Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights.

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome.

Trends in cardiovascular complications of pregnancy: A nationwide inpatient sample analysis.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of pregnancy-related mortality in the United States. Physiologic stress of pregnancy can induce several hemodynamic changes that contribute to an increased risk of cardiac complications in the peripartum period. There are ongoing efforts to improve cardiovascular mortality in pregnant patients. Understanding trends in cardiovascular complications during pregnancy may provide insight into improving care for high-risk pregnancies. METHODS: We retrospectively analyzed data from the National Inpatient Sample (NIS) Database and identified all inpatient hospitalizations for pregnancy and delivery. We then analyzed trends in the rates of cardiac complications in the pregnant patient. RESULTS: There are concerning increases in trends of cardiac complications and comorbidities in pregnant people including: acute coronary syndrome, spontaneous coronary artery dissection, cardiogenic shock, pulmonary hypertension, chronic congestive heart failure, heart transplant, aortic syndromes, stroke, and pulmonary embolism. While the rates of STEMI have decreased, the incidence of peripartum cardiomyopathy has remained stable. CONCLUSION: There are concerning increases in certain cardiac complications during pregnancy. This is likely due to increasing age at the time of pregnancy and associated comorbidities.

Natriuretic peptide biomarkers in the imminent development of preeclampsia.

Preeclampsia is the most common cause of morbidity and mortality in pregnancy, the incidence being significantly higher in low-income countries with reduced access to health care. Women with preeclampsia are at a higher risk of developing cardiovascular disease with a poorer long-term outcome. Early recognition and treatment are key to improving short- and long-term outcomes. Approximately 3%-5% of pregnant women will develop preeclampsia, with potentially fatal outcomes. Despite ongoing research, the exact pathophysiologic mechanism behind its development remains unclear. In this brief report, we describe the potential role of natriuretic peptides as biomarkers in the imminent development of preeclampsia. In a retrospective manner, we analyzed changes in the left ventricular ejection fraction and left atrial volume and increases in natriuretic peptide in correlation with the development of preeclampsia. We found that three out of four patients developed a significant increase in natriuretic peptide, which correlated with the development of preeclampsia and/or peripartum cardiomyopathy. Significant increases in natriuretic peptides around the time of delivery might be a marker for the imminent development of preeclampsia. Close monitoring of natriuretic peptide levels in the peripartum period could give important insight into the imminent development of preeclampsia in high-risk patients. Close follow-up in specialized cardio-obstetric clinics is highly recommended.

Association of chronic kidney dysfunction and preeclampsia: insights of the Nationwide Inpatient Sample.

BACKGROUND: Preeclampsia occurs in 3% to 5% of pregnancies and can lead to potentially fatal outcomes for parent and child. Disparities in socioeconomic status, medical access, racial or ethnic, and regional background within the United States result in a very heterogenic population. OBJECTIVE: We aimed to assess the regional differences in the severity of chronic kidney disease in pregnant patients as well as the risk of preeclampsia in a contemporary cohort within the United States. STUDY DESIGN: Pregnant patients were identified within the National Inpatient Sample database between 2015 and 2019. Patients were stratified by diagnosis of end-stage kidney disease or chronic kidney disease. The primary endpoint of this study was to determine the incidence of mild preeclampsia, severe preeclampsia, and eclampsia in hospitalized pregnant patients with kidney dysfunction compared with controls. Secondary endpoints were to determine regional, racial or ethnic, and socioeconomic differences within the United States. RESULTS: A total of 16,343,563 pregnant patients were identified from 2015 to 2019. Presence of chronic kidney disease increased risk of mild and severe preeclampsia independent of the stage of chronic kidney disease (odds ratio >2 each). There was a markedly difference in prevalence of chronic kidney disease in regard to geographic location within the United States, with patients in the Northeast having predominantly milder stages of chronic kidney disease and patients in the South and West having more progressive kidney disease. There was a significant difference in chronic kidney disease distribution in relation to racial/ethnic background within the United States. Black and Latinx patients were at increased risk of eclampsia and death. There was no significant difference regarding chronic kidney disease and socioeconomic background. However, a larger proportion of patients with very low income had advanced stages of chronic kidney disease. CONCLUSION: Our data add to the previous findings that patients with chronic kidney disease are at increased risk of developing preeclampsia even in the modern era of medical management, independent of the cause of chronic kidney disease. Racial or ethnic and geographic differences in chronic kidney disease prevalence exist. A multidisciplinary team approach to follow-up with pregnant patients with chronic kidney disease could decrease maternal and neonatal mortality.

Management of pregnancy in left ventricular assist device and heart transplant recipients: a concise review.

PURPOSE OF REVIEW: Women of reproductive age are increasingly undergoing heart transplantation (HT) or left ventricular assist device (LVAD) implantation for advanced heart failure. This review is intended to give an overview of the current state of the art management of pregnancy in patients with LVAD or HT recipients. RECENT FINDINGS: Heart transplant recipients are at increased risk for graft rejection, renal dysfunction, preeclampsia and worsening of comorbidities (hypertension and diabetes). Patients with LVAD are at higher risk of thromboembolic events, infections, right ventricular failure and require close surveillance during pregnancy. Preconception counseling must be offered to all women of reproductive age group with HT or LVAD to avoid unplanned pregnancies. SUMMARY: A multidisciplinary approach with close antepartum and postpartum surveillance is recommended.

COVID-19 associated development of antibody mediated rejection in orthotopic heart transplantation patients.

Solid organ transplant candidates encountered increased wait times and mortality rates during the coronavirus 2019 (COVID-19) pandemic. Despite improvement in medical management and vaccination efficacy, this patient population remains at increased risk for complications post COVID-19 including organ rejection. We describe the development of antibody mediated rejection with or without cellular rejection in heart transplant (HT) recipients and previous COVID-19 infection or vaccination. Although centers have changed their management of outpatient follow-up for orthotopic heart transplant patients, little is known on surveillance of rejection and management of HT recipients after COVID-19 infection. We recommend frequent surveillance for rejection or allograft dysfunction after COVID-19 infection. We have adopted a transplant surveillance protocol for HT recipients with COVID-19 infection, given our recent experience with transplanted patients affected of COVID-19.

Cardiogenic Shock Due to Atrial Arrhythmia as the Initial Presentation of Transthyretin Cardiac Amyloidosis.

Atrial arrhythmias are common in transthyretin cardiac amyloidosis (ATTR-CA), with a prevalence of ≤80%. They are often not well tolerated. We describe 3 patients with decompensated heart failure and cardiogenic shock precipitated by atrial arrhythmias who ultimately received diagnoses of ATTR-CA. (Level of Difficulty: Intermediate.).

Percutaneous Decommissioning 11 Years After Initial CF-LVAD Placement.

An 80-year-old man with severe nonischemic cardiomyopathy status post left ventricular assist device (LVAD) placement 11 years prior presented for recurrent LVAD alarms from internal driveline fracture. Given his partial myocardial recovery and his preference to avoid surgical procedures, percutaneous LVAD decommissioning was performed by occlusion of the outflow graft and subsequently driveline removal. (Level of Difficulty: Advanced.).

Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of noncongenital heart disease in children. Studies in mice and humans propound the NLRP3/IL-1ß pathway as the principal driver of KD pathophysiology. Endoplasmic reticulum (ER) stress can activate the NLRP3 inflammasome, but the potential implication of ER stress in KD pathophysiology has not been investigated to our knowledge. We used human patient data and the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to characterize the impact of ER stress on the development of cardiovascular lesions. KD patient transcriptomics and single-cell RNA sequencing of the abdominal aorta from LCWE-injected mice revealed changes in the expression of ER stress genes. Alleviating ER stress genetically, by conditional deletion of inositol-requiring enzyme 1 (IRE1) in myeloid cells, or pharmacologically, by inhibition of IRE1 endoribonuclease (RNase) activity, led to significant reduction of LCWE-induced cardiovascular lesion formation as well as reduced caspase-1 activity and IL-1ß secretion. These results demonstrate the causal relationship of ER stress to KD pathogenesis and highlight IRE1 RNase activity as a potential new therapeutic target.

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1ß pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

Hypothermia promotes mitochondrial elongation In cardiac cells via inhibition of Drp1.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.

Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation.

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1ß release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1ß production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

Minimal Invasive Pericardial Perfusion Model in Swine: A Translational Model for Cardiac Remodeling After Ischemia/Reperfusion Injury.

RATIONALE: Adverse remodeling leads to heart failure after myocardial infarction (MI), with important impact on morbidity and mortality. New therapeutic approaches are needed to further improve and broaden heart failure therapy. We established a minimally invasive, reproducible pericardial irrigation model in swine, as a translational model to study the impact of temperature on adverse cardiac remodeling and its molecular mechanisms after MI. OBJECTIVE: Chronic heart failure remains a leading cause of death in western industrialized countries, with a tremendous economic impact on the health care system. Previously, many studies have investigated mechanisms to reduce infarct size after ischemia/reperfusion injury, including therapeutic hypothermia. Nonetheless, the molecular mechanisms of adverse remodeling after MI remain poorly understood. By deciphering the latter, new therapeutic strategies can be developed to not only reduce rehospitalization of heart failure patients but also reduce or prevent adverse remodeling in the first place. METHODS AND RESULTS: After 90 min of MI, a 12Fr dual lumen dialysis catheter was place into the pericardium via minimal invasive, sub-xiphoidal percutaneous puncture. We performed pericardial irrigation with cold or warm saline for 60 min in 25 female farm pigs after ischemia and reperfusion. After one week of survival the heart was harvested for further studies. After cold pericardial irrigation we observed a significant decrease of systemic body temperature measured with a rectal probe in the cold group, reflecting that the heart was chilled throughout its entire thickness. The temperature remained stable in the control group during the procedure. We did not see any difference in arrhythmia or hemodynamic stability between both groups. CONCLUSION: We established a minimally invasive, reproducible and translational model of pericardial irrigation in swine. This method enables the investigation of mechanisms involved in myocardial adverse remodeling after ischemia/reperfusion injury in the future.

Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.

BACKGROUND: During pancreatitis, autophagy is activated, but lysosomal degradation of dysfunctional organelles including mitochondria is impaired, resulting in acinar cell death. Retrospective cohort analyses demonstrated an association between simvastatin use and decreased acute pancreatitis incidence. METHODS: We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20 mg/kg) for 24 h followed by 7 hourly cerulein injections and sacrificed 1 h after last injection to harvest blood and tissue for analysis. RESULTS: Pancreatic histopathology revealed that simvastatin reduced necrotic cell death, inflammatory cell infiltration and edema. We found that cerulein triggered mitophagy with autophagosome formation in acinar cells. However, autophagosome-lysosome fusion was impaired due to altered levels of LAMP-1, AMPK and ULK-1, resulting in autophagosome accumulation (incomplete autophagy). Simvastatin abrogated these effects by upregulating LAMP-1 and activating AMPK which phosphorylated ULK-1, resulting in increased formation of functional autolysosomes. In contrast, autophagosomes accumulated in control group during pancreatitis. The effects of simvastatin to promote autophagic flux were inhibited by chloroquine. Mitochondria from simvastatin-treated mice were resistant to calcium overload compared to control, suggesting that simvastatin induced mitochondrial quality control to eliminate susceptible mitochondria. Clinical specimens showed a significant increase in cell-free mtDNA in plasma during pancreatitis compared to normal controls. Furthermore, genetic deletion of parkin abrogated the benefits of simvastatin. CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.

Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury.

Animal studies have demonstrated beneficial effects of therapeutic hypothermia on myocardial function, yet exact mechanisms remain unclear. Impaired autophagy leads to heart failure and mitophagy is important for mitigating ischemia/reperfusion injury. This study aims to investigate whether the beneficial effects of therapeutic hypothermia are due to preserved autophagy and mitophagy. Under general anesthesia, the left anterior descending coronary artery of 19 female farm pigs was occluded for 90 minutes with consecutive reperfusion. 30 minutes after reperfusion, we performed pericardial irrigation with warm or cold saline for 60 minutes. Myocardial tissue analysis was performed one and four weeks after infarction. Therapeutic hypothermia induced a significant increase in autophagic flux, mitophagy, mitochondrial mass and function in the myocardium after infarction. Cell stress, apoptosis, inflammation as well as fibrosis were reduced, with significant preservation of systolic and diastolic function four weeks post infarction. We found similar biochemical changes in human samples undergoing open chest surgery under hypothermic conditions when compared to the warm. These results suggest that autophagic flux and mitophagy are important mechanisms implicated in cardiomyocyte recovery after myocardial infarction under hypothermic conditions. New therapeutic strategies targeting these pathways directly could lead to improvements in prevention of heart failure.

Decrease of Cardiac Parkin Protein in Obese Mice.

Mitophagy plays a major role in heart physiology. Impairment of Parkin-dependent mitophagy in heart is known to be deleterious. Obesity is a known cardiovascular risk factor. Impaired autophagy has been reported in models of obesity or hyperlipidemia/hypercholesterolemia; however less is known regarding obesity and mitophagy. The aim of this study was to evaluate the regulation of Parkin expression in hearts of mice fed a high fat diet. Interestingly, we found a significant decrease in Parkin protein in hearts of HFD mice compared those fed a low-fat diet. This was associated with mitochondrial dysfunction in the context of ischemia/reperfusion (I/R). This downregulation was not associated with a decrease in Parkin mRNA expression. We did not detect any change in the degradation rate of Parkin and only a slight decrease in its translation. The reduction of Parkin protein abundance in HFD hearts remains a mystery and will need further studies. However, Parkin depletion in the setting of obesity may contribute to cardiovascular risk.