Vitamin D and Cardiovascular Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90252/1/phco.29.6.691.pd

Circulatory Assist Devices 2000: An Update

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71424/1/j.1527-5299.2000.80165.x.pd

Utility of routine evaluations for rejection in patients greater than 2 years after heart transplantation

AimsGuidelines support routine surveillance testing for rejection for at least 5 years after heart transplant (HT). In patients greater than 2 years post‐HT, we examined which clinical characteristics predict continuation of routine surveillance studies, outcomes following discontinuation of routine surveillance, and the cost‐effectiveness of different surveillance strategies.Methods and resultsWe retrospectively identified subjects older than 18 who underwent a first HT at our centre from 2007 to 2016 and who survived ≥760 days (n = 217) post‐HT. The clinical context surrounding all endomyocardial biopsies (EMBs) and gene expression profiles (GEPs) was reviewed to determine if studies were performed routinely or were triggered by a change in clinical status. Subjects were categorized as following a test‐based surveillance (n = 159) or a signs/symptoms surveillance (n = 53) strategy based on treating cardiologist intent to continue routine studies after the second post‐transplant year. A Markov model was constructed to compare two test‐based surveillance strategies to a baseline strategy of discontinuing routine studies. One thousand twenty studies were performed; 835 were routine. Significant rejection was absent in 99.0% of routine EMBs and 99.8% of routine GEPs. The treating cardiologist’s practice duration, patient age, and immunosuppressive regimen predicted surveillance strategy. There were no differences in outcomes between groups. Routine surveillance EMBs cost more and were marginally less effective than a strategy of discontinuing routine studies after 2 years; surveillance GEPs had an incremental cost‐effectiveness ratio of $1.67 million/quality‐adjusted life‐year.ConclusionsAcute asymptomatic rejection is rare after the second post‐transplant year. Obtaining surveillance studies beyond the second post‐transplant year is not cost‐effective.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156231/2/ehf212745.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156231/1/ehf212745_am.pd

Statin intensity and risk for cardiovascular events after heart transplantation

AimsStatins improve survival and reduce rejection and cardiac allograft vasculopathy after heart transplantation (HT). The impact of different statin intensities on clinical outcomes has never been assessed. We set out to determine the impact of statin exposure on cardiovascular outcomes after HT.Methods and resultsWe performed a retrospective study of 346 adult patients who underwent HT from 2006 to 2018. Statin intensity was determined longitudinally after HT based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The primary outcome was the time to the first primary event defined as the composite of heart failure hospitalization, myocardial infarction, revascularization, and all‐cause mortality. Secondary outcomes included time to significant rejection and time to moderate–severe cardiac allograft vasculopathy. Adverse events were evaluated for subjects on high‐intensity statin therapy. A Cox proportional hazards model was used to evaluate the relationship between clinical variables, statin intensity, and outcomes. Most subjects were treated with low‐intensity statin therapy although this declined from 89.9% of the population at 1month after HT to 42.8% at 5years after HT. History of ischaemic cardiomyopathy, significant acute rejection, older donor age, and lesser statin intensity (p ≤ 0.001) were associated with reduced time to the primary outcome in a multivariable Cox model. Greater intensity of statin therapy was most beneficial early after HT. There were no statin‐related adverse events for the 14 subjects on high‐intensity statin therapy.ConclusionsGreater statin intensity was associated with a reduction in adverse cardiovascular outcomes after HT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162686/2/ehf212784.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162686/1/ehf212784_am.pd

The effect of Crataegus oxycantha special extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure ☆

Aim To examine whether hawthorn ( Crataegus Special Extract WS 1442 {CSE}) inhibits progression in heart failure (HF) patients. Methods We performed a retrospective analysis of data from the HERB CHF study in which patients with mild to moderate HF were randomised to either CSE 900 mg or placebo for 6months. The primary outcome was time to progression of HF (HF death, hospitalisation, or sustained increase in diuretics) as assessed by log‐rank tests and by Cox modelling. Results Progression of HF occurred in 46.6% of the CSE and 43.3% of the placebo groups (OR 1.14, 95% CI=0.56, 2.35: p =0.86). Patients receiving CSE were 3.9 times (95% CI=1.1−13.7: p =0.035) more likely to experience HF progression at baseline. In adjusted analysis, the risk of having early HF progression in the CSE group increased to 6.4 (95% CI=1.5, 26.5: p =0.011). In patients with LVEF≤35%, those taking CSE were at significantly greater risk (3.2, 95% CI=1.3, 8.3: p =0.02) than the placebo group. Conclusions CSE does not reduce heart failure progression in patients who have HF. CSE appears to increase the early risk of HF progression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102656/1/ejhf2008-04-008.pd

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

BACKGROUND: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system. AIM: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF. METHODS AND RESULTS: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation. CONCLUSION: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

A novel, highly discriminatory risk model predicting acute severe right ventricular failure in patients undergoing continuous‐flow left ventricular assist device implant

Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)‐LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF‐LVAD implantation, were randomly divided into equal‐sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF‐LVADs [HeartMate II LVAD, 76% (n = 560), HeartWare HVAD, 24% (n = 174)]. A RVAD was required in 4.5% (n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients (n = 143) were female, median age at implant was 59 years (IQR, 49.4–65.3), and median INTERMACS profile was 3 (IQR, 2–3). RVAD was required in 4.5% (n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150536/1/aor13413_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150536/2/aor13413.pd

A Novel Tropical Geometry-based Interpretable Machine Learning Method: Pilot Application to Delivery of Advanced Heart Failure Therapies

Abstract—A model’s interpretability is essential to many practical applications such as clinical decision support systems. In this paper, a novel interpretable machine learning method is presented, which can model the relationship between input variables and responses in humanly understandable rules. The method is built by applying tropical geometry to fuzzy inference systems, wherein variable encoding functions and salient rules can be discovered by supervised learning. Experiments using synthetic datasets were conducted to demonstrate the performance and capacity of the proposed algorithm in classification and rule discovery. Furthermore, we present a pilot application in identifying heart failure patients that are eligible for advanced therapies as proof of principle. From our results on this particular application, the proposed network achieves the highest F1 score. The network is capable of learning rules that can be interpreted and used by clinical providers. In addition, existing fuzzy domain knowledge can be easily transferred into the network and facilitate model training. In our application, with the existing knowledge, the F1 score was improved by over 5%. The characteristics of the proposed network make it promising in applications requiring model reliability and justification

The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT‐HFpEF): Rationale and design

AIMS: Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. METHODS: SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. CONCLUSION: SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions

Comparison of Evaluations for Heart Transplant Before Durable Left Ventricular Assist Device and Subsequent Receipt of Transplant at Transplant vs Nontransplant Centers

IMPORTANCE: In 2020, the Centers for Medicare & Medicaid Services revised its national coverage determination, removing the requirement to obtain review from a Medicare-approved heart transplant center to implant a durable left ventricular assist device (LVAD) for bridge-to-transplant (BTT) intent at an LVAD-only center. The association between center-level transplant availability and access to heart transplant, the gold-standard therapy for advanced heart failure (HF), is unknown. OBJECTIVE: To investigate the association of center transplant availability with LVAD implant strategies and subsequent heart transplant following LVAD implant before the Centers for Medicare & Medicaid Services policy change. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of the Society of Thoracic Surgeons Intermacs multicenter US registry database was conducted from April 1, 2012, to June 30, 2020. The population included patients with HF receiving a primary durable LVAD. EXPOSURES: LVAD center transplant availability (LVAD/transplant vs LVAD only). MAIN OUTCOMES AND MEASURES: The primary outcomes were implant strategy as BTT and subsequent transplant by 2 years. Covariates that might affect listing strategy and outcomes were included (eg, patient demographic characteristics, comorbidities) in multivariable models. Parameters for BTT listing were estimated using logistic regression with center-level random effects and for receipt of a transplant using a Cox proportional hazards regression model with death as a competing event. RESULTS: The sample included 22 221 LVAD recipients with a median age of 59.0 (IQR, 50.0-67.0) years, of whom 17 420 (78.4%) were male and 3156 (14.2%) received implants at LVAD-only centers. Receiving an LVAD at an LVAD/transplant center was associated with a 79% increased adjusted odds of BTT LVAD designation (odds ratio, 1.79; 95% CI, 1.35-2.38; P \u3c .001). The 2-year transplant rate following LVAD implant was 25.6% at LVAD/transplant centers and 11.9% at LVAD-only centers. There was an associated 33% increased rate of transplant at LVAD/transplant centers compared with LVAD-only centers (adjusted hazard ratio, 1.33; 95% CI, 1.17-1.51) with a similar hazard for death at 2 years (adjusted hazard ratio, 0.99; 95% CI, 0.90-1.08). CONCLUSIONS AND RELEVANCE: Receiving an LVAD at an LVAD-transplant center was associated with increased odds of BTT intent at implant and subsequent transplant receipt for patients at 2 years. The findings of this study suggest that Centers for Medicare & Medicaid Services policy change may have the unintended consequence of further increasing inequities in access to transplant among patients at LVAD-only centers