Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Upper body thermal images and associated clinical data from a pilot cohort study of COVID-19.

OBJECTIVES: The data was collected for a cohort study to assess the capability of thermal videos in the detection of SARS-CoV-2. Using this data, a published study applied machine learning to analyze thermal image features for Covid-19 detection. DATA DESCRIPTION: The study recorded a set of measurements from 252 participants over 18 years of age requesting a SARS-CoV-2 PCR (polymerase chain reaction) test at the Hospital Zambrano-Hellion in Nuevo León, México. Data for PCR results, demographics, vital signs, food intake, activities and lifestyle factors, recently taken medications, respiratory and general symptoms, and a thermal video session where the volunteers performed a simple breath-hold in four different positions were collected. Vital signs recorded include axillary temperature, blood pressure, heart rate, and oxygen saturation. Each thermal video is split into 4 scenes, corresponding to front, back, left and right sides, and is available in MPEG-4 format to facilitate inclusion into pipelines for image processing. Raw JPEG images of the background between subjects are included to register variations in room temperatures.

Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.

Soluble factors in COVID-19 mRNA vaccine-induced myocarditis causes cardiomyoblast hypertrophy and cell injury: a case report.

BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

Prevalence of Depression, Anxiety, Post-Traumatic Stress, and Insomnia Symptoms Among Frontline Healthcare Workers in a COVID-19 Hospital in Northeast Mexico.

OBJECTIVE: Frontline healthcare workers (FHCWs) exposed to COVID-19 patients are at an increased risk of developing psychological burden. This study aims to determine the prevalence of mental health symptoms and associated factors among Mexican FHCWs attending COVID-19 patients. METHODS: FHCWs, including attending physicians, residents/fellows, and nurses providing care to COVID-19 patients at a private hospital in Monterrey, Mexico, were invited to answer an online survey between August 28, and November 30, 2020. Symptoms of depression, anxiety, post-traumatic stress, and insomnia were evaluated with the Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder (GAD)-7, Impact of Event Scale-Revised (IES-R), and Insomnia Severity Index (ISI). Multivariate analysis was performed to identify variables associated with each outcome. RESULTS: 131 FHCWs, 43.5% attending physicians, 19.8% residents/fellows, and 36.6% nurses were included. The overall prevalence of depression, anxiety, post-traumatic stress, and insomnia was 36%, 21%, 23%, and 24% respectively. Multivariate analysis revealed that residents/fellows and nurses reported more depression and insomnia than attending physicians. Although not significant, residents/fellows were more likely to experience all symptoms than nurses. CONCLUSIONS: Mexican FHCWs, especially nurses and residents/fellows, experienced a significant psychological burden while attending to COVID-19 patients. Tailored interventions providing support to FHCWs during future outbreaks are required.

Early increase of serum ferritin among COVID-19 patients is associated with need of invasive mechanical ventilation and with in-hospital death.

BACKGROUND: COVID-19 may trigger an acute hyperinflammatory syndrome characterised by heightened levels of acute phase reactants and is associated with adverse outcomes among hospitalised individuals. The relationship between 48-hour changes in acute phase reactants and adverse outcomes is unclear. This study evaluated the relationship between change in four acute phase reactants (interleukin-6, procalcitonin, ferritin, and C-reactive protein), and the risk for in-hospital death and invasive mechanical ventilation. METHODS: A retrospective cohort among 2,523 adult patients hospitalised with COVID-19 pneumonia was conducted. Changes in IL-6, procalcitonin, ferritin, and CRP from admission to 48 h after admission were recorded. Delta was calculated using the difference in each acute phase reactant at admission and at 48-hours. Delta in acute phase reactants and the risk for in-hospital death and invasive mechanical ventilation was assessed using logistic regression models adjusting for demographics and comorbidities. RESULTS: Patients with both admission and 48-hour measurement for interleukin-6 (IL-6) (n = 541), procalcitonin (n = 828), ferritin (n = 1022), and C-reactive protein (CRP) (n = 1919) were included. Baseline characteristics were similar across all four populations. Increases in ferritin associated with a heightened risk of in-hospital death (OR 1.00032; 95%CI 1.00007- 1.00056; p < .001) and invasive mechanical ventilation (OR 1.00035; 95%CI 1.00014- 1.00055; p = .001). Therefore, for every 100 ng/mL increase in ferritin, the odds for in-hospital death and invasive mechanical ventilation increase by 3.2% and 3.5%, respectively. CONCLUSIONS: Delta in ferritin is associated with in-hospital death and invasive mechanical ventilation. Other acute phase reactants were not associated with these outcomes among COVID-19 inpatients.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.

Long term development of diastolic dysfunction and heart failure with preserved left ventricular ejection fraction in heart transplant recipients.

Heart transplant recipients (HTX) have several risk factors for heart failure which can trigger pro-inflammatory and fibrosis factors and set into motion pathophysiologic changes leading to diastolic dysfunction and HFpEF. The objective of the study was to determine if HTX recipients with dyspnea have diastolic dysfunction and HFpEF. Twenty-five HTX were included. LV systolic and diastolic functions were evaluated using conductance catheters to obtain pressure volume loops. LV function was assessed at rest and during moderate intensity exercise of the upper extremities. A significant increase occurred in LV minimal pressure (3.7 ± 3.3 to 6.5 ± 3.5 mmHg) and end diastolic pressure or EDP (11.5 ± 4 to 18 ± 3.8 mmHg, both P < 0.01) with exercise. With exercise, the time constant of LV relaxation shortened in 2, was unchanged in 3, and increased in the remaining patients (group results: rest 40 ± 11.6 vs 46 ± 9 ms, P < 0.01). LV chamber stiffness constant was abnormally increased in all but 2 patients. Indices of LV systolic properties were normal at rest but failed to augment with exercise. In 15 who agreed to blood draw, inflammation and fibrosis markers were obtained. A significant association was observed between LV EDP and Pro-Col III N-terminal (r = 0.58, P = 0.024) and IL-1-soluble receptor (r = 0.59, P = 0.02) levels. HTX have diastolic dysfunction and can develop HFpEF several years after cardiac transplantation. The abnormally increased LV chamber stiffness and the prolongation or lack of shortening of the time constant of LV relaxation with exercise are the underlying reasons behind the observed changes in LV diastolic pressures with exercise.

Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis.

AIMS: This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: First, we performed an ICI pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than those treated with anti-CTLA-4 (69.4% vs. 20%). Then, we analysed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to 31 August 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the ClinicalTrials.gov database, finding an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were reported in 2.5% of patients treated solely with chemotherapy. CONCLUSIONS: Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rates of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

Remote versus early corticosteroid wean outcomes in heart transplant recipients in the contemporary era.

PURPOSE: The risks and benefits of remote corticosteroid weaning in heart transplant recipients more than 2 years post-transplant are unknown. We compared outcomes in patients undergoing early and remote steroid weaning after heart transplantation. METHODS: We performed a retrospective study (range 09, 1991-04, 2017). Primary outcomes included short-term and long-term mortality, allograft dysfunction, and burden of rejection. Secondary outcomes included impact on hemoglobin A1c, lipid panel, bone scan T-score, and body mass index. RESULTS: 63 patients underwent corticosteroid weaning between 2012 and 2017. Outcomes of patients weaned early (n = 34; median time from transplant = 1.1 years) were compared with those weaned late (n = 29; median time from transplant = 4.4 years). 52 (82.5%) patients were successfully weaned off corticosteroids. No statistically significant difference in outcomes was found between the early and late weaning groups (p = .20). There were no differences in allograft function (p-value = .16), incidence of rejection (p = .46), or mortality (p = .15). Improvement in metabolic profile was seen in both groups but was not statistically significant. CONCLUSIONS: In heart transplant recipients, remote vs early weaning of corticosteroids is not associated with significant differences in graft function or the incidence of rejection after 1-year follow-up. Moreover, there were no significant differences in survival up to 3 years between the two groups.

Endothelial Dysfunction-related Neurological Bleeds with Continuous Flow-Left Ventricular Assist Devices Measured by Digital Thermal Monitor.

Endothelial dysfunction has been demonstrated in patients with Continuous Flow-Left Ventricular Assist Devices (CF-LVADs) but association with adverse events has not been shown. We used a noninvasive, operator-independent device called VENDYS® to assess vasodilatory function based on digital thermal measurements postrelease of a brachial artery occlusion in ambulatory patients with CF-LVAD (n = 56). Aortic valve opening and pulse perception were also documented before the test. Median duration of CF-LVAD support was 438 days. The VENDYS® test generates a vascular reactivity index (VRI). Outcomes for the CF-LVAD patients were compared between VRI < 1 and VRI ≥ 1. The bleeding events were driven primarily by a difference in neurologic bleeds. Multivariate analysis showed that VRI < 1 correlated with future bleeding events (HR: 5.56; P = 0.01). The C-statistic with the VRI dichotomized as above was 0.82. There was a trend toward a worse survival in patients with poor endothelial function. Endothelial vasodilatory dysfunction measured by a simple test utilizing digital thermal monitoring can predict adverse bleeding events in patients with CF-LVADs.

Pulse assessment is important with blood pressure measurement in individuals with continuous flow left ventricular assist devices.

While Doppler and cuff blood pressure techniques are prevalent methods of assessing blood pressure in patients with continuous flow left ventricular assist devices, the impact of pulsatility on measurement is not well established. Retrospective chart analysis of clinical variables including pulse perception, blood pressure (Doppler and standard cuff), and aortic valve opening on echo at clinic visit were abstracted. Stable outpatients on continuous flow left ventricular assist devices support with concomitant portable echo assessment were included. Mean average difference was calculated and Pearson's correlation performed for all those patients who had both Doppler and cuff pressure obtained. In all, 74 Heartmate-II patients with a median time from implant of 380 days were analyzed. A pulse was perceived in 82% of patients with persistent aortic valve opening on portable echo and also in 30% of those who had a persistently closed aortic valve. The mean average difference between the Doppler and systolic cuff pressure was ~13 mmHg (r = 0.5, p = 0.004) when a pulse was present and ~11 mmHg when aortic valve was open (r = 0.68, p < 0.0001). Pulse presence seems to reflect aortic valve opening a majority of the time but not always. In the presence of a prominent pulse or persistent aortic valve opening, the Doppler pressure seems to be more reflective of a systolic pressure than mean perfusion pressure. Hence, assessment of pulsatility needs to be incorporated into blood pressure measurement methods for patients with continuous flow left ventricular assist devices.

Heat shock protein 60 and cardiovascular diseases: An intricate love-hate story.

Cardiovascular diseases (CVDs) are the result of complex pathophysiological processes in the tissues comprising the heart and blood vessels. Inflammation is the main culprit for the development of cardiovascular dysfunction, and it may be traced to cellular stress events including apoptosis, oxidative and shear stress, and cellular and humoral immune responses, all of which impair the system's structure and function. An intracellular chaperone, heat shock protein 60 (HSP60) is an intriguing example of a protein that may both be an ally and a foe for cardiovascular homeostasis; on one hand providing protection against cellular injury, and on the other triggering damaging responses through innate and adaptive immunity. In this review we will discuss the functions of HSP60 and its effects on cells and the immune system regulation, only to later address its implications in the development and progression of CVD. Lastly, we summarize the outcome of various studies targeting HSP60 as a potential therapeutic strategy for cardiovascular and other diseases.

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

PURPOSE OF REVIEW: In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. RECENT FINDINGS: Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.

The role of B cells in heart failure and implications for future immunomodulatory treatment strategies.

Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.

Percutaneous Left Axillary Artery Placement of Intra-Aortic Balloon Pump in Advanced Heart Failure Patients.

OBJECTIVES: This study presents the largest clinical experience of percutaneously placed axillary intra-aortic balloon pump (IABP) in patients with advanced heart failure. BACKGROUND: Transfemoral placement of IABP limits mobility and recuperation in patients who need prolonged support. We had previously reported a novel percutaneous method of IABP placement in the axillary artery and now present our expanded experience with this technique. METHODS: We performed a retrospective chart review of patients with advanced heart failure with percutaneous axillary IABP placement from November 2007 to June 2018 at Houston Methodist Hospital. We defined successful cardiac replacement therapy as heart transplant or left ventricular assist device implantation. We compared patients who had successful cardiac replacement with those who died and those who needed unplanned escalation of mechanical circulatory support. RESULTS: Of the 195 patients identified, 133 (68%) underwent successful cardiac replacement (120 transplants and 13 left ventricular assist device) as planned. End-organ function improved on IABP support in patients bridged to next therapy. There were 16 patients that died while on IABP support and 18 needed escalation of support. Higher right atrial/wedge ratio, higher right atrial pressure, smaller left ventricular end diastolic dimension, and ischemic cardiomyopathy were associated with death on the IABP in multivariate analysis. Post-transplant and post left ventricular assist device survival for those bridged successfully was 87% and 62%, respectively. Although bedside repositioning was frequent, 37% needed replacement for malfunction. Vascular complications occurred in a minority. CONCLUSIONS: Percutaneous axillary approach for IABP placement is a feasible strategy for prolonged mechanical circulatory support in patients with advanced heart failure.