Oxygen Uptake Efficiency Slope and Prognosis in Heart Failure With Reduced Ejection Fraction.

The prognostic utility of the oxygen uptake efficiency slope (OUES) in heart failure with reduced ejection fraction is uncertain. In this post hoc analysis of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (n = 2,074), we tested for associations of OUES and peak oxygen uptake (VO2) with heart failure hospitalization or cardiovascular death in multivariable Cox regression models, adjusting for minute ventilation/carbon dioxide production (VE/VCO2) slope and other important confounders. Harrell's C-statistics assessed the discriminatory performance of OUES and peak VO2. Lower OUES was associated with increased risk of the outcome (quartile 1 vs 4: hazard ratio 2.1 [1.5 to 2.9, p <0.001]). Peak VO2 had greater discrimination than OUES in comparable models (e.g., C-statistic = 0.73 vs 0.70, p <0.001, respectively). In the subgroup with respiratory exchange ratio <1 (n = 358), peak VO2 was associated with the outcome (p <0.001) but OUES was not (p = 0.96). In conclusion, whereas OUES was associated with clinical outcomes independently of VE/VCO2 slope, its prognostic utility was inferior to that of peak VO2, even when measured at submaximal effort.

Phenomapping a Novel Classification System for Patients With Destination Therapy Left Ventricular Assist Devices.

Patients with continuous flow destination therapy (DT) left ventricular assist devices (LVAD) comprise a heterogeneous population. We hypothesized that phenotypic clustering of individuals with DT LVADs by their implantation characteristics will be associated with different long-term risk profiles. We analyzed 5,999 patients with continuous flow DT LVADs in Interagency Registry for Mechanically Assisted Circulatory Support using 18 continuous variable baseline characteristics. We Z-transformed the variables and applied a Gaussian finite mixture model to perform unsupervised clustering resulting in identification of 4 phenogroups. Survival analyses considered the competing risk for cumulative incidence of transplant or the composite end point of death or heart transplant where appropriate. Phenogroup 1 (n = 1,163, 19%) was older (71 years) and primarily white (81%). Phenogroups 2 (n = 648, 11%) and 3 (n = 3,671, 61%) were of intermediate age (70 and 62 years), weight (85 and 87 kg), and ventricular size. Phenogroup 4 (n = 517, 9%) was younger (40 years), heavier (108 kg), and more racially diverse. The cumulative incidence of death, heart transplant, bleeding, LVAD malfunction, and LVAD thrombosis differed among phenogroups. The highest incidence of death and the lowest rate of heart transplant was seen in phenogroup 1 (p <0.001). For adverse outcomes, phenogroup 4 had the lowest incidence of bleeding, whereas LVAD device thrombosis and malfunction were lowest in phenogroup 1 (p <0.001 for all). Finally, the incidence of stroke, infection, and renal dysfunction were not statistically different. In conclusion, the present unsupervised machine learning analysis identified 4 phenogroups with different rates of adverse outcomes and these findings underscore the influence of phenotypic heterogeneity on post-LVAD implantation outcomes.

A library of induced pluripotent stem cells from clinically well-characterized, diverse healthy human individuals.

A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22 to 61 years. The hiPSCs match the karyotype and short tandem repeat identities of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole-genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-sequencing-derived cell clusters, and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

Discordance Between Severity of Heart Failure as Determined by Patient Report Versus Cardiopulmonary Exercise Testing.

Background Patient-reported outcomes may be discordant to severity of illness as assessed by objective parameters. The frequency of this discordance and its influence on clinical outcomes in patients with heart failure is unknown. Methods and Results In HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), participants (N=2062) had baseline assessment of health-related quality of life via the Kansas City Cardiomyopathy Clinical Summary score (KCCQ-CS) and objective severity by cardiopulmonary stress testing (minute ventilation [VE]/carbon dioxide production [VCO2] slope). We defined 4 groups by median values: 2 concordant (lower severity: high KCCQ-CS and low VE/VCO2 slope; higher severity: low KCCQ-CS and high VE/VCO2 slope) and 2 discordant (symptom minimizer: high KCCQ-CS and high VE/VCO2 slope; symptom magnifier: low KCCQ-CS and low VE/VCO2 slope). The association of group assignment with mortality was assessed in adjusted Cox models. Symptom magnification (23%) and symptom minimization (23%) were common. Despite comparable KCCQ-CS scores, the risk of all-cause mortality in symptom minimizers versus concordant-lower severity participants was increased significantly (hazard ratio [HR], 1.79; 95% CI, 1.27-2.50; P<0.001). Furthermore, despite symptom magnifiers having a KCCQ-CS score 28 points lower (poorer QOL) than symptom minimizers, their risk of mortality was not increased (HR, 0.79; 95% CI, 0.57-1.1; P=0.18, respectively). Conclusions Severity of illness by patient report versus cardiopulmonary exercise testing was frequently discordant. Mortality tracked more closely with the objective data, highlighting the importance of relying not only on patient report, but also objective data when risk stratifying patients with heart failure.

Durable Mechanical Circulatory Support in Patients With Amyloid Cardiomyopathy: Insights From INTERMACS.

BACKGROUND: Many patients with amyloid cardiomyopathy (ACM) develop advanced heart failure, and durable mechanical circulatory support (MCS) may be a consideration. However, data describing clinical outcomes after MCS in this population are limited. METHODS: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support with dilated cardiomyopathy (DCM, n=19 921), nonamyloid restrictive cardiomyopathy (RCM, n=248), or ACM (n=46) between 2005 and 2017 were included. Patient and device characteristics were compared between cardiomyopathy groups. The primary end point was the cumulative incidence of death with heart transplantation as a competing risk. RESULTS: Patients with ACM (n=46) were older (61 years [interquartile range, 55-69 years] versus 58 years [interquartile range, 49-66 years] for DCM and 55 years [interquartile range, 46-62 years] for nonamyloid RCM, P<0.001) and were more commonly Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (30.4% versus 17.9% for DCM and 21.0% for nonamyloid RCM, P=0.04) at device implantation. Use of biventricular support (biventricular assist device or total artificial heart) was the highest for patients with ACM (41.3% versus 6.7% and 19.4% for patients with DCM and nonamyloid RCM, respectively, P=0.014). The cumulative incidence of death was highest for patients with ACM relative to those with DCM or nonamyloid RCM (P<0.001) but did not differ significantly between groups for those who required biventricular MCS. CONCLUSIONS: Compared with patients with DCM or nonamyloid RCM who received durable MCS, those with ACM experienced the highest use of biventricular support and the worst survival. These data highlight concerns with the use of durable MCS for patients with ACM.

Impact of body mass index on surgical coronary revascularization for ischaemic heart failure: insights from STICHES.

AIMS: Patients with obesity and ischaemic heart failure may counter-intuitively have better outcomes compared with patients with normal body weight due to an 'obesity paradox'. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). METHODS AND RESULTS: We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P-interaction = 0.90). There was a non-significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85-1.00, P = 0.051]. Increasing body size (per 5 kg/m2 ) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45-4.26, P < 0.001) and infectious mediastinitis (odds ratio 2.09, 95% CI 1.10-3.97, P = 0.024) at 30 days but not other 30 day safety outcomes. CONCLUSIONS: The benefit of CABG vs. medical therapy for ischaemic heart failure was consistent regardless of BMI or WHO obesity class for death or secondary clinical outcomes. However, higher BMI was associated with some short-term post-CABG complications.

Dynamic Forecasts of Survival for Patients Living With Destination Left Ventricular Assist Devices: Insights From INTERMACS.

Background Left ventricular assist devices (LVADs) improve outcomes in patients with end-stage heart failure and are increasingly implanted for destination therapy. We describe dynamic estimates of event-free survival with conditional survival probabilities in a destination therapy LVAD population. Methods and Results We studied 8245 adult patients in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) implanted with a continuous-flow destination therapy LVAD. The composite primary end point was death, device exchange or removal, or heart transplantation. Conditional survival probabilities were calculated and stratified by implantation characteristics and nonfatal adverse events experienced within the first year after implant. Probabilities of surviving an additional 1 to 3 years were numerically higher after longer prior event-free survival. INTERMACS profile 1, extracorporeal membrane oxygenation support, prior or concomitant surgery, and dialysis within 48 hours of implantation were associated with significantly lower event-free survival in the first year but did not impact event-free survival beyond then. For patients who experienced a nonfatal adverse event within the first year, subsequent 1-year conditional survival was lower than in the absence of that event for stroke (65% [95% CI, 57%-73%] versus 75% [95% CI, 73%-77%]; P<0.001), device-related infection (64% [95% CI 57%-71%] versus 76% [95% CI, 74%-78%]; P<0.001), and pump thrombosis or malfunction (64% [95% CI, 57%-70%] versus 76% [95% CI, 74%-78%]; P<0.001). Conclusions Conditional survival in patients with destination therapy LVADs improves over time, even for patients with unfavorable implantation characteristics. However, LVAD-related complications including stroke, device-related infection, and pump thrombosis or malfunction have an enduring negative influence on dynamic estimates of long-term prognosis.

Cutaneous Vasculitis and Central Nervous System Infarctions due to Varicella Zoster Virus Vasculopathy in an Immunocompromised Patient.

Varicella zoster virus (VZV) infection commonly presents as varicella during childhood, and zoster, later in life. Here, we present a rare and interesting case of VZV infection that manifested with both cerebral and spinal infarctions and cutaneous vasculitis in the absence of a classic vesicular rash in an immunocompromised patient.

A plasma proteogenomic signature for fibromuscular dysplasia.

AIMS: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. METHODS AND RESULTS: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. CONCLUSION: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries.

Mesenchymal stem cells (MSCs) reportedly exist in a vascular niche occupying the outer adventitial layer. However, these cells have not been well characterized in vivo in medium- and large-sized arteries in humans, and their potential pathological role is unknown. To address this, healthy and diseased arterial tissues were obtained as surplus surgical specimens and freshly processed. We identified that CD90 marks a rare adventitial population that co-expresses MSC markers including PDGFRα, CD44, CD73, and CD105. However, unlike CD90, these additional markers were widely expressed by other cells. Human adventitial CD90+ cells fulfilled standard MSC criteria, including plastic adherence, spindle morphology, passage ability, colony formation, and differentiation into adipocytes, osteoblasts, and chondrocytes. Phenotypic and transcriptomic profiling, as well as adoptive transfer experiments, revealed a potential role in vascular disease pathogenesis, with the transcriptomic disease signature of these cells being represented in an aortic regulatory gene network that is operative in atherosclerosis.

Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.

Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-ß signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.

Coronary artery manifestations of fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic "string of beads" that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.

New vessel formation in the context of cardiomyocyte regeneration--the role and importance of an adequate perfusing vasculature.

The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50 year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply.

Effect of electronic prescription on attainment of cholesterol goals.

BACKGROUND: Although recent federal mandate provides incentives for physicians to use electronic prescribing (e-prescribing), clinical end points to support its use are lacking. HYPOTHESIS: E-prescribing should improve low-density lipoprotein (LDL) goal attainment. METHODS: In this retrospective cohort study, we queried the electronic medical records (Allscripts Electronic Health Record [EHR]) of a multispecialty outpatient academic medical practice to identify patient encounters during which consecutive lipid panels were drawn in 2007 (n = 2218). The EHR did not include a clinical decision tool for guideline adherence but did include formulary decision support (FDS), which informs physicians about drug costs specific to each patient. Logistic regression was used to examine whether the odds of reaching LDL goal were influenced by e-prescribing and adjusted for characteristics known to affect prescribing patterns and goal attainment. RESULTS: Of 796 patients not at LDL goal at baseline, 49% (n = 393) were at goal at follow-up. Patients receiving an e-prescription with FDS were 59% more likely to achieve LDL goal than those with a manual prescription (95% confidence interval [CI]: 1.12-2.25). Superior LDL goal attainment may be from lower cost of medications; patients with an e-prescription were significantly more likely to receive a generic statin than patients with a manual prescription (38% vs 22.9%; P = 0.0004), and for each $10 increase in prescription price, the likelihood of being at goal decreased by 5% (odds ratio = 0.95; 95% CI: 0.93-0.98). CONCLUSIONS: Our study is the first to demonstrate that e-prescribing with FDS is associated with improved LDL goal attainment. Therefore, e-prescribing can deliver tangible clinical gains to patients, likely from improved adherence to more affordable treatment.