Lenabasum showed promising anti-inflammatory and pro-resolutive properties in the management of Pg-elicited inflammation, and thus, its potential as adjuvant periodontal treatment should be further investigated.

Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

BACKGROUND: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. METHODS: We queried Veterans Affairs' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. RESULTS: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70-0.74], P<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes. CONCLUSIONS: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.

Mechanical circulatory support in pre and postheart transplant period.

PURPOSE OF REVIEW: Progression of heart failure (HF) and its unpredictable and volatile nature, often requires advanced therapies including heart transplant. Mechanical circulatory support plays an integral part in the advanced treatment options. This technology can be deployed in several ways, particularly in the preparation and patient optimization for heart transplants. This article discusses the use of temporary and durable devices and their deployment strategies in the pre and posttransplant period. RECENT FINDINGS: Recently temporary mechanical support devices have allowed us to improve survival to transplant as well as posttransplant. Early implementation of temporary devices both for stabilization of advanced HF patients being considered for transplant as well as those with posttransplant primary graft dysfunction (although utilization of extracorporeal membrane oxygenation has repeatedly shown to be associated with worse outcomes compared to the other devices discussed), is reflective of the degree of disease progression in these patients. The outcomes of patients supported with durable devices have significantly improved with advancing technology. HeartMate 3 device has not only been shown to improve survival as well as the quality of life but in comparison to its predecessor, has been shown to decrease the morbidity associated with this technology. SUMMARY: Both temporary and durable devices are now associated with improved survival and allow us to transplant patients in a more stable and safer manner with fewer adverse events. Based on the new United Network of Organ Sharing allocation system, it allows us to upgrade those who do not have the luxury of time to wait for a transplant. Primary graft dysfunction now also can be assisted with those devices, which is reflected in improved survival of posttransplant patients.

COVID-19 and Heart Transplant: A Case Series and Review of the Literature.

Coronavirus disease 2019 (COVID-19) has resulted in many challenges in patient care, especially among high-risk populations such as heart transplant recipients. Patients with heart transplant experience a significantly higher mortality rate with COVID-19 infection, and management is based on extrapolation from clinical trials done on nontransplant patients and from clinical experience. Here we report 4 cases of patients with heart transplant who presented with COVID-19 infection in late 2020. Patients presented with symptoms similar to those seen in the general population. All 4 patients were admitted to the hospital, and they were all treated with dexamethasone. In addition, 2 patients received remdesivir. Immunosuppressive medications were adjusted to maintain adequate levels of immunosuppression but at the same time allow for an adequate immune response against the infection. All patients were discharged alive from the hospital. We then performed a literature review on studies that included heart transplant patients who developed the infection and developed suggestions for a standardized management approach, which we share in this article.

Pulmonary Arterial Hypertension: a Pharmacotherapeutic Update.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) leads to progressive increases in pulmonary vascular resistance (PVR), right heart failure, and death if left untreated. This review will summarize and discuss recent updates in the classification and management of patients with PAH. RECENT FINDINGS: PAH requires careful hemodynamic assessment and is defined by a mean pulmonary artery pressure > 20 mmHg with normal left-sided filling pressures and a PVR ≥ 3 Wood units. Most patients with PAH require targeted pharmacotherapy based on multiparametric risk stratification. Significant improvements in clinical outcome have been realized through the approval of 14 unique pharmacotherapeutic options. The latest clinical recommendations provide the updated hemodynamic definition and clinical classification as well as evidence-based treatment recommendations. An important change is the focus on initial upfront combination therapy for most patients with PAH. Structured follow-up and escalation of treatment for those not achieving low-risk status is paramount.

A "Cat"-astrophic Case of Bartonella henselae infective endocarditis followed by cardiac transplantation salvage therapy.

To our knowledge, no cases of Bartonella henselae endocarditis leading to subsequent heart transplantation salvage therapy have been published. We present a case of a 29-year-old man with cat-inflicted B henselae endocarditis and concurrent worsening heart failure, who then underwent successful heart transplantation 50 days following diagnosis. Treatment and monitoring strategies used in this patient are discussed. Furthermore, we review literature related to heart transplantation salvage therapy for endocarditis due to other intracellular pathogens.

Surgical Approaches in Heart Failure.

Heart failure is a progressive condition that continues to increase in both incidence and prevalence despite pharmacologic treatment. The high rate of morbidity and mortality associated with advanced heart failure has led to exploration of additional treatments, which include surgical interventions to improve outcomes. Heart transplant remains the gold standard but, because of the persistent donor shortage and increasing number of patients with advanced heart failure, mechanical circulatory support is gaining acceptance and can be used as a bridge to heart transplant for those eligible or as destination therapy.