Pulmonary Artery Catheter Usage and Impact on Mortality in Patients With Cardiogenic Shock: Results From a Canadian Single-Centre Registry.

BACKGROUND: Hemodynamic assessment for cardiogenic shock (CS) phenotyping in patients has led to renewed interest in the use of pulmonary artery catheters (PACs). METHODS: We included patients admitted with CS from January 2014 to December 2020 and compared clinical outcomes among patients who received PACs and those who did not. The primary outcome was the rate of in-hospital mortality. Secondary outcomes included use of advanced heart failure therapies and coronary intensive care unit (CICU) and hospital lengths of stay. RESULTS: A total of 1043 patients were analysed and 47% received PACs. Patients selected for PAC-guided management were younger and had lower left ventricular function. They also had higher use of vasopressor and inotropes, and 15.2% of them were already supported with temporary mechanical circulatory support (MCS). In-hospital mortality was lower in patients who received PACs (29.3% vs 36.2%; P = 0.02), mainly driven by a reduction in mortality among those in Society for Cardiovascular Angiography and Interventions (SCAI) stages D and E CS. Patients who received PACs were more likely to receive temporary MCS with Impella, durable ventricular assist devices (VADs), or orthotopic heart transplantation (OHT) (P < 0.001 for all analyses). CICU and hospital lengths of stay were longer in patients who used PACs. CONCLUSIONS: Among patients with CS, the use of PACs was associated with lower in-hospital mortality, especially among those in SCAI stages D and E. Patients who received PACs were also more frequently rescued with temporary MCS or received advanced heart failure therapies, such as durable VADs or OHT.

Improved mortality and haemodynamics with milrinone in cardiogenic shock due to acute decompensated heart failure.

AIMS: Studies in cardiogenic shock (CS) often have a heterogeneous population of patients, including those with acute myocardial infarction and acute decompensated heart failure (ADHF-CS). The therapeutic profile of milrinone may benefit patients with ADHF-CS. We compared the outcomes and haemodynamic trends in ADHF-CS receiving either milrinone or dobutamine. METHODS AND RESULTS: Patients presenting with ADHF-CS (from 2014 to 2020) treated with a single inodilator (milrinone or dobutamine) were included in this study. Clinical characteristics, outcomes, and haemodynamic parameters were collected. The primary endpoint was 30 day mortality, with censoring at the time of transplant or left ventricular assist device implantation. A total of 573 patients were included, of which 366 (63.9%) received milrinone and 207 (36.1%) received dobutamine. Patients receiving milrinone were younger, had better kidney function, and lower lactate at admission. In addition, patients receiving milrinone received mechanical ventilation or vasopressors less frequently, whereas a pulmonary artery catheter was more frequently used. Milrinone use was associated with a lower adjusted risk of 30 day mortality (hazard ratio = 0.52, 95% confidence interval 0.35-0.77). After propensity-matching, the use of milrinone remained associated with a lower mortality (hazard ratio = 0.51, 95% confidence interval 0.27-0.96). These findings were associated with improved pulmonary artery compliance, stroke volume, and right ventricular stroke work index. CONCLUSIONS: The use of milrinone compared with dobutamine in patients with ADHF-CS is associated with lower 30 day mortality and improved haemodynamics. These findings warrant further study in future randomized controlled trials.

Clonal haematopoiesis is associated with higher mortality in patients with cardiogenic shock.

AIMS: Cardiogenic shock (CS) with variable systemic inflammation may be responsible for patient heterogeneity and the exceedingly high mortality rate. Cardiovascular events have been associated with clonal haematopoiesis (CH) where specific gene mutations in haematopoietic stem cells lead to clonal expansion and the development of inflammation. This study aims to assess the prevalence of CH and its association with survival in a population of CS patients in a quaternary centre. METHODS AND RESULTS: We compared the frequency of CH mutations among 341 CS patients and 345 ambulatory heart failure (HF) patients matched for age, sex, ejection fraction, and HF aetiology. The association of CH with survival and levels of circulating inflammatory cytokines was analysed. We detected 266 CH mutations in 149 of 686 (22%) patients. CS patients had a higher prevalence of CH-related mutations than HF patients (odds ratio 1.5; 95% confidence interval [CI] 1.0-2.1, p = 0.02) and was associated with decreased survival (30 days: hazard ratio [HR] 2.7; 95% CI 1.3-5.7, p = 0.006; 90 days: HR 2.2; 95% CI 1.3-3.9, p = 0.003; and 3 years: HR 1.7; 95% CI 1.1-2.8, p = 0.01). TET2 or ASXL1 mutations were associated with lower survival in CS patients at all time-points (p ≤ 0.03). CS patients with TET2 mutations had higher circulating levels of SCD40L, interferon-γ, interleukin-4, and tumour necrosis factor-α (p ≤ 0.04), while those with ASXL1 mutations had decreased levels of CCL7 (p = 0.03). CONCLUSIONS: Cardiogenic shock patients have high frequency of CH, notably mutations in TET2 and ASXL1. This was associated with reduced survival and dysregulation of circulating inflammatory cytokines in those CS patients with CH.

CALL-K score: predicting the need for renal replacement therapy in cardiogenic shock.

AIMS: The clinical predictors and outcomes of patients with cardiogenic shock (CS) requiring renal replacement therapy (RRT) have not been studied previously. This study assesses the impact of RRT on mortality in patients with CS and aims to identify clinical factors that contribute to the need of RRT. METHODS AND RESULTS: Consecutive patients presenting with CS were included from a prospective registry of cardiac intensive care unit admissions at a single institution between 2014 and 2020. Of the 1030 patients admitted with CS, 123 (11.9%) received RRT. RRT was associated with higher 1-year mortality [adjusted hazard ratio = 1.62, 95% confidence interval (CI) 1.02-2.14], and a higher in-hospital incidence of sepsis [risk ratio = 2.76, P < 0.001], and pneumonia (risk ratio = 2.9, P = 0.001). Those who received RRT were less likely to receive guideline-directed medical treatment at time of discharge, undergo heart transplantation (2.4% vs. 11.5%, P = 0.002) or receive a durable left ventricular assist device (0.0% vs. 11.6%, P < 0.001). Five variables at admission best predicted the need for RRT (age, lactate, haemoglobin, use of pre-admission loop diuretics, and admission estimated glomerular filtration rate) and were used to generate the CALL-K 9-point risk score, with better discrimination than creatinine alone (P = 0.008). The score was internally validated (area under the curve = 0.815, 95% CI 0.739-0.835) with good calibration (Hosmer-Lemeshow P = 0.827). CONCLUSIONS: RRT is associated with worse outcomes, including a lower likelihood to receive advanced heart failure therapies in patients with CS. A risk score comprising five variables routinely collected at admission can accurately estimate the risk of needing RRT.

Crossing the chasm: caution for use of angiotensin receptor-neprilysin inhibition in patients with cardiogenic shock- a case report.

BACKGROUND: Vasoplegia has been reported in patients receiving angiotensin receptor-neprilysin inhibitors (ARNI) with heart failure with reduced ejection fraction (HFrEF). We present a case of vasoplegic shock after initiation of ARNI in a hospitalized 65-year-old man recovering from cardiogenic shock (CS) and acute kidney injury (AKI). CASE SUMMARY: A 65-year-old man with HFrEF presented to a community hospital with CS with evidence of poor perfusion with a lactate of 5.6 mmol/L and creatinine (Cr) 125 µmol/L. He was treated with intravenous furosemide infusion. Subsequently, his lactate normalized but he developed an AKI with a Cr of 176 µmol/L. He was then started on ARNI and beta blockers. Over the next 24 h, he developed a vasoplegic shock necessitating multiple vasopressors and a transfer to a tertiary academic centre. With supportive therapy, his vasoplegic shock improved and he was discharged home. DISCUSSION: PARADIGM-HF found that the introduction of an ARNI in patients with ambulatory symptomatic HFrEF reduces the risk of death and heart failure hospitalization. Most recently, PIONEER-HF showed that ARNI reduced N-terminal pro-B-type natriuretic peptide levels at 4 and 8 weeks, without significantly different rates of medication-related adverse effects. However, thus far, no clinical trials have examined the role of ARNI in CS. Our case report highlights the risk of vasoplegic shock caused by initiation of ARNI in patients hospitalized with CS especially in whom renal and hepatic impairment is present.

Editor's Choice-Effects of targeted temperature management on mortality and neurological outcome: A systematic review and meta-analysis.

AIMS: The purpose of this study was to conduct a systematic review, and where applicable meta-analyses, examining the evidence underpinning the use of targeted temperature management following resuscitation from cardiac arrest. METHODS AND RESULTS: Multiple databases were searched for publications between January 2000-February 2016. Nine Population, Intervention, Comparison, Outcome questions were developed and meta-analyses were performed when appropriate. Reviewers extracted study data and performed quality assessments using Grading of Recommendations, Assessment, Development and Evaluation methodology, the Cochrane Risk Bias Tool, and the National Institute of Health Study Quality Assessment Tool. The primary outcomes for each Population, Intervention, Comparison, Outcome question were mortality and poor neurological outcome. Overall, low quality evidence demonstrated that targeted temperature management at 32-36°C, compared to no targeted temperature management, decreased mortality (risk ratio 0.76, 95% confidence interval 0.61-0.92) and poor neurological outcome (risk ratio 0.73, 95% confidence interval 0.60-0.88) amongst adult survivors of out-of-hospital cardiac arrest with an initial shockable rhythm. Targeted temperature management use did not benefit survivors of in-hospital cardiac arrest nor out-of-hospital cardiac arrest survivors with a non-shockable rhythm. Moderate quality evidence demonstrated no benefit of pre-hospital targeted temperature management initiation. Low quality evidence showed no difference between endovascular versus surface cooling targeted temperature management systems, nor any benefit of adding feedback control to targeted temperature management systems. Low quality evidence suggested that targeted temperature management be maintained for 18-24 h. CONCLUSIONS: Low quality evidence supports the in-hospital initiation and maintenance of targeted temperature management at 32-36°C amongst adult survivors of out-of-hospital cardiac arrest with an initial shockable rhythm for 18-24 h. The effects of targeted temperature management on other populations, the optimal rate and method of cooling and rewarming, and effects of fever require further study.

HCV Specific IL-21 Producing T Cells but Not IL-17A Producing T Cells Are Associated with HCV Viral Control in HIV/HCV Coinfection.

BACKGROUND: Decreased hepatitis C virus (HCV) clearance, faster cirrhosis progression and higher HCV RNA levels are associated with Human Immunodeficiency virus (HIV) coinfection. The CD4+ T helper cytokines interleukin (IL)-21 and IL-17A are associated with virus control and inflammation, respectively, both important in HCV and HIV disease progression. Here, we examined how antigen-specific production of these cytokines during HCV mono and HIV/HCV coinfection was associated with HCV virus control. METHODS: We measured HCV-specific IL-21 and IL-17A production by transwell cytokine secretion assay in PBMCs from monoinfected and coinfected individuals. Viral control was determined by plasma HCV RNA levels. RESULTS: In acutely infected individuals, those able to establish transient/complete HCV viral control tended to have stronger HCV-specific IL-21-production than non-controllers. HCV-specific IL-21 production also correlated with HCV viral decline in acute infection. Significantly stronger HCV-specific IL-21 production was detected in HAART-treated coinfected individuals. HCV-specific IL-17A production was not associated with lower plasma HCV RNA levels in acute or chronic HCV infection and responses were stronger in HIV coinfection. HCV-specific IL-21/ IL-17A responses did not correlate with microbial translocation or fibrosis. Exogenous IL-21 treatment of HCV-specific CD8+ T cells from monoinfected individuals enhanced their function although CD8+ T cells from coinfected individuals were somewhat refractory to the effects of IL-21. CONCLUSIONS: These data show that HCV-specific IL-21 and IL-17A-producing T cells are induced in HIV/HCV coinfection. In early HIV/HCV coinfection, IL-21 may contribute to viral control, and may represent a novel tool to enhance acute HCV clearance in HIV/HCV coinfected individuals.

LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells.

Type 1 long-interspersed nuclear elements (L1s) are autonomous retrotransposable elements that retain the potential for activity in the human genome but are suppressed by host factors. Retrotransposition of L1s into chromosomal DNA can lead to genomic instability, whereas reverse transcription of L1 in the cytosol has the potential to activate innate immune sensors. We hypothesized that HIV-1 infection would compromise cellular control of L1 elements, resulting in the induction of retrotransposition events. Here, we show that HIV-1 infection enhances L1 retrotransposition in Jurkat cells in a Vif- and Vpr-dependent manner. In primary CD4(+) cells, HIV-1 infection results in the accumulation of L1 DNA, at least the majority of which is extrachromosomal. These data expose an unrecognized interaction between HIV-1 and endogenous retrotransposable elements, which may have implications for the innate immune response to HIV-1 infection, as well as for HIV-1-induced genomic instability and cytopathicity.

HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates.

The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics.

Human endogenous retrovirus K(HML-2) Gag- and Env-specific T-cell responses are infrequently detected in HIV-1-infected subjects using standard peptide matrix-based screening.

T-cell responses to human endogenous retrovirus (HERV) K(HML-2) Gag and Env were mapped in HIV-1-infected subjects using 15 mer peptides. Small peptide pools and high concentrations were used to maximize sensitivity. In the 23 subjects studied, only three bona fide HERV-K(HML-2)-specific responses were detected. At these high peptide concentrations, we detected false-positive responses, three of which were mapped to an HIV-1 Gag peptide contaminant. Thus, HERV-K(HML-2) Gag- and Env-specific T-cell responses are infrequently detected by 15 mer peptide mapping.