Cardiovascular Therapy Research Articles

β-Hydroxybutyrate in Cardiovascular Diseases : A Minor Metabolite of Great Expectations.

Despite recent advances in therapies, cardiovascular diseases ( CVDs ) are still the leading cause of mortality worldwide. Previous studies have shown that metabolic perturbations in cardiac energy metabolism are closely associated with the progression of CVDs. As expected, metabolic interventions can be applied to alleviate metabolic impairments and, therefore, can be used to develop therapeutic strategies for CVDs. β-hydroxybutyrate (β-HB) was once known to be a harmful and toxic metabolite leading to ketoacidosis in diabetes. However, the minor metabolite is increasingly recognized as a multifunctional molecular marker in CVDs. Although the protective role of β-HB in cardiovascular disease is controversial, increasing evidence from experimental and clinical research has shown that β-HB can be a “super fuel” and a signaling metabolite with beneficial effects on vascular and cardiac dysfunction. The tremendous potential of β-HB in the treatment of CVDs has attracted many interests of researchers. This study reviews the research progress of β-HB in CVDs and aims to provide a theoretical basis for exploiting the potential of β-HB in cardiovascular therapies.

Temporal trends in abdominal aortic aneurysmal disease: a nationwide cohort study on cardiovascular morbidity and medical cardioprotective therapy.

Abdominal aortic aneurysmal disease is associated with increased risk of cardiovascular morbidity and death, which potentially can be reduced with cardioprotective medical therapy. The aim of this study was to observe temporal trends in prevalence and incidence of cardiovascular comorbidity as well as use of medical cardioprotective treatment in patients diagnosed with abdominal aortic aneurysmal disease. This was a population-based cohort study based on data from national health registries, including all patients diagnosed with abdominal aortic aneurysms between 1998 and 2018. Data were stratified into four time periods (1999-2003, 2004-2008, 2009-2013, and 2014-2018) to illustrate trends over time. Outcome measures were (i) cardiovascular comorbidity and medical cardioprotective therapy at time of diagnosis, (ii) new admissions for atherosclerotic cardiovascular disease, and (iii) all-cause mortality after 2-year follow-up. The study cohort included 33 296 individuals. Mean age was 74 years. Prevalence of atherosclerotic cardiovascular comorbidity at diagnosis decreased from 41.5 to 32.6%. Use of statins increased from 17.9 to 66.9%, antiplatelets from 45.6 to 63.3%, and combined therapy with both antiplatelets and statins from 11.3 to 44.8%, and from 12.1 to 50.7% when anticoagulant therapy was included. Developments in medication use plateaued after 2013. Prevalence and incidence of atherosclerotic cardiovascular disease decreased through all four time periods. The same applied to all-cause mortality, which decreased from 24.3 to 12.4 deaths (per 100 person-years). In patients diagnosed with abdominal aortic aneurysm, cardiovascular comorbidity at diagnosis, risk of future cardiovascular events, and all-cause mortality is decreasing. Nevertheless, cardiovascular burden and mortality rates remain substantial, and medical cardioprotective therapy can be further improved.

On-Demand Drug Delivery: Recent Advances in Cardiovascular Applications

Cardiovascular diseases (CVD), including life-threatening atherosclerosis and arterial thrombosis, account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Despite the ongoing improvement and accessibility of invasive cardiovascular interventions and pharmacological therapies, pathological processes often progress asymptomatically, before manifesting themselves as unstable angina pectoris, myocardial infarction, sudden cardiac death or stroke. Since atherosclerosis and thrombosis represent localized disease processes, insufficient response to systemically-administered drugs is a common problem. The available pharmacological therapies are often burdened by poor tolerability, limited efficacy and/or bioavailability. Although encapsulating drugs in a nanoscale shell increases their circulation time and availability, it does not guarantee disease-specific targeting, or the proper control of the drug release. In contrast, on-demand drug delivery has the advantage of localized treatment and allows reducing off-target effects by a stimuli-controlled drug release in the affected region. Such “smart” systems are expected to have a great therapeutic potential in CVD. This mini-review article highlights recent advances in stimuli-responsive drug delivery approaches to CVD, with specific drug release triggered either internally or externally.

PATIENT PERSPECTIVES ON TREATMENT ADHERENCE IN HYPERTENSION: PRELIMINARY RESULTS OF AN ESH SURVEY IN FIVE COUNTRIES

Objective: The ESH Working group on Lifestyle, Cardiovascular Therapy and Adherence, in partnership with Servier, has developed a web-based questionnaire in different languages to investigate patients’ perspectives on hypertension and treatment adherence. The objective of this survey was to decipher patients’ perception, motivations and barriers to drug treatment adherence in hypertension. Design and method: Eligible participants were men and women aged > 18 years, living in France, Germany, Italy, Spain and UK, with a diagnosis of hypertension made by a physician and internet access. Data were collected through patients’ websites and organizations from January to March 2022. Results: We included 595 participants (329 women, 55.3%, mean age 65 y); 72% were hypertensive for > 5 years, 93% were treated with antihypertensive medications for > 3 months and 50% had uncontrolled (140/90 mmHg) office BP at 3 months. The median number of all medications taken every day was 4 of which 2 were antihypertensive drugs. On a 10-point Likert scale, participants reported a modest impact of hypertension on their quality of life (3) or social and family life (3.1). The median level of stress was 5.2. In 76.6% of participants home BP was measured several times weekly (25%) or monthly (31%) or more. Antihypertensive medications were stopped unintentionally by 40% or taken irregularly by 44% of patients. The reasons for non-adherence to medications were forgetfulness (45%), side effects (17%) and running out of medications (15%). In 50% of cases, patients do not inform their physicians when stopping medications. The most useful approaches to support adherence reported by participants were single-pill combinations and smaller and cheaper pills. Information on hypertension and its treatment were considered sufficient for 33% of patients. Conclusions: In patients with internet access and willing to participate, our survey shows that despite having an uncontrolled office 3 month BP in 50% of them, participants report: 1) a modest impact of hypertension on their quality of life and a moderate level of anxiety, 2) frequent and usually non intentional non-adherence to prescribed antihypertensive medications, and 3) the necessity to improve the information provided to them.

Macroencapsulation Devices for Cell Therapy

Macroencapsulation has been widely used in cell therapy due to its capability to provide immune-privileged sites for implanted allogeneic or xenogeneic cells. Macroencapsulation also serves to provide mechanical and physiochemical support for maintaining cell expansion and promoting therapeutic functions. Macroencapsulation devices such as membrane-controlled release systems, hydrogels, microneedle (MN) array patches, and three-dimensional (3D) stents have shown promising in-lab and preclinical results in the maintenance of long-term cell survival and the strengthening of treatment efficacy. Recent studies focus on expanding the applications of these devices to new cell-based areas such as chimeric antigen receptor (CAR)-T cell delivery, cardiovascular disease therapy, and the exploration of new materials, construction methods, and working principles to augment treatment efficacy and prolong therapy duration. Here, we survey innovative platforms and approaches, as well as translation outcomes, for advancing the performance and applications of macrodevices for cell-based therapies. A discussion and critique regarding future opportunities and challenges is also provided.

178-OR: Prescription Patterns of Cardiovascular and Kidney Protective Therapies among Patients with Type 2 Diabetes

Background: Recent guidelines recommend use of SGLT2i and/or GLP1-RA in persons with type 2 diabetes (T2D) and CVD or CKD, regardless of glycemic control. The degree of adoption of these recommendations thus far is unclear Methods: Among T2D patients receiving care within the VA Health Care System, we evaluated the prevalence and correlates of SGLT2i and GLP1-RA prescription during 20 and 2020. Logistic regression was used to examine associations of atherosclerotic CVD (ASCVD) , heart failure, and CKD (defined by lab values and/or administrative codes) as well as predicted risks of ASCVD and end-stage kidney disease (ESKD) , with prescription of SGLT2i and GLP1-RA Results: Of 1,319,500 adults with T2D, 10% and 7% were prescribed SGLT2is and GLP1-RAs, respectively. Prescription prevalence of SGLT2i and GLP1-RA were 13% and 9% in patients with established ASCVD; 14% and 11% in those with heart failure; and 11% and 10% in those with CKD. In adjusted models, patients with severe albuminuria were less likely to be prescribed an SGLT2i or a GLP1-RA versus non-albuminuric patients with CKD: aOR (95% CI) = 0.89 (0.87, 0.91) and 0.95 (0.93, 0.98) , respectively. In patients with 10-year ASCVD risk >20% versus those with risk <5%, ASCVD risk was inversely associated with prescription: SGLT2i OR=0.70 (0.60, 0.80) and GLP1-RA OR=0.60 (0.50, 0.70) . Patients with 5-year ESKD risk >5% were less likely to be prescribed an SGLT2i: OR=0.61 (0.57, 0.66) , versus those with ESKD risk <1% Conclusions: Among a national VA cohort of patients with T2D, prescription of SGLT2i and GLP1-RA was pervasively low across conditions for which they are currently indicated to lower the risk of CVD and CKD progression. Furthermore, we observed a “risk-treatment paradox”, where patients with higher risk of adverse outcomes were less likely to receive these therapies. Intensive implementation efforts are needed to prioritize prescription of these medications to patients who would derive the largest benefit. Disclosure J.A. Lamprea Montealegre: Research Support; Bayer AG. E. Madden: None. S. Tummalapalli: Consultant; Bayer AG. Research Support; Scanwell Health. C. Chu: Research Support; Bayer AG. Y. Du: Employee; Bayer AG. Stock/Shareholder; Bayer AG. R. Singh: None. S. Kong: Employee; Bayer AG. D.S. Tuot: None. C. Peralta: Employee; Cricket Health, Inc. Research Support; American Heart Association, National Institutes of Health. M.G. Shlipak: Advisory Panel; TAI Diagnostics. Consultant; Cricket Health, Intercept Pharmaceuticals, Inc. Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH. M. Estrella: Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH.

Artificial Intelligence and Machine Learning Based Models for Prediction and Treatment of Cardiovascular Diseases: A Review

Advances in Machine Learning (ML) algorithms, computing and Artificial Intelligence (AI)-based systems have been gradually finding applications in several domains including medical and health care systems. By using big data analytics and machine learning methodologies, AI has become a promising tool in the diagnosis and treatment of cardiovascular diseases. AI-ML based applications enhance our understanding of different parameters and phenotypes of heart diseases and lead to newer therapeutic strategies to tackle different types of cardiovascular ailments, a newer approach to cardiovascular drug therapy and a post-marketing survey of prescription drugs. Although AI has wide range of applications, it is in infant stage and has certain limitations in the clinical use of results and their interpretations such as data privacy, selection bias etc, which may result in wrong conclusions. Thus, AI-ML is a transformative technology and has immense potential in health care systems. This review covers various aspects of cardiovascular diseases (CVDs) and illustrate AI and ML based methods including supervised, unsupervised and deep learning and their applications in cardiovascular imaging, cardiovascular risk prediction and newer drug targets.

Chitosan-Heparin Polyelectrolyte Multilayer-Modified Poly(vinyl alcohol) Vascular Patches based on a Decellularized Scaffold for Vascular Regeneration.

Vascular patches play an important role in vascular reparation and cardiovascular diseases therapy. Recently, decellularized scaffold (DCS)-based vascular patches have drawn attention for their good biocompatibility and blood compatibility. In this work, we developed a poly(vinyl alcohol)-coated DCS as a vascular patch for vascular regeneration. Polyelectrolyte multilayers (PEMs) were further decorated on the surface via layer-by-layer (LbL) self-assembly to improve the biocompatibility of the vascular patch. According to the in vitro experiment, the vascular patch exhibited rapid endothelialization and good hemocompatibility. Compared with unmodified poly(vinyl alcohol)/DCS, the PEM-modified vascular patch possesses improved hemocompatibility, for example, enhanced anti-platelet adhesion ability, prolonged in vitro coagulation time, and decreased hemolysis rate. Therefore, this vascular patch is conducive to the proliferation and attachment of endothelial progenitor cells. Meanwhile, the in vivo performance in a porcine model was investigated with the in vivo computed tomography angiography and B ultrasound was used to further confirm the vascular regeneration. Excitedly, the porcine artery could remain unblocked for 5 months after implantation. Our current research provides a potential strategy for treating diseased blood vessels in clinical surgery.

The Heart in Fabry Disease: Mechanisms Beyond Storage and Forthcoming Therapies.

In patients with Fabry disease (FD), cardiovascular involvement is the main cause of death and reduction of quality of life. Left ventricular hypertrophy mimicking hypertrophic cardiomyopathy is the main feature of FD cardiac involvement although glycolipid storage occurs in all cardiac cellular types. Accumulation of lysosomal globotriasylceramide represents the main mechanism of cardiac damage in early stages, but secondary pathways of cellular and tissue damage, triggered by lysosomal storage, and including altered energy production, inflammation and cell death, contribute to cardiac damage and disease progression. These mechanisms appear prominent in more advanced stages, hampering and reducing the efficacy of FD-specific treatments. Therefore, additional cardiovascular therapies are important to manage cardiovascular symptoms and reduce cardiovascular events. Although new therapies targeting lysosomal storage are in development, a better definition and comprehension of the complex pathophysiology of cardiac damage in FD, may lead to identify new therapeutic targets beyond storage and new therapeutic strategies.

Myocardial Injury in COVID-19 and Its Implications in Short- and Long-Term Outcomes.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a pandemic with high mortality and morbidity rates. Clinical manifestation is widely variable, including asymptomatic or mild respiratory tract illness to severe pneumonia and death. Myocardial injury is a significant pathogenic feature of COVID-19 and it is associated with worse in-hospital outcomes, mainly due to a higher number of hospital readmissions, with over 50% mortality. These findings suggest that myocardial injury would identify COVID-19 patients with higher risk during active infection and mid-term follow-up. Potential contributors responsible for myocardial damage are myocarditis, vasculitis, acute inflammation, type 1 and type 2 myocardial infarction. However, there are few data about cardiac sequelae and its long-term consequences. Thus, the optimal screening tool for residual cardiac sequelae, clinical follow-up, and the benefits of a specific cardiovascular therapy during the convalescent phase remains unknown. This mini-review explores the different mechanisms of myocardial injury related to COVID-19 and its short and long-term implications.

Clinical predictors of hyponatremia in patients with heart failure according to severity of chronic kidney disease

Chronic kidney disease (CKD) has been associated with adverse clinical outcomes. Hyponatremia, amarker of illness severity and poor prognosis, is commonly exhibited in patients with CKD. This cross-sectional study included patients hospitalized due to heart failure (HF). We used stepwise logistic regression to investigate the independent association of cardiovascular drugs, markers of HF severity, and baseline clinical characteristics with hyponatremia in three subgroups; normal renal function, mild-to-moderate CKD, and severe CKD. Of the 1232patients, 38.6% were hyponatremic. Patients with severe CKD, compared to those with normal renal function and mild-to-moderate CKD, were more likely to be hyponatremic (47.1%, 34.4% and 36.6%, respectively; p ≤ 0.0001). Alcohol consumption, female sex, n-terminal pro-brain natriuretic peptide (NT-proBNP), hydrochlorothiazide (HCT), and mineralocorticoid receptor antagonist (MRA) use, or angiotensinII receptorI blocker (ARB) non-use were associated with hyponatremia in patients with normal renal function (p ≤ 0.03 in all cases). Current smoking, diabetes mellitus, NT-proBNP, loop diuretic dose, and MRA use were predictors in mild-to-moderate CKD (p ≤ 0.04 in all cases). ARB use, loop diuretic dose, and HCT use were predictors in severe CKD (p ≤ 0.03 in all cases). Non-use of dihydropyridine calcium channel blocker (CCB) was an independent predictor of hyponatremia in all CKD stages (p ≤ 0.04 in all cases). Apart from afirm favorable effect of CCBs, cardiovascular therapy should be carefully tailored to avoid hyponatremia in patients with cardiorenal syndrome.

Pharmacological Treatment of Chronic Congestive Heart Failure

Abstract Chronic congestive heart failure is a clinical syndrome based on the progressive deterioration of contractile (systolic) heart function due to structural or functional disorders. The incidence of the disease increases with age, so the prevalence in people older than 75 years is greater than 10%. Due to the different clinical presentation, the pharmacological approach to the patient is individual, and most patients are treated on an outpatient basis, according to the guidelines taken from the recommendations of professional associations. Hospitalization is necessary in severe forms of CHF or acute exacerbations. Patients with severe hemodynamic disturbances due to acute CHF require treatment in intensive care units, due to specific cardiovascular therapy, respiratory support and vital functions monitoring. Individualized, stepwise and rational pharmacological therapy achieves significant symptomatic and functional improvement in most patients.

Role of Physical Therapists in the Management of Individuals at Risk for or Diagnosed With Venous Thromboembolism: Evidence-Based Clinical Practice Guideline 2022.

No matter the practice setting, physical therapists work with patients who are at risk for or who have a history of venous thromboembolism (VTE). In 2016, the first clinical practice guideline (CPG) addressing the physical therapist management of VTE was published with support by the American Physical Therapy Association's Academy of Cardiovascular and Pulmonary Physical Therapy and Academy of Acute Care, with a primary focus on lower extremity deep vein thrombosis (DVT). This CPG is an update of the 2016 CPG and contains the most current evidence available for the management of patients with lower extremity DVT and new key action statements (KAS), including guidance on upper extremity DVT, pulmonary embolism, and special populations. This document will guide physical therapist practice in the prevention of and screening for VTE and in the management of patients who are at risk for or who have been diagnosed with VTE. Through a systematic review of published studies and a structured appraisal process, KAS were written to guide the physical therapist. The evidence supporting each action was rated, and the strength of statement was determined. Clinical practice algorithms based on the KAS were developed that can assist with clinical decision-making. Physical therapists, along with other members of the health care team, should implement these KAS to decrease the incidence of VTE, improve the diagnosis and acute management of VTE, and reduce the long-term complications of VTE.

Targeted trapping of endogenous endothelial progenitor cells for myocardial ischemic injury repair through neutrophil-mediated SPIO nanoparticle-conjugated CD34 antibody delivery and imaging

Endothelia progenitor cell (EPC)-based revascularization therapies have shown promise for the treatment of myocardial ischemic injury. However, applications and efficacy are limited by the relatively inefficient recruitment of endogenous EPCs to the ischemic area, while implantation of exogenous EPCs carries the risk of tumorigenicity. In this study, we developed a therapeutic protocol that relies on the capacity of neutrophils (NEs) to target lesions and release preloaded EPC-binding molecules for high efficiency capture. Neutrophils were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface marker CD34 (SPIO-antiCD34/NEs), and the therapeutic efficacy in ischemic mouse heart following SPIO-antiCD34/NEs injection was monitored by SPIO-enhanced magnetic resonance imaging (MRI). These SPIO-antiCD34/NEs exhibited unimpaired cell viability, superoxide generation, and chemotaxis in vitro as well as satisfactory biocompatibility in vivo. In a mouse model of acute myocardial infarction (MI), SPIO-antiCD34 accumulation could be observed 0.5 h after intravenous injection of SPIO-antiCD34/NEs. Moreover, the degree of CD133+ EPC accumulation at MI sites was three-fold higher than in control MI model mice, while ensuing microvessel density was roughly two-fold higher than controls and left ventricular ejection fraction was > 50%. Therapeutic cell biodistribution, MI site targeting, and treatment effects were confirmed by SPIO-enhanced MRI. This study offers a new strategy to improve the endogenous EPC-based myocardial ischemic injury repair through NEs mediated SPIO nanoparticle conjugated CD34 antibody delivery and imaging. Statement of SignificanceThe efficacy of endogenous endothelial progenitor cell (EPC)-based cardiovascular repair therapy for ischemic heart damage is limited by relatively low EPC accumulation at the target site. We have developed a method to improve EPC capture by exploiting the strong targeting ability of neutrophils (NEs) to ischemic inflammatory foci and the capacity of these treated cells to release of preloaded cargo with EPC-binding affinity. Briefly, NEs were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface protein CD34 (SPIO-antiCD34). Thus, we explored sites targeting with nanocomposites cargo for non-invasive EPCs interception and therapy tracking. We demonstrate that SPIO-antiCD34 released from NEs can effectively capture endogenous EPCs and thereby promote heart revascularization and functional recovery in mice. Moreover, the entire process can be monitored by SPIO-enhanced magnetic resonance imaging including therapeutic cell biodistribution, myocardial infarction site targeting, and tissue repair.

Rapid translation of a cellular therapeutic from research to clinic

Cell therapies face regulatory and manufacturing challenges long before they are accessible to patients. Even as therapies prove effective and safe, raw material and manufacturing decisions made during early development can either stall progression or rapidly accelerate it. Utilizing scalable manufacturing processes and translation friendly raw materials during product development​ of MSCs and extracellular vesicle (EV) therapies will enable cell therapy developers to accelerate leading candidates into clinical trials, ultimately enabling more curative treatments to reach patients.Ashish Patel is a Clinical Senior Lecturer in the School of Cardiovascular Medicine & Sciences at King’s College London and Consultant Vascular and Endovascular Surgeon at Guy’s and St Thomas’ NHS Foundation Trust, London, UK. His British Heart Foundation-funded PhD, focusing on monocyte/macrophage biology in tissue remodelling, was awarded in 2013. He completed his Higher Surgical Training in General & Vascular Surgery as a Clinical Academic Lecturer at King’s College London & Guy’s & St Thomas’ NHS Foundation Trust. During this time, he received an Academy of Medical Sciences Grant and the Circulation Foundation’s George Davies Visionary Award. Dr Patel’s research interests are focused on the bench-to-bedside development and translation of novel cardiovascular advanced therapies, particularly for the treatment of peripheral arterial disease. He is an investigator within the BHF Centres of Regenerative Medicine and a Phase I accredited Principal Investigator at Guy’s & St Thomas’ NHS Foundation Trust. His research is funded by the Royal College of Surgeons, Rosetrees Trust, Advanced Therapies Network and the Frances and Augustus Newman Foundation.Joseph Candiello is a bioengineering expert with years of experience working at the nexus of biomaterials, biophysics, and organoid engineering. During 10+ years in academic research, he focused primarily on engineering a stem cell based vascularized islet organoid system for diabetes research as well as previous studies understanding the biophysical properties of developing interstitial tissues during his PhD in Bioengineering at the University of Pittsburgh. Prior to his PhD, Joe received his BSc from the Pennsylvania State University in Engineering Science and Mechanics, where he currently serves on the department's Industry & Professional Advisory Council. Dr. Candiello joined RoosterBio as a Field Application Scientist in 2017 before his current role as Senior Product Manager helping to bring new and innovative products to the market to support MSC based therapeutics.

64P Concomitant discontinuation of cardiovascular therapy and adjuvant hormone therapy in breast cancer patients

With survival increases, many breast cancer patients concomitantly use adjuvant hormone therapy and cardiovascular therapy. However, whether discontinuation of these two therapies is associated, and tends to occur at the same time has not been evaluated.

Adequate enrollment of women in cardiovascular drug trials and the need for sex-specific assessment and reporting

Cardiovascular disease (CVD) is the leading cause of death for women in the United States and globally. There is an abundance of evidence-based trials evaluating the efficacy of drug therapies to reduce morbidity and mortality in CVD. Additionally, there are well-established influences of sex, through a variety of mechanisms, on pharmacologic treatments in CVD. Despite this, the majority of drug trials are not powered to evaluate sex-specific outcomes, and much of the data that exists is gathered post hoc and through meta-analysis. The FDA established a committee in 1993 to increase the enrollment of women in clinical trials to improve this situation. Several authors, reviewing committees, and professional societies have highlighted the importance of sex-specific analysis and reporting. Despite these statements, there has not been a major improvement in representation or reporting. There are ongoing efforts to assess trial design, female representation on steering committees, and clinical trial processes to improve the representation of women.This review will describe the pharmacologic basis for the need for sex-specific assessment of cardiovascular drug therapies. It will also review the sex-specific reporting of landmark drug trials in hypertension, coronary artery disease (CAD), hyperlipidemia, and heart failure (HF). In reporting enrollment of women, several therapeutic areas like antihypertensives and newer anticoagulation trials fare better than therapeutics for HF and acute coronary syndromes. Further, drug trials and cardiometabolic or lifestyle intervention trials had a higher percentage of female participants than the device or procedural trials.

Hemodynamics of the right ventricle and the pulmonary circulation

Most cardiac diseases affect the left ventricle (LV), with its treatment being the focus of the majority of cardiovascular medical therapies and mechanical support. Many diseases also affect the right ventricle (RV) and pulmonary circulation, either directly or from secondary effects on the LV and systemic circulation. The development of therapies to treat RV failure is critical for the management of many patients with advanced heart and lung disease, but models to develop mechanical therapies to target the RV are currently lacking. While the RV and pulmonary vasculature have many similarities to the LV and systemic vasculature, there are notable differences between them at a morphological and functional level. This results in distinct patterns of coupling between the RV and pulmonary circulation. Models such as the Windkessel use lumped parameters that characterize the mechanical properties of the entire RV and pulmonary circulation. Contemporary computational approaches that have been used to model the pulmonary vasculature rely on patient-derived anatomy for the proximal pulmonary arteries and other approaches, such as fractal-based models for the distal vasculature. At this time, these models are still being optimized and significantly more work will be required to fully implement them and test their utility across multiple patient-derived anatomies. The development of these models for the RV and pulmonary circulation will be critical to address the unmet need of mechanical therapies for disease of the RV and pulmonary circulation.

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications.

Hydrogen sulfide (H2S) plays an important role in regulating various pathological processes such as protecting mammalian cell from harmful injuries, promoting tissue regeneration, and regulating the process of various diseases caused by physiological disorders. Studies have revealed that the physiological effects of H2S are highly associated with its concentrations. At relatively low concentration, H2S shows beneficial functions. However, long-time and high-dose donation of H2S would inhibit regular biological process, resulting in cell dysfunction and apoptosis. To regulate the dosage of H2S delivery for precision medicine, H2S delivery systems with intelligent characteristics were developed and a variety of biocompatibility polymers have been utilized to establish intelligent polymeric H2S delivery systems, with the abilities to specifically target the lesions, smartly respond to pathological microenvironments, as well as real-timely monitor H2S delivery and lesion conditions by incorporating imaging-capable moieties. In this review, we focus on the design, preparation, and therapeutic applications of intelligent polymeric H2S delivery systems in cardiovascular therapy, inflammatory therapy, tissue regenerative therapy, cancer therapy and bacteria-associated therapy. Strategies for precise H2S therapies especially imaging-guided H2S theranostics are highlighted. Since H2S donors with stimuli-responsive characters are vital components for establishing intelligent H2S delivery systems, the development of H2S donors is also briefly introduced.

Coverage with evidence development: where are we now?

CMS' coverage with evidence development (CED) policy allows Medicare beneficiaries to access promising therapies and services while additional data are collected. CED program characteristics are mostly unreported, and qualities associated with retirement of CED data collection requirements are unknown. We aimed to review and systematically describe CED program history and components and report programmatic elements correlated with retirement of CED data collection requirements, while identifying areas for policy improvement. Systematic review. We extracted CED information from the CMS website, ClinicalTrials.gov, PubMed, internet searches, and communication with CMS. There were 27 CED determinations from 2005 to 2022 in 8 therapeutic areas, with the most for cardiovascular diseases (8/27; 30%). Duration of CED programs (range, 1-16 years) and the number of related registries and clinical trials (range, 0-34) were widely variable. Only 4 CEDs have had data collection requirements with continued National Coverage Determination (NCD); 3 relate to cardiovascular therapies, and all have some public availability of findings resulting from CED-related data collection mechanisms. There were 2 instances of NCD revocation and deferral to local coverage decisions. Changes in the CED program through improving program predictability and transparency with regard to outstanding questions, roles of relevant stakeholders, and requirements for reporting and reevaluation would strengthen the program's effectiveness. Ultimately, these improvements would provide incentives for stakeholder participation in data collection to achieve the goal of increasing access to beneficial therapies and improving clinical outcomes.