Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) in a General Population-Brief Report.

BACKGROUND: PCSK9 (proprotein convertase subtilisin-kexin type 9) chaperones the hepatic LDLR (low-density lipoprotein receptor) for lysosomal degradation, elevating serum LDL (low-density lipoprotein) cholesterol and promoting atherosclerotic heart disease. Though the major effect on the hepatic LDLR comes from secreted PCSK9, the details of PCSK9 reuptake into the hepatocyte remain unclear. In both tissue culture and animal models, HSPGs (heparan sulfate proteoglycans) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We hypothesized that if this PCSK9:HSPG interaction is important in humans, disrupting it with unfractionated heparin (UFH) would acutely displace PCSK9 from the liver and increase plasma PCSK9. METHODS: We obtained remnant plasma samples from 160 subjects undergoing cardiac catheterization before and after administration of intravenous UFH. PCSK9 levels were determined using a commercial enzyme-linked immunosorbent assay. RESULTS: Median plasma PCSK9 was 113 ng/mL prior to UFH and 119 ng/mL afterward. This difference was not significant (P=0.83 [95% CI, -6.23 to 6.31 ng/mL]). Equivalence testing provided 95% confidence that UFH would not raise plasma PCSK9 by > 4.7%. Among all subgroups, only subjects with the lowest baseline PCSK9 concentrations exhibited a response to UFH (8.8% increase, adj. P=0.044). A modest correlation was observed between baseline plasma PCSK9 and the change in plasma PCSK9 due to UFH (RS=-0.3634; P<0.0001). CONCLUSIONS: Administration of UFH does not result in a clinically meaningful effect on circulating PCSK9 among an unselected population of humans. The results cast doubt on the clinical utility of disrupting the PCSK9:HSPG interaction as a general therapeutic strategy for PCSK9 inhibition. However, the observations suggest that in selected populations, disrupting the PCSK9:HSPG interaction could still affect PCSK9 reuptake and offer a therapeutic benefit.

Noninvasive estimation of pulmonary vascular resistance improves portopulmonary hypertension screening in liver transplant candidates.

Despite limitations in sensitivity and specificity, estimation of the pulmonary artery systolic pressure (ePASP) on echocardiography is used for portopulmonary hypertension (PoPH) screening in liver transplant (LT) candidates. We proposed that alternative echocardiographic models, such as estimated pulmonary vascular resistance (ePVR), may provide improved testing characteristics in PoPH screening. In a retrospective analysis of 100 LT candidates, we found that the formula ePVR = ePASP/VTIRVOT  + 3 if MSN (VTIRVOT  = right ventricular outflow tract time velocity integral; MSN = mid-systolic notching of the VTIRVOT Doppler signal) significantly improves accuracy of PoPH screening compared to ePASP. We determined the optimal ePVR cutoff for PoPH screening to be 2.76 Wood units, as this cutoff provided 100% sensitivity and 73% specificity in screening for clinically significant PoPH. Comparatively, ePASP at a cutoff of 40 mm Hg provided 91% sensitivity and 48% specificity. We devised a new screening algorithm based on the use of ePVR at intermediate ePASP values (35-54 mm Hg), and we confirmed the testing characteristics of this algorithm in a separate validation cohort of 50 LT candidates. In screening LT candidates for PoPH, the ePASP lacks accuracy, leading to unnecessary RHCs and undiagnosed cases of PoPH. A screening algorithm which incorporates the ePVR may be more reliable.

Association Between Coronary Assessment in Heart Failure and Clinical Outcomes Within a Safety-Net Setting Using a Target Trial Emulation Observational Design.

BACKGROUND: Ischemic cardiomyopathy is the leading cause of heart failure (HF). Most patients do not undergo coronary assessment after HF diagnosis. There are no randomized clinical trials of coronary assessment after HF diagnosis. METHODS: Using an electronic health record cohort of all individuals with HF within the San Francisco Health Network from 2001 to 2019, we identified factors associated with coronary assessment. Then, we studied the association of coronary assessment within 30 days of HF diagnosis with all-cause mortality and a composite of mortality and emergent angiography using a target trial emulation observational comparative-effectiveness approach. Target trial emulation is an approach to causal inference based on creating a hypothetical randomized clinical trial protocol and using observational data to emulate the protocol. We used propensity scores for covariate adjustment. We used national death records to improve the ascertainment of mortality and included falsification end points for the cause of death. RESULTS: Among 14 829 individuals with HF (median, 62 years old; 5855 [40%] women), 3987 (26.9%) ever completed coronary assessment, with 2467/13 301 (18.5%) with unknown coronary artery disease status at HF diagnosis assessed. Women, older individuals, and people without stable housing were less likely to complete coronary assessment. Among 5972 eligible persons of whom 627 underwent early elective coronary assessment, coronary assessment was associated with lower mortality (hazard ratio, 0.84 [95% CI, 0.72-0.97]; P=0.025), reduced risk of the composite outcome (hazard ratio, 0.86 [95% CI, 0.73-1.00]), higher rates of revascularization (odds ratio, 7.6 [95% CI, 5.4-10.6]), and higher use of medical therapy (odds ratio, 2.5 [95% CI, 1.7-3.6]), but not the falsification end points. CONCLUSIONS: In a safety-net population, disparities in coronary assessment after HF diagnosis are not fully explained by coronary artery disease risk factors. Early coronary assessment is associated with improved HF outcomes possibly related to higher rates of revascularization and guideline-directed medical therapy but with low certainty that this finding is not attributable to unmeasured confounding.

Surrogate decision makers' interpretation of prognostic information: a mixed-methods study.

BACKGROUND: Little is known about why surrogate decision makers for patients with advanced illness often have overly optimistic expectations about prognosis. OBJECTIVE: To determine how surrogates interpret prognostic statements and to explore factors influencing surrogates' interpretations of grim prognostic information. DESIGN: Multicenter, mixed-methods study. SETTING: Intensive care units of 3 hospitals in San Francisco, California. PARTICIPANTS: 80 surrogates of critically ill patients. MEASUREMENTS: Participants recorded their interpretation of 16 prognostic statements using a standard probability scale. Generalized estimating equations were used to determine whether participants interpreted statements more optimistically as the expressed probability of survival decreased. Fifteen surrogates whose responses exhibited this trend participated in a semistructured interview. RESULTS: Participants' interpretations of prognostic statements expressing a low risk for death were relatively accurate, but interpretations of statements conveying a high risk for death were more optimistic than the actual meaning (P < 0.001; generalized estimating equation model). Interpretations of the statement "90% chance of surviving" did not differ from the actual meaning, but interpretations of "5% chance of surviving" were more optimistic and showed substantial variability (median, 90% [interquartile range, 90% to 95%; P = 0.11] vs. 15% [interquartile range, 5% to 40%; P < 0.001], respectively). Two main themes from the interviews explained this trend: surrogates' need to register optimism in the face of a poor prognosis and surrogates' belief that patient attributes unknown to the physician would lead to better-than-predicted outcomes. LIMITATION: Surrogates' interpretations were elicited in an experimental setting rather than during actual clinician-surrogate conversations. CONCLUSION: Inaccurate interpretations of physicians' prognostications by surrogates arise partly from optimistic biases rather than simply from misunderstandings. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Coronary Assessment in Heart Failure within a Safety-Net Setting: Disparities and Outcomes.

Background: Though ischemic cardiomyopathy is the leading cause of heart failure (HF), most patients do not undergo coronary assessment after heart failure diagnosis. In a safety-net population, referral patterns have not been studied, and it is unknown whether coronary assessment is associated with improved HF outcomes. Methods: Using an electronic health record cohort of all individuals with HF within San Francisco Health Network from 2001-2019, we identified factors associated with completion of coronary assessment (invasive coronary angiography, nuclear stress, or coronary computed tomographic angiography). Then we emulated a randomized clinical trial of elective coronary assessment with outcomes of all-cause mortality and a composite outcome of mortality and emergent angiography. We used propensity scores to account for differences between groups. We used national death records to improve ascertainment of mortality. Results: Among 14,829 individuals with HF (median 62 years old, 5,855 [40%] women), 3,987 (26.9%) ever completed coronary assessment, with 2,467 (18.5%) assessed out of 13,301 with unknown CAD status at HF diagnosis. Women and older individuals were less likely to complete coronary assessment, with differences by race/ethnicity, medical history, substance use, housing, and echocardiographic findings. Among 5,972 eligible for inclusion in the "target trial," 627 underwent early elective coronary assessment and 5,345 did not. Coronary assessment was associated with lower mortality (HR 0.84; 95% CI 0.72-0.97; p=0.025), reduced risk of the composite outcome, higher rates of revascularization, and higher use of medical therapy. Conclusions: In a safety-net population, disparities in coronary assessment after HF diagnosis are not fully explained by CAD risk factors. Our target trial emulation suggests coronary assessment is associated with improved HF outcomes possibly related to higher rates of revascularization and GDMT use, but with low certainty that this is finding is not attributable to unmeasured confounding.

Echocardiographic estimation of pulmonary vascular resistance in advanced lung disease.

Noninvasive assessment of pulmonary hemodynamics is often performed by echocardiographic estimation of the pulmonary artery systolic pressure (ePASP), despite limitations in the advanced lung disease population. Other noninvasive hemodynamic variables, such as echocardiographic pulmonary vascular resistance (ePVR), have not been studied in this population. We performed a retrospective analysis of 147 advanced lung disease patients who received both echocardiography and right heart catheterization for lung transplant evaluation. The ePVR was estimated by four previously described equations. Noninvasive and invasive hemodynamic parameters were compared in terms of correlation, agreement, and accuracy. The ePVR models strongly correlated with invasively determined PVR and had good accuracy with biases of <1 Wood units (WU), although with moderate precision and wide 95% limits of agreement varying from 5.9 to 7.8 Wood units. The ePVR models were accurate to within 1.9 WU in over 75% of patients. In comparison to the ePASP, ePVR models performed similarly in terms of correlation, accuracy, and precision when estimating invasive hemodynamics. In screening for pulmonary hypertension, ePVR models had equivalent testing characteristics to the ePASP. Mid-systolic notching of the right ventricular outflow tract Doppler signal identified a subgroup of 11 patients (7%) with significantly elevated PVR and mean pulmonary artery pressures without relying on the acquisition of a tricuspid regurgitation signal. Analysis of ePVR and determination of the notching pattern of the right ventricular outflow tract Doppler flow velocity envelope provide reliable insights into hemodynamics in advanced lung disease patients, although limitations in precision exist.

Predictors of All-Cause 30-Day Readmissions in Patients with Heart Failure at an Urban Safety Net Hospital: The Importance of Social Determinants of Health and Mental Health.

Introduction: Heart failure (HF) is a frequent cause of readmissions. Despite caring for underresourced patients and dependence on government funding, safety net hospitals frequently incur penalties for failing to meet pay-for-performance readmission metrics. Limited research exists on the causes of HF readmissions in safety net hospitals. Therefore, we sought to investigate predictors of 30-day all-cause readmission in HF patients in the safety net setting. Methods: We performed a retrospective chart review of patients admitted for HF from October 2018 to April 2019. We extracted data on demographics and medical comorbidities and performed patient-specific review of social determinants and mental health in 4 domains: race/ethnicity, housing status, substance use, and mental illness. Multivariable Poisson regression modeling was employed to evaluate associations with 30-day all-cause readmission. Results: The study population included 290 patients, among whom the mean age was 59 years and 71% (n = 207) were male; 42% (120) were Black/African American (AA), 22% (64) were Hispanic/Latino, and 96% (278) had public insurance; 28% (79) were not housed, 19% (56) had a diagnosis of mental illness, and active substance use was common. The 30-day readmission rate was 25.5% (n = 88). Factors that were associated with increased risk of readmission included self-identifying as Black/AA (relative risk 2.28, 95% confidence interval 1.00-5.20) or Hispanic/Latino (2.53, 1.07-6.00), experiencing homelessness (2.07, 1.21-3.56), living in a shelter (3.20, 1.27-8.02), or intravenous drug use (IVDU) (2.00, 1.08-3.70). Conclusion: Race/ethnicity, housing status, and substance use were associated with increased risk of 30-day all-cause readmission in HF patients in a safety net hospital. In contrast to prior studies, medical comorbidities were not associated with increased risk of readmission.

Effect of a Novel, Evidence-Based, Standardized Discharge Checklist on 30-Day All-Cause Readmissions in Patients Hospitalized for Heart Failure in an Urban Safety Net Hospital.

Safety net hospitals frequently incur financial penalties for high readmission rates. Heart failure (HF) is a common driver of readmissions, but effectively lowering readmission rates in patients with HF has proved challenging. There are few evidence-based interventions validated within safety net systems. Between October 2018 and April 2019, we implemented an evidence-based discharge checklist. We evaluated the hypothesis that it would reduce 30-day all-cause readmissions in patients admitted for HF at an urban safety net hospital. We retrospectively compared all-cause 30-day readmission rates between the cohort discharged using the checklist and historical controls. Demographics were similar between the intervention (n = 103) and control (n = 187) groups and reflected the diverse and vulnerable population cared for in the safety net. The mean age was 60 years, 71% were male, 42% were Black, 22% were Hispanic/Latinx, 28% were not housed, 35% used illicit stimulants, and 73% had a left ventricular ejection fraction ≤40%. Use of the checklist was associated with a 12.4% absolute reduction in the 30-day readmission rate (29.9% vs 17.5%, p = 0.02). The intervention group was more likely to be discharged on appropriate guideline-directed medical therapy for reduced systolic function, including ß blockers (93% vs 73%, p = 0.0004), angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (92% vs 66%, p <0.0001) and mineralocorticoid receptor antagonists (50% vs 27%, p = 0.0007). Multivariable analysis demonstrated that using the discharge checklist was associated with a lower risk of 30-day all-cause readmission (risk ratio 0.54, 0.33 to 0.90). Therefore, a low-cost, novel, evidence-based discharge checklist significantly reduced 30-day all-cause readmission rates in patients hospitalized for HF at a safety net hospital.

Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.

Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.

Successful Use of Pulmonary Vasodilators in Acute Chest Syndrome Complicated by Persistent Right Ventricular Failure.

Pulmonary hypertension (PH) is a known consequence of sickle cell disease (SCD) and is associated with increased mortality and more frequent episodes of acute chest syndrome (ACS). Pulmonary pressures are known to increase during ACS, and right ventricular (RV) failure has been described as a significant cause of mortality in this condition. Management of ACS includes exchange transfusion, pain control, and prevention of hypovolemia and hypoxemia. However, in patients with a history of precapillary PH in whom ACS is complicated by persistent RV failure and cardiogenic shock, RV afterload reduction with pulmonary vasodilators may be an effective treatment strategy. Here, we present a case of a young man with SCD-associated PH and ACS who was successfully managed with inhaled and oral pulmonary vasodilators in the setting of persistent elevations in pulmonary vascular resistance leading to acute RV failure and cardiogenic shock.

Doubt and belief in physicians' ability to prognosticate during critical illness: the perspective of surrogate decision makers.

OBJECTIVES: Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers. DESIGN, SETTING, AND PATIENTS: Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking. MEASUREMENTS AND MAIN RESULTS: Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive. CONCLUSIONS: Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes.

Cardiopulmonary exercise testing in the evaluation of liver disease in adults who have had the Fontan operation.

BACKGROUND: Liver disease (LD) is a long-term complication in patients with a single ventricle who have had the Fontan operation. A decline in cardiopulmonary exercise testing (CPET) variables is associated with increased risk of hospitalization, but its association with LD is unknown. AIM: To determine the association between CPET variables and LD in adults who have had the Fontan operation. METHODS: We retrospectively reviewed the medical records from two tertiary institutions. RESULTS: We identified 114 adults (≥18 years; mean 30.9±7.4 years) who had undergone the Fontan operation: 56% were women; 63% had total cavopulmonary connection; 66% had New York Heart Association (NYHA) class I status; 42% had arrhythmias; 22% had systemic right ventricle; and 35% had ventricular dysfunction. Of 81 patients with liver-imaging data, 41% had LD (i.e. imaging evidence of cirrhosis, with or without portal hypertension, splenomegaly or varices). There were no differences in clinical or echocardiographic variables between those with and without LD. Among the 58 patients with CPET data, mean peak oxygen consumption (VO2) was 18.6±5.7mL/kg/min, per-cent-predicted peak VO2 was 53.9±15.5%, peak oxygen pulse was 9.3±2.9mL/beat and per-cent-predicted peak oxygen pulse was 82.6±21.5%. Of the 44 patients with liver and CPET data, each standard deviation decrease in per-cent-predicted peak VO2 (16%) and per-cent-predicted peak oxygen pulse (22%) was associated with a 2.3-fold increase in the odds of LD, after adjusting for NYHA, institution and Fontan type (P=0.04). Similarly, each standard deviation decrease in per-cent-predicted peak VO2 and oxygen pulse was associated with an estimated 5.9-year and 4.9-year earlier onset of LD, respectively (P>0.05). CONCLUSIONS: Decline in per-cent-predicted peak VO2 and oxygen pulse was associated with increased odds of LD in adults who had undergone the Fontan operation. Our study supports more rapid hepatic evaluation among patients with abnormal or worsening CPET variables.

To close or not to close: contemporary indications for patent foramen ovale closure.

INTRODUCTION: Patent foramen ovale (PFO) is a common congenital cardiac abnormality and that has been associated with several disease processes including transient ischemic attacks (TIA), stroke, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Controversy exists regarding closure of PFO as a therapeutic treatment modality for these disease processes. This review addresses the contemporary clinical indications for PFO closure. Areas covered: We conducted a comprehensive literature search of contemporary research studies focusing on randomized trials and meta-analyses comparing medical therapy and device closure of PFOs for the treatment of PFO associated clinical syndromes. We synthesized this literature into a review addressing indications for PFO closure in stroke, TIA, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Expert commentary: Because in many PFO associated conditions it can be difficult to determine the degree to which the PFO is a causative factor in the disease process, we recommend a comprehensive diagnostic evaluation to exclude other obvious etiologies of PFO associated conditions before implicating the PFO and proceeding with closure. However in the properly selected patient population there is growing clinical experience and experimental evidence suggesting that closure of PFO is a safe and effective treatment modality.

Surrogate decision makers' responses to physicians' predictions of medical futility.

BACKGROUND: Although physicians sometimes use the futility rationale to limit the use of life-sustaining treatments, little is known about how surrogate decision makers view this rationale. We sought to determine the attitudes of surrogates of patients who are critically ill toward whether physicians can predict futility and whether these attitudes predict surrogates' willingness to discontinue life support when faced with predictions of futility. METHODS: This multicenter, mixed qualitative and quantitative study took place at three hospitals in California from 2006 to 2007. We conducted semistructured interviews with surrogate decision makers for 50 patients who were critically ill and incapacitated that addressed their beliefs about medical futility and inductively developed an organizing framework to describe these beliefs. We used a hypothetical scenario with a modified time-trade-off design to examine the relationship between a patient's prognosis and a surrogate's willingness to withdraw life support. We used a mixed-effects regression model to examine the association between surrogates' attitudes about futility and their willingness to limit life support in the face of a very poor prognosis. Validation methods included the use and integration of multiple data sources, multidisciplinary analysis, and member checking. RESULTS: Sixty-four percent of surrogates (n = 32; 95% confidence interval [CI], 49 to 77%) expressed doubt about the accuracy of physicians' futility predictions, 32% of surrogates (n = 16; 95% CI, 20 to 47%) elected to continue life support with a < 1% survival estimate, and 18% of surrogates (n = 9; 95% CI, 9 to 31%) elected to continue treatment when the physician believed that the patient had no chance of survival. Surrogates with religious objections to the futility rationale (n = 18) were more likely to request continued life support (odds ratio, 4; 95% CI, 1.2 to 14.0; p = 0.03) than those with secular or experiential objections (n = 15; odds ratio, 0.95; 95% CI, 0.3 to 3.4; p = 0.90). CONCLUSIONS: Doubt about physicians' ability to predict medical futility is common among surrogate decision makers. The nature of the doubt may have implications for responding to conflicts about futility in clinical practice.