Predictors of intra-aortic balloon pump hemodynamic failure in non-acute myocardial infarction cardiogenic shock.

OBJECTIVES: To characterize patient profile and hemodynamic profile of those undergoing intra-aortic balloon pump (IABP) for cardiogenic shock and define predictors of hemodynamic failure of IABP support. BACKGROUND: Clinical characteristics of IABP support in cardiogenic shock not related to acute myocardial infarction (AMI) remain poorly characterized. METHODS: We retrospectively studied a cohort of 74 patients from 2010 to 2015 who underwent IABP insertion for cardiogenic shock complicating acute decompensated heart failure not due to AMI. RESULTS: In the overall cohort, which consisted primarily of patients with chronic systolic heart failure (89%), IABP significantly augmented cardiac index and lowered systemic vascular resistance (P<.05). Despite this improvement, 28% of these patients died (24%) or require urgent escalation in mechanical circulatory support (MCS) (4%). Multivariable regression revealed that baseline left ventricular cardiac power index (LVCPI), a measure of LV power output derived from cardiac index and mean arterial pressure (P=.01), and history of ischemic cardiomyopathy (P=.003) were significantly associated with the composite adverse-event endpoint of death or urgent MCS escalation. An IABP Failure risk score using baseline LVCPI <0.28 W/m2 and ischemic history predicted 28-day adverse events with excellent discrimination. CONCLUSION: Despite hemodynamic improvements with IABP support, patients with non-AMI cardiogenic shock still suffer poor outcomes. Patients with ischemic cardiomyopathy and low LVPCI fared significantly worse. These patients may warrant closer observation or earlier consideration of more advanced hemodynamic support.

The on- and off-target effects of morphine in acute coronary syndrome: A narrative review.

With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest pain due to acute Myocardial Infarction (MI). However, observational data suggest that morphine administration during MI may have negative consequences. While vomiting, hypotension and respiratory depression are established side effects, recent reports have demonstrated attenuated and delayed oral anti-platelet agent absorption, as well as suboptimal reperfusion after MI, all of which may translate into adverse cardiovascular outcomes. These data have resulted in reduced support for morphine in recent European and U.S. clinical practice guidelines for MI; despite the absence of any prospective randomized outcomes trials addressing this question. As such, randomized trials are now necessary to confirm whether or not morphine, which is administered in up to 30% of MI cases, causes adverse clinical outcomes in these patients. However, given that placebo-controlled randomized trial designs evaluating morphine in MI are limited by an ethical requirement for appropriate analgesia, alternative investigational approaches may be necessary. In this article we review the updated evidence for morphine in MI and outline novel strategies that may facilitate future investigation of this clinical dilemma.

Thromboxane A(2) generation, in the absence of platelet COX-1 activity, in patients with and without atherothrombotic myocardial infarction.

BACKGROUND: Aspirin's therapeutic action is via inhibition of platelet cyclooxygenase 1 (COX-1) thromboxane A2 (TxA2) production. The aim of this study was to evaluate TxA2 production, in the absence of platelet COX-1 activity, in coronary atherosclerotic heart disease patients with and without atherothrombotic myocardial infarction (MI). METHODS AND RESULTS: TxA2 production, in the absence of platelet COX-1 activity, was evaluated in 44 patients taking aspirin on 3 commercially available assays that detect metabolites of TxA2 in the urine. Two assays measure urine 11-dehydro-thromboxane B2 (TxB2) alone and 1 measures urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2. Platelet COX-1 inhibition was confirmed on <10% platelet aggregation in response to ≥1 mmol/L arachidonic acid. Median urine 11-dehydro-TxB2 was no different in those with and without a diagnosis of atherothrombotic MI (325 vs. 311 pg/mg creatinine, P=0.59 via polyclonal ELISA) and (312 vs. 244 pg/mg creatinine, P=0.11 via LC-MS/MS). Median urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2, however, was higher in those with vs. those without a diagnosis of atherothrombotic MI (1,035 vs. 606 pg/mg creatinine, P=0.03 via monoclonal ELISA). CONCLUSIONS: Differences in TxA2 production, in the absence of platelet COX-1 activity, between those with vs. without atherothrombotic MI were not observed when TxA2 generation was assessed on 11-dehydro-TxB2 production alone (polyclonal ELISA or LC-MS/MS), but differences were observed when TxA2 generation was assessed using 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 (monoclonal ELISA). These findings highlight important differences between different commercially available assays for TxA2 generation and suggest that 11-dehydro-2,3-dinor-TxB2 may be critical to the biology of atherothrombosis.

Prevalence and Correlates of Elevated NT-proBNP in Pregnant Women in the General U.S. Population.

BACKGROUND: Physiologic changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) across trimesters of pregnancy have not been well studied. OBJECTIVES: The authors aimed to measure NT-proBNP in adult women, by pregnancy status and trimester, in a nationally representative sample from the National Health and Nutrition Examination Survey 1999 to 2004. METHODS: We conducted a cross-sectional analysis of 2,134 women (546 pregnant) aged 20 to 40 years without a history of cardiovascular disease. RESULTS: Among pregnant women in the first trimester, the prevalence of elevated NT-proBNP (>125 pg/mL) was 20.0% (SE, 6.6%) compared to 2.4% (SE, 0.8%) among women in the third trimester and 8.0% among nonpregnant women. After adjustment for demographics and cardiovascular risk factors, NT-proBNP was 44% higher (absolute difference 26.4 [95% CI: 11.2-41.6] pg/mL) in the first trimester of pregnancy compared to nonpregnant women. Among pregnant women only, adjusted NT-proBNP was 46% lower (absolute difference -22.2 [95% CI: -36.9 to -7.5] pg/mL) in women in the third trimester compared to women in the first trimester. NT-proBNP was inversely associated with body mass index and with systolic blood pressure. CONCLUSIONS: Women in the first trimester of pregnancy had significantly higher NT-proBNP than those in the third trimester and compared to similarly aged nonpregnant women. The dynamic nature of NT-proBNP should be taken into consideration when ordering NT-proBNP lab tests in pregnant women.

Use of the Frank-Starling mechanism during exercise is linked to exercise-induced changes in arterial load.

Effective arterial elastance(E(A)) is a measure of the net arterial load imposed on the heart that integrates the effects of heart rate(HR), peripheral vascular resistance(PVR), and total arterial compliance(TAC) and is a modulator of cardiac performance. To what extent the change in E(A) during exercise impacts on cardiac performance and aerobic capacity is unknown. We examined E(A) and its relationship with cardiovascular performance in 352 healthy subjects. Subjects underwent rest and exercise gated scans to measure cardiac volumes and to derive E(A)[end-systolic pressure/stroke volume index(SV)], PVR[MAP/(SV*HR)], and TAC(SV/pulse pressure). E(A) varied with exercise intensity: the ΔE(A) between rest and peak exercise along with its determinants, differed among individuals and ranged from -44% to +149%, and was independent of age and sex. Individuals were separated into 3 groups based on their ΔE(A)I. Individuals with the largest increase in ΔE(A)(group 3;ΔE(A)≥0.98 mmHg.m(2)/ml) had the smallest reduction in PVR, the greatest reduction in TAC and a similar increase in HR vs. group 1(ΔE(A)<0.22 mmHg.m(2)/ml). Furthermore, group 3 had a reduction in end-diastolic volume, and a blunted increase in SV(80%), and cardiac output(27%), during exercise vs. group 1. Despite limitations in the Frank-Starling mechanism and cardiac function, peak aerobic capacity did not differ by group because arterial-venous oxygen difference was greater in group 3 vs. 1. Thus the change in arterial load during exercise has important effects on the Frank-Starling mechanism and cardiac performance but not on exercise capacity. These findings provide interesting insights into the dynamic cardiovascular alterations during exercise.

Instituting a Curriculum for Cardio-Obstetrics Subspecialty Fellowship Training.

Maternal mortality is rising in the United States, and cardiovascular disease is the leading cause. Adverse pregnancy outcomes such as preeclampsia and gestational diabetes heighten the risk of cardiovascular complications during pregnancy and the peripartum period and are associated with long-term cardiovascular risks. The field of cardio-obstetrics is a subspecialty within adult cardiology that focuses on the management of women with or at high risk for heart disease who are considering pregnancy or have become pregnant. There is growing recognition of the need for more specialists with dedicated expertise in cardio-obstetrics to improve the cardiovascular care of this high-risk patient population. Current recommendations for cardiovascular fellowship training programs accredited by the Accreditation Council for Graduate Medical Education involve establishing core competency in the knowledge of managing heart disease in pregnancy. However, little granular detail is available of what such training should entail, which can lead to knowledge gaps. Additionally, dedicated advanced subspecialty training in this area is not commonly offered. Multidisciplinary collaborative teams have been shown to improve outcomes in cardiac patients during pregnancy, and cardiovascular fellows-in-training interested in cardio-obstetrics should have the opportunity to participate in and contribute to a pregnancy heart team. In this document, we describe a proposed specialized cardio-obstetrics training pathway that could serve to adequately prepare trainees to competently and comprehensively care for women with cardiovascular disease before, during, and after pregnancy.

Plasma Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in the Acute Respiratory Distress Syndrome.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is a mediator of the immune response to sepsis. PCSK9 is also highly expressed in pneumocytes and pulmonary endothelial cells. We hypothesized that serum PCSK9 levels would be associated with death and ICU outcomes in patients with ARDS. Methods: Using data and plasma samples from the NIH BioLINCC data repository, we assembled a cohort of 1,577 patients with the acute respiratory distress syndrome (ARDS) enrolled in two previously completed clinical trials, EDEN and SAILS. We measured PCSK9 levels in plasma within 24 h of intubation using commercially available ELISA kits (R&D Systems). We assessed the association of PCSK9 with mortality using Cox proportional hazard models. We also assessed clinical factors associated with PCSK9 level and the association of PCSK9 with the number of days free of mechanical ventilation and days free of ICU care. Results: In 1,577 ARDS patients, median age was 53 years (IQR 42-65 years) and median APACHE III score 91 (72-111) connoting moderate critical illness. PCSK9 levels were 339.3 ng/mL (IQR 248.0-481.0). In multivariable models, race, cause of ARDS, body mass index, pre-existing liver disease, body temperature, sodium, white blood cell count and platelet count were associated with PCSK9 level. Presence of sepsis, use of vasopressors and ventilator parameters were not associated with PCSK9 level. PCSK9 levels were not associated with in-hospital mortality (HR per IQR 0.96, 95% CI 0.84-1.08, P = 0.47). Higher PCSK9 levels were associated with fewer ICU and ventilator free days. Conclusions: Plasma PCSK9 is not associated with mortality in ARDS, however higher PCSK9 levels are associated with secondary outcomes of fewer ICU free and ventilator free days. Clinical factors associated with PCSK9 in ARDS are largely unmodifiable. Further research to define the mechanism of this association is warranted.

The Trajectory of Lipoprotein(a) During the Peri- and Early Postinfarction Period and the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition.

Lipoprotein(a), or Lp(a), levels and the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on Lp(a) during the peri-infarction and early postinfarction period are not well characterized. This study aimed to describe the trajectory of Lp(a), as well as the effect of PCSK9 inhibition on that trajectory during the peri-infarction and early postinfarction period. Lp(a) levels were obtained within 24 hours of hospital admission as well as within 24 hours of hospital discharge and at 30 days from 74 participants who presented with a NSTEMI (troponin I >5 ng/ml) or with a STEMI and were enrolled in 2 randomized, double-blind trials of evolocumab and placebo (Evolocumab in Acute Coronary Syndrome [EVACS I]; ClinicalTrials.gov, NCT03515304 and Evolocumab in Patients With STEMI [EVACS II]; ClinicalTrials.gov Identifier: NCT04082442). There was a significant increase from the pretreatment level in the placebo-treated patients, from 64 (41,187) nmol/L to 80 (47, 172) nmol/L at hospital discharge and to 82 (37, 265) at 30 days. This was primarily driven by the results from participants with high Lp(a) at hospital admission (>75 nmol/L) in whom the median increase was 28% as compared with a 10% increase in those with pretreatment Lp(a) of <75 nmol/L. In contrast, there was no significant change from the pretreatment level in the evolocumab-treated patients regardless of pretreatment Lp(a) levels. In conclusion, Lp(a) rises during the peri-infarction and early postinfarction period in patients with acute myocardial infarction. The increase was prevented by a single dose of subcutaneous evolocumab given within 24 hours of hospital admission.

Abnormalities in arterial-ventricular coupling in older healthy persons are attenuated by sodium nitroprusside.

The coupling between arterial elastance (E(A); net afterload) and left ventricular elastance (E(LV); pump performance), known as E(A)/E(LV), is a key determinant of cardiovascular performance and shifts during exercise due to a greater increase in E(LV) versus E(A). This normal exercise-induced reduction in E(A)/E(LV) decreases with advancing age. We hypothesized that sodium nitroprusside (SNP) can acutely ameliorate the age-associated deficits in E(A)/E(LV). At rest and during graded exercise to exhaustion, E(A) was characterized as end-systolic pressure/stroke volume and E(LV) as end-systolic pressure/end-systolic volume. Resting E(A)/E(LV) did not differ between old (70 ± 8 yr, n = 15) and young (30 ± 5 yr, n = 17) subjects because of a tandem increase in E(A) and E(LV) in older subjects. During peak exercise, a blunted increase in E(LV) in old (7.8 ± 3.1 mmHg/ml) versus young (11.4 ± 6.5 mmHg/ml) subjects blunted the normal exercise-induced decline in E(A)/E(LV) in old (0.25 ± 0.11) versus young (0.16 ± 0.05) subjects. SNP administration to older subjects lowered resting E(A)/E(LV) by 31% via a reduction in E(A) (10%) and an increase in E(LV) (47%) and lowered peak exercise E(A)/E(LV) (36%) via an increase in E(LV) (68%) without a change in E(A). Importantly, SNP attenuated the age-associated deficits in E(A)/E(LV) and E(LV) during exercise, and at peak exercise E(A)/E(LV) in older subjects on drug administration did not differ from young subjects without drug administration. In conclusion, some age-associated deficiencies in E(A)/E(LV), E(A), and E(LV), in older subjects can be acutely abolished by SNP infusion. This is relevant to common conditions in older subjects associated with a significant impairment of exercise performance such as frailty or heart failure with preserved ejection fraction.

Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction.

PURPOSE: Prior studies demonstrate an association between specific beta-adrenergic receptor (ß-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to differences in left ventricular remodeling. This study was undertaken to explore the relationship between LV remodeling after myocardial infarction and polymorphisms in the cardiac ß1-AR and ß2-AR genes. METHODS: After first ST-segment elevation myocardial infarction (STEMI), 122 patients on chronic ß1 receptor antagonist therapy underwent baseline and 6-month LV volume evaluation. We assessed the relationships between changes in LV volumes and the polymorphisms in ß1-AR, ß1-Arg389Gly and ß1-Ser49Gly, and in ß2-AR, ß2-Gly16Arg and ß2-Gln27Glu. RESULTS: We found that patients homozygous for the ß2-Glu27 variant were 5.2 times more likely to be in the group with the highest end systolic volume (ESV) progression (OR 5.2, 95%CI 1.4-19.0). They were also more likely to have the largest progression of end diastolic volume (EDV) and decrease in LV ejection fraction (LVEF). For those with baseline LV dysfunction, being homozygous for Arg at amino acid position 389 in ß1-AR was associated with decreases in ESV (-46 mL, CI -3.1, -88) and EDV (-40 mL, CI -1.1, -79) and an increase in LVEF (11%, CI 0.3, 22). CONCLUSION: We found that polymorphisms of the ß1-AR and ß2-AR genes are associated with differential LV remodeling in patients treated with a ß1 receptor antagonist following STEMI.

Reduced myocardial creatine kinase flux in human myocardial infarction: an in vivo phosphorus magnetic resonance spectroscopy study.

BACKGROUND: Energy metabolism is essential for myocellular viability. The high-energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) are reduced in human myocardial infarction (MI), reflecting myocyte loss and/or decreased intracellular ATP generation by creatine kinase (CK), the prime energy reserve of the heart. The pseudo-first-order CK rate constant, k, measures intracellular CK reaction kinetics and is independent of myocyte number within sampled tissue. CK flux is defined as the product of [PCr] and k. CK flux and k have never been measured in human MI. METHODS AND RESULTS: Myocardial CK metabolite concentrations, k, and CK flux were measured noninvasively in 15 patients 7 weeks to 16 years after anterior MI using phosphorus magnetic resonance spectroscopy. In patients, mean myocardial [ATP] and [PCr] were 39% to 44% lower than in 15 control subjects (PCr=5.4+/-1.2 versus 9.6+/-1.1 micromol/g wet weight in MI versus control subjects, respectively, P<0.001; ATP=3.4+/-1.1 versus 5.5+/-1.3 micromol/g wet weight, P<0.001). The myocardial CK rate constant, k, was normal in MI subjects (0.31+/-0.08 s(-1)) compared with control subjects (0.33+/-0.07 s(-1)), as was PCr/ATP (1.74+/-0.27 in MI versus 1.87+/-0.45). However, CK flux was halved in MI [to 1.7+/-0.5 versus 3.3+/-0.8 micromol(g . s)(-1); P<0.001]. CONCLUSIONS: These first observations of CK kinetics in prior human MI demonstrate that CK ATP supply is significantly reduced as a result of substrate depletion, likely attributable to myocyte loss. That k and PCr/ATP are unchanged in MI is consistent with the preservation of intracellular CK metabolism in surviving myocytes. Importantly, the results support therapies that primarily ameliorate the effects of tissue and substrate loss after MI and those that reduce energy demand rather than those that increase energy transfer or workload in surviving tissue.

Incidence, Predictors, and Outcomes of Failure of Noninvasive Ventilation in Acute Heart Failure Hospitalization.

BACKGROUND: Some patients with acute heart failure (AHF) who are treated initially with noninvasive ventilation (NIV) will require endotracheal intubation, which indicates NIV failure. The incidence and prognosis of NIV failure in patients with AHF are not well characterized. METHODS: Using the National In-Patient Sample (NIS), we conducted a retrospective cohort study of subjects hospitalized with AHF between 2008 and 2014 who were treated with NIV within 24 h of hospital admission. We determined predictors of NIV failure and determined the association between NIV failure and in-hospital mortality using Cox proportional hazard models. RESULTS: Of 279,534 subjects hospitalized with AHF and treated with NIV, 4,257 (1.52%) failed NIV and required intubation. Cardiogenic shock (odds ratio 8.79, 95% CI 6.89-11.2) and in-hospital arrest (odds ratio 24.9, 95% CI 18.71-33.14) were associated with NIV failure. In-hospital mortality was 26.5% for NIV failure compared to 5.6% for those without NIV (P < .001). After adjustment for demographics, comorbidities, cardiogenic shock, and in-hospital arrest, NIV failure was associated with nearly a 2-fold risk of in-hospital mortality (odds ratio 1.95, 95% CI 1.59-2.40). CONCLUSIONS: Intubation after initial NIV treatment was required in 1.5% of subjects hospitalized with AHF and treated with NIV, and was associated with high in-hospital mortality. These findings can guide future prospective interventional trials and quality improvement ventures.

In-Hospital Management and Outcomes of Patients With Acute Myocardial Infarction and Influenza.

Patients with influenza infection are at increased risk of acute myocardial infarction (AMI). There are limited data on the short-term prognosis and management of patients with AMI and concomitant influenza. We examined the National Inpatient Sample from 2010 to 2014 for adult patients with a diagnosis of AMI. Patients were stratified into those with or without concomitant influenza. In-hospital therapies and outcomes were compared between groups in unadjusted and adjusted analyses. Standardized differences of >10% and p values <0.05 were considered significant. Propensity matching was performed using a caliper radius of 0.01*sigma. Of 4,285,641 patients with a discharge diagnosis of AMI, 12,830 had concomitant influenza. Patients with influenza were older, had a higher burden of co-morbidities, and more often presented with non-ST elevation AMI (90% vs 74%) as compared with those without influenza. Coronary angiography (23% vs 54%) and revascularization (11% vs 41%) were less often pursued in AMI patients with influenza. Patients with AMI and influenza had elevated in-hospital mortality (14%) and multiorgan failure (33%). In a propensity-matched analysis of 23,415 patients, in-hospital mortality (odds ratio [OR] 1.26; p = 0.01), acute kidney injury (OR 1.36; p <0.01), multiorgan failure (OR 1.81; p <0.01), length-of-stay, and hospital costs were significantly higher in those with influenza. In conclusion, patients with AMI and concomitant influenza have an adverse in-hospital prognosis as compared with those without influenza.

Highest Obesity Category Associated With Largest Decrease in N-Terminal Pro-B-Type Natriuretic Peptide in Patients Hospitalized With Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) constitutes half of hospitalized heart failure cases and is commonly associated with obesity. The role of natriuretic peptide levels in hospitalized obese patients with HFpEF, however, is not well defined. We sought to evaluate change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels by obesity category and related clinical outcomes in patients with HFpEF hospitalized for acute heart failure. Methods and Results A total of 89 patients with HFpEF hospitalized with acute decompensated heart failure were stratified into 3 obesity categories: nonobese (body mass index [BMI] <30.0 kg/m2, 19%), obese (BMI 30.0-39.9 kg/m2, 29%), and severely obese (BMI ≥40.0 kg/m2, 52%), and compared for percent change in NT-proBNP during hospitalization and clinical outcomes. Clinical characteristics were compared between patients with normal NT-proBNP (≤125 pg/mL) and elevated NT-proBNP. Admission NT-proBNP was inversely related to BMI category (nonobese, 2607 pg/mL [interquartile range, IQR: 2112-5703]; obese, 1725 pg/mL [IQR: 889-3900]; and severely obese, 770.5 pg/mL [IQR: 128-1268]; P<0.01). Severely obese patients had the largest percent change in NT-proBNP with diuresis (-64.8% [95% CI, -85.4 to -38.9] versus obese -40.4% [95% CI, -74.3 to -12.0] versus nonobese -46.9% [95% CI, -57.8 to -37.4]; P=0.03). Nonobese and obese patients had significantly worse 1-year survival compared with severely obese patients (63% versus 76% versus 95%, respectively; P<0.01). Patients with normal NT-proBNP (13%) were younger, with higher BMI, less atrial fibrillation, and less structural heart disease than those with elevated NT-proBNP. Conclusions In hospitalized patients with HFpEF, NT-proBNP was inversely related to BMI with the largest decrease in NT-proBNP seen in the highest obesity category. These findings have implications for the role of NT-proBNP in the diagnosis and assessment of treatment response in obese patients with HFpEF.

Crossing the Bridge to Heart Transplantation: Biventricular Impella to Support an Unstable LVAD Patient.

We report the first case of a patient with a durable left ventricular assist device admitted with cardiogenic shock and managed with biventricular Impella support as a successful bridge to heart transplantation. (Level of Difficulty: Advanced.).