Publications by authors named "Richard Karas"
Article Synopsis
- The STEMI-DTU pilot study investigated the safety and practicality of using a trans-valvular pump for left ventricular (LV) unloading before reperfusion in patients with acute STEMI.
- A total of 50 patients with anterior STEMI were enrolled, but only 32 completed the study after excluding those who didn't meet criteria; cardiac imaging was used to assess infarct size and microvascular obstruction.
- Results showed that LV unloading did significantly reduce infarct size relative to the area at risk, particularly when performed within 180 minutes of symptom onset, but did not show a significant difference in microvascular obstruction between the two patient groups.
Background: Reducing congestion remains a primary target of therapy for acutely decompensated heart failure. The VENUS-HF EFS (VENUS-Heart Failure Early Feasibility Study) is the first clinical trial testing intermittent occlusion of the superior vena cava with the preCARDIA system, a catheter mounted balloon and pump console, to improve decongestion in acutely decompensated heart failure.
Methods: In a multicenter, prospective, single-arm exploratory safety and feasibility trial, 30 patients with acutely decompensated heart failure were assigned to preCARDIA therapy for 12 or 24 hours.
Article Synopsis
- Phosphodiesterase 5 inhibitors (PDE5i), like sildenafil, can improve heart failure by activating a protein called cGMP-dependent protein kinase (PKG), but their effect on mitochondrial functions isn't fully understood.
- In experiments with mice lacking PGC1α, a key mitochondrial regulator, sildenafil treatment still improved heart function and mitochondrial performance despite PGC1α's absence.
- The study found that PKG helps induce PGC1α in heart cells, indicating that the PKG-PGC1α pathway is crucial for the benefits of PDE5i in treating heart failure.
Article Synopsis
- cGMP-dependent protein kinase 1α (PKG1α) supports heart function in response to pressure overload, but its activation often leads to hypotension, which limits its therapeutic use in heart failure.* -
- The study found that mixed lineage kinase 3 (MLK3) interacts with PKG1α and is crucial for maintaining left ventricle (LV) function without affecting blood pressure (BP), even in conditions of heart failure.* -
- Results indicate that enhancing MLK3 activity could help improve heart function in heart failure patients while preventing the drop in blood pressure typically associated with PKG1α activation.*
Article Synopsis
- - New research reveals that acute myocardial infarction (AMI) heightens inflammation and MMP-9 activity in the kidney, underscoring a need for better understanding of this response.
- - A study involving swine showed that using Impella support before heart reperfusion decreased MMP-9 levels and reduced kidney damage compared to ischemia-reperfusion or VA-ECMO methods.
- - Impella support not only lessened heart injury but also mitigated harmful kidney signaling pathways, suggesting it may offer protective benefits during cardiac events like AMI.
Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies.
View Article and Find Full Text PDFBackground: Myocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size.
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- This study used genetically engineered mice to investigate how non-nuclear signaling from estrogen receptor-α protects the heart during pressure overload by activating a specific protein kinase G pathway.
- The findings revealed that this estrogen signaling is crucial for the effectiveness of certain heart medications (like phosphodiesterase 5 inhibitors) but not others (like soluble guanylate cyclase stimulators).
- The results point to the importance of developing targeted heart failure treatments for women, especially post-menopause, given the differences in therapeutic effects observed.
Article Synopsis
- * IVC occlusion decreased left ventricular pressures, volumes, cardiac output, and mean arterial pressure, while SVC occlusion mainly reduced left ventricular diastolic pressure and volumes without impacting cardiac output.
- * The preCARDIA system, a new technology for SVC occlusion, showed promise in achieving stable cardiac function while reducing filling pressures, and will be further evaluated in the upcoming VENUS-HF trial.
Article Synopsis
- Acutely decompensated heart failure can cause serious health issues due to fluid overload affecting the heart and kidneys; the study aimed to see if temporarily blocking the superior vena cava (SVC) could help.* -
- In a trial with eight patients suffering from systolic heart failure, temporarily occluding the SVC successfully lowered heart filling pressures without negatively impacting blood pressure or cardiac output.* -
- The initial results showed that SVC occlusion was safe and well-tolerated, paving the way for further research to explore its potential as a treatment for acute heart failure.*
There is abundant evidence that low circulating testosterone levels in older men are associated with adverse cardiovascular outcomes; however, the direction of causality is unclear. Although there is burgeoning interest in the potential of androgen therapy in older men, the effect of androgens on cardiovascular regeneration in aging males remains poorly defined. We investigated the role of androgens in age-related impairment in ischemia-induced neovascularization.
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- The DTU-STEMI pilot trial explored the safety and feasibility of left ventricle (LV) unloading before reperfusion in patients with ST-segment-elevation myocardial infarction (STEMI).
- In the study, 50 patients were randomly assigned to either immediate reperfusion after LV unloading (U-IR) or delayed reperfusion after 30 minutes of unloading (U-DR).
- Results showed no significant differences in major adverse events or infarct size between the two groups, indicating that LV unloading before reperfusion is a safe approach for STEMI treatment.
Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.
Am J Physiol Heart Circ Physiol
January 2019
Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF.
View Article and Find Full Text PDFBackground: Acute heart failure refractory to medical therapy is a major cause of morbidity and mortality. The Aortix device (Procyrion Inc) is a percutaneously delivered entrainment pump positioned in the descending aorta.
Methods And Results: Using the newest generation Aortix device in 8 adult male Yorkshire swine, we tested the hypothesis that positioning in the abdominal aorta may provide superior hemodynamic effects than thoracic positioning in a swine model of postinfarct left ventricular injury.
Article Synopsis
- Heart failure following acute myocardial infarction (AMI) significantly impacts patient health, and research indicates that reducing left ventricular (LV) work before restoring blood flow (primary unloading) could minimize heart damage.
- This study in male swine showed that 30 minutes of LV unloading before reperfusion effectively reduced infarct size and improved heart function long-term, compared to immediate reperfusion.
- Mechanistic findings revealed that unloading enhances cellular respiration and protects against heart tissue damage by increasing levels of a cardioprotective protein (SDF-1α), ultimately leading to less scar tissue and better cardiac performance after 28 days.
Estrogen receptor α (ERα) is a ligand-activated transcriptional activator that is also involved vascular inflammation and atherosclerosis. Whether different ligands may affect this activity has not been explored. We screened a panel of phytoestrogens for their role in ERα binding and transcriptional transcription, and correlated the findings to anti-inflammatory activities in vascular endothelial cells stably expressing either a wild-type or mutant form of ERα deficient in its membrane association.
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- * A study using a special mouse model revealed that blocking a specific estrogen receptor pathway leads to significant weight gain and glucose intolerance.
- * The research showed that activating a protein called PP2A can improve metabolism issues linked to missing this estrogen signaling, highlighting its importance in metabolic balance during menopause.
Article Synopsis
- The study investigates how biological sex affects the relationship between aldosterone, a hormone, and blood pressure responses to salt intake and angiotensin II (AngII) in a large cohort of 1592 individuals.
- Findings reveal that women show a greater sensitivity to salt and a stronger blood pressure response to AngII, with higher aldosterone levels accompanying these responses, regardless of age or hypertension status.
- Additionally, experiments indicate that female rat cells produce more aldosterone than male cells, suggesting that increased aldosterone may play a role in cardiovascular disease, indicating women could benefit more from treatments targeting mineralocorticoid receptors.
Article Synopsis
- Heart failure is a critical health concern that involves the development of cardiac fibrosis, which can worsen heart function; TGF-β1 is a key player in promoting fibrosis but also has regulatory pathways, while BMP9, a TGF-β family member, may help mitigate this effect.
- Research indicates that BMP9 levels are elevated in heart failure patients and that it reduces collagen production in human cardiac fibroblasts, suggesting a protective role against fibrosis.
- In animal models, BMP9 treatment showed potential benefits in reducing cardiac fibrosis and improving heart function, while disruption of endoglin, which interacts with BMP9, further enhances BMP9's positive effect on the heart.
Background: The prevalence and significance of right ventricular dysfunction (RVD) in patients with cardiogenic shock due to acute myocardial infarction (AMI-CS) have not been well characterized. We hypothesized that RVD is common in AMI-CS and associated with worse clinical outcomes.
Methods And Results: We retrospectively analyzed patients with available hemodynamics enrolled in the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial (n = 139) and registry (n = 258) to identify RVD in AMI-CS.
Introduction: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure.
Hypothesis: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure.
Article Synopsis
- The study investigates the effectiveness of intra-aortic balloon counterpulsation pumps (IABPs) in improving hemodynamic status in patients with advanced heart failure (HF) before LVAD surgery.
- It compares 10 patients with advanced HF receiving IABP therapy to 5 control patients with preserved left ventricular function, examining changes in various cardiac metrics.
- Results show that IABP therapy significantly increased cardiac index and improved the myocardial oxygen supply:demand ratio while reducing left ventricular stroke work, particularly benefiting those classified as CI-responders.
Article Synopsis
- Activin like kinase-1 (AlK-1) is important for signaling in the TGFβ family and affects blood vessel growth; reduced activity is linked to abnormal blood vessel formations.
- A study using AlK-1 conditional knockout mice showed that removing AlK-1 led to worse heart health outcomes, like reduced survival rates and heart function deterioration.
- After 14 days, cKO-TAM mice (with AlK-1 deletion) had smaller body mass, increased heart and lung weight, and changes in heart pressure and contractility compared to control groups, but no signs of heart fibrosis were found.
Article Synopsis
- * Research shows that unliganded ERα inhibits endothelial cell migration and proliferation while promoting smooth muscle cell growth and inflammation in blood vessels.
- * When activated by estrogen (E2), ERα reverses these harmful effects, indicating that estrogen's cardiovascular benefits may stem from its ability to mitigate the negative impacts of unliganded ERα on vascular health.