Myocardial Contractility Research Articles

Mavacamten: A Review of a Novel Therapeutic Approach for Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is a heart disease that can cause left ventricular hypertrophy, arrhythmias, heart failure, and sudden cardiac death. Currently, pharmacological treatment is limited and ineffective. Mavacamten (CamzyosTM) is a cardiac myosin inhibitor developed as a therapeutic option to reduce myocardial contractility and restoration of myocardial function. The Food and Drug Administration (FDA) approved the use of Mavacamten in 2022 for HCM symptoms. Clinical studies have proven that Mavacamten can reduce Left Ventricular Outflow Tract (LVOT) involvement, cardiac hypercontraction, and hypertrophy. This review provides an overview of HCM, its pathophysiology, current treatments, synthesis of Mavacamten, and the clinical trials of Mavacamten.

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study

IntroductionCardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. MethodsA rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg−1.min−1, and serial doses of apelin-13 (50, 150 and 450 μg.kg−1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. ResultsCompared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). ConclusionExogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.

(708) - Preservation of Ventricular Contractility of Old Donor Hearts During Static Cold Storage by the Senomorphic Agent Ruxolitinib is More Effective in Hearts from Female Donors

(708) - Preservation of Ventricular Contractility of Old Donor Hearts During Static Cold Storage by the Senomorphic Agent Ruxolitinib is More Effective in Hearts from Female Donors

Adrenaline and Anesthesia - Clinical Review

Abstract Adrenaline or epinephrine is one of the primarily important catecholamines in the general stress response and is manufactured in the adrenal medulla. In stress, it is secreted into the blood circulation and evokes many bodily transformations which prepare the body for the fight or flight response, some of which include tachycardia and hypertension, dilation of the air passages, and mobilization of energy reserves. This catecholamine surge can, however, cause myocardial stress, as evidenced during acute ischemia, hence an implication of increased risk of myocardial injury. In terms of functioning at the molecular level, adrenaline interacts with adrenergic receptors, which trigger intracellular processes associated with the readiness of a body to act fast as well as affecting more general forms of cardiac activity. Adrenaline stimulates beta-adrenergic receptors, enhancing heart rate and contractility, vital under stress but harmful with constant exposure. It is metabolized in the liver and may also cause dysrhythmias when used together with some inhaled anesthesia such as halothane. In anesthesia, adrenaline gets used to increase the local anesthetic action of the drug by constricting blood vessels and thereby increasing the duration and extent of analgesia besides reducing the uptake of the anesthetic into the systemic circulation. The common dose schedule is 1 in 2 lakh of adrenaline which means 5 μ/mL. The usual dose should not increase to 3 μ/kg. Preferably, the dose can be supplemented after 10–15 min. The use of adrenaline also creates a plane to dissect. The duration of action of local anesthetic drug is prolonged following the addition of adrenaline. Epidural test doses detect accidental intravascular catheterization. There is evidence that adrenaline belongs to anesthetic protocols, enabling deeper anesthesia, which, in turn, contributes to more effective outcomes of the surgery and easier recovery. Adrenaline by way of its alpha 2 agonism is likely to increase the effects of local anesthetic drugs and inhalational agents. Still, practitioners must address those benefits against possible side effects since minor, albeit significant, changes in the electrocardiographic characteristics have been recorded with lignocaine–adrenaline mixtures. Adrenaline nebulization is used for acute respiratory conditions like croup postextubation. The dose is 0.5 mg/kg, max 5 mg, diluted in 2–3 mL saline, repeated every 30 min if needed, with monitoring for tachycardia and hypertension. For perioperative anaphylaxis, administer 0.5 mg intramuscular for adults, adjusted by age for children. Hence, adrenaline is extremely useful in local anesthesia because of its vasoconstrictive effects, which must, however, be monitored continuously for patient and operational safety.

Роль полиморфных вариантов генов цитохромов Р450, а также генов GSTP1 и MDR1 в развитии токсических осложнений при проведении программной противоопухолевой лекарственной терапии у пациентов с классической лимфомой Ходжкина

Background. Although considerable progress has been achieved in the treatment of classical Hodgkin lymphoma (cHL), toxic complications of program drug chemotherapy remain an issue. Standard cytostatic agents used in cHL therapy are metabolized in liver by the enzymes with Р450 cytochrome and GSTP1 gene-controlled synthesis. At the same time, the excretion of active metabolites of antitumor drugs is mediated by MDR1 coded P-glycoprotein. Polymorphisms[1] of these genes may change the processes of antitumor drug biotransformation and their metabolite excretion. Additionally, they may result in organo-toxic complications, disablement of patients, and even death.&#x0D; Aim. To assess the role of polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1 in organ toxicity dynamics during program chemotherapy (CT) in cHL patients.&#x0D; Materials &amp; Methods. The study enrolled 122 cHL patients treated with first-line regimens (ABVD, BEACOPP) of program drug chemotherapy. The patients were aged 18–78 years (median 35 years); there were 67 (54.9 %) women and 55 (45.1 %) men. In compliance with the NCCN CTC (2003) criteria of hepatotoxicity and practical recommendations for correcting cardiovascular toxicity of chemotherapy (2021), the signs of toxic liver and heart damage were assessed in all patients. PCR was used to analyze polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1, their association with toxic complications of CT was analyzed.&#x0D; Results. Drug-induced liver damage on program CT was identified in 80 % of cHL patients. The toxicity was increasing from CT cycle 1 to cycle 6 both on ABVD and BEACOPP. Complications grade 3/4 were observed only in BEACOPP recipients. Significant (p &lt; 0.05) associations were found between hepatotoxic complications with increased cytolytic (AST, ALT) and cholestatic (ALP) values and polymorphic variants of MDR1. Significant (p &lt; 0.05) reduction of left ventricle myocardium contractility in cHL patients was associated with Т-allele presence in genotypes CYP2D6*10 (rs1065852), CYP2C9*2 (rs1799853) and A-allele deletion in genotype CYP2D6_3 (rs4986774).&#x0D; Conclusion. The identification of genetic predictors for toxic effects of program CT in cHL patients at the baseline examination can minimize the risks of drug chemotherapy-related adverse events and allow these patients to maintain a satisfactory quality of life.&#x0D; &#x0D; [1] Gene polymorphism is a structural difference between alternative variants of a gene. Alternative variants of genes result from mutations.

Anesthesia in A Patient with Pulmonary Atresia with Intact Ventricular Septum (PA IVS) Underwent Bidirectional Cavo-Pulmonary Shunt (BCPS)

Background: Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare condition, encompassing approximately 1%–3% of congenital heart diseases. Patients with PA-IVS have functional single-ventricle physiology. The ultimate possible outcomes for patients with PA-IVS are biventricular circulation, 1.5-ventricle or single-ventricle palliation, or cardiac transplantation. The bidirectional cavopulmonary shunt (BCPS) procedure directs flow from the superior vena cava into both the right and left pulmonary arteries, permitting flow to both lungs. The shunt is considered to be the second stage of palliation and is generally preparative for the third-stage Fontan procedure. The BCPS improves systemic arterial oxygen saturation without increasing ventricular work or pulmonary vascular resistance.Case: A 10-month-old, 25-day-old boy, weight 9.93 kg, body length 72 cm, diagnosed with PA-IVS, restricted persistent foramen ovale (PFO), right ventricle hypoplastic, and turtuous patent ductus arteriosus (PDA), underwent BCPS, atrial septectomy, and PDA stent evacuation surgery. The patient underwent a PDA stenting and ballooning atrial septectomy (BAS) at 17 days of age at the cathlab. The patient was cyanotic with stable hemodynamics and a saturation of 72% preoperatively.Discussion: Preoperative fasting must be observed to maintain the patient's hydration state. Pulmonary blood flow and systemic blood flow must be balanced. An adequate analgetic can prevent pain stimuli that increase pulmonary vascular resistance. Drugs to reduce the afterload, such as milrinone, are needed. Mechanical ventilation was set to get PaCO2 between 40 and 45 mmHg. Maintain the normal heart beat, preload, and contractility to maintain cardiac output (CO) with saturation 80–85%. Wean from mechanical ventilation as soon as possible.Conclusion: Anesthetic management for BCPS in patients with single ventricles from the preoperative period, intraoperative period, and postoperative period. Understanding single ventricle phsiology is important in order to treat the patient.

Monitoring of infusion therapy in patients with reduced cardiac reserve during abdominal operations

Background. In the pathogenesis of many intra- and postoperative complications, the composition, volume and rate of infusion therapy (IT) play a significant role. This problem is especially relevant for patients with concomitant chronic pathology of the cardiovascular, respiratory systems and kidneys. Informative indicators for assessing the correctness of IT and early diagnosis of intraoperative complications associated with errors in its implementation are complex monitoring of functional indicators of the cardiovascular and respiratory systems. Purpose – of the study is to investigate changes in biochemical markers of heart failure and ultrasound signs of venous stasis in two modes of infusion therapy (restrictive and liberal), on the basis of a comparative study, to determine the optimal mode of perioperative IT in patients undergoing elective surgery for diseases of the abdominal cavity and have comorbid pathology in the form of coronary heart disease (CHD) and heart failure (HF). Materials and Methods. 86 patients were included in a single-center, prospective, randomized study. All patients were randomly divided into two groups depending on the mode of intraoperative IT: in the first group (n = 44) – a restrictive mode of 5–8 ml/kg/hour was applied, in the second (n = 42) – a liberal mode. Echocardiography was performed at the stages of the study. Heart contractility, central hemodynamics, and ejection fraction were evaluated. An ultrasound scan of the inferior vena cava (IVC) was performed during breathing as a non-invasive method of assessing the intravascular blood volume. The diameter of the vein during inhalation and exhalation was evaluated. Based on the respiratory change in the diameter of the IVC, the caval index is calculated, which is expressed as a percentage. An index approaching 100% indicates near-complete collapse and probable volume depletion, while an index close to 0% indicates minimal collapse and intravascular overflow. Ultrasound of the lungs was performed according to the BLUE protocol with a convex sensor in 8 zones along the front chest wall. The severity of pulmonary congestion was assessed based on the sum of B-lines: 5 and less – no congestion, 6 to 15 – slight congestion, 15 to 29 – moderate, 30 and more – significant. Results. The conducted study shows the advantage of the restrictive regimen of IT in patients with concomitant coronary artery disease and minimal signs of congestive heart failure during abdominal surgical operations. The regime with restriction of intravenous fluid administration was better, as it reduces venous congestion, reduces the amount of fluid in the interstitial space of the lungs, causes a smaller compensatory reaction of the cardiovascular system to infusion with normal values of NT-proBNP. The task of the anesthesiologist in this case is careful control of daily and cumulative water balance, adequate monitoring of indicators of the cardiovascular system, use of modern ultrasound technologies and protocols for controlling volemic status, assessment of the dynamics of biomarkers of heart failure, which will allow complex abdominal operations to be safely performed in patients with reduced cardiac reserve. Conclusions. As a result of the conducted research, it was established that: the use of a liberal regimen of infusion therapy in the perioperative period in patients with coronary heart disease and HF I, I-II FC compared to a restrictive regimen leads to a statistically significant increase in biomarkers of heart failure and ultrasound signs of volemic overload. The restrictive regimen of IT in a dose of 5–8 ml/kg/hour, in comparison with a liberal one in a dose of 12–15 ml/kg/hour, can be recognized as optimal and safe in patients with coronary heart disease and HF I, I-II FC during surgery on the organs of the abdominal cavity. The use and widespread implementation in practice of complex determination of the level of the amino-terminal prohormone of brain natriuretic peptide (NT-proBNP) NT-proBNP, non-invasive methods of ultrasound of the heart – echocardiography, ultrasound of the lungs and central vessels – assessment of the dynamic filling of the inferior vena cava (IVC) allows significantly supplement clinical information on volemic status, venous stasis, contractility of the heart and fluid retention in the interstitial space of the lungs and may be key in the prevention of cardiac complications in this category of patients.

Utilizing Point-Of-Care Ultrasound (POCUS) for Diagnosis in a Resource-Limited Setting: A Case Report of Pulmonary Embolism

Introduction: Acute pulmonary embolism (PE) is a common cause of cardiovascular-related deaths and poses diagnostic challenges due to its variable and non-specific symptoms. Computed tomography pulmonary angiography (CTPA) is the gold standard imaging method for PE diagnosis, but its availability is limited in resource-constrained settings. Point-of-care ultrasound (POCUS) has emerged as a valuable tool for emergency physicians, aiding accurate diagnoses, procedural guidance, and resuscitation efforts. Case Presentation: This case report presents a 76-year-old woman with non-specific symptoms diagnosed with PE using POCUS in the Emergency Department of the Korle Bu Teaching Hospital. The POCUS findings included an enlarged right ventricle with a flattened septum (D sign), poor cardiac contractility, thrombi in the right ventricle and a plethoric Inferior Vena Cava (IVC). Prompt diagnosis facilitated timely management, leading to improved patient outcomes. Conclusion: POCUS has proven to be indispensable in resource-constrained settings where confirmatory diagnostics are limited. Incorporating POCUS training into emergency medicine residency programs and establishing emergency ultrasound fellowships in under-resourced regions like Africa can enhance its utilization and empower clinicians in such environments. Equipping emergency room clinicians with POCUS skills enables timely diagnosis, early interventions, shorter Emergency Department stays, and improved patient outcomes. This approach can contribute to building an African faculty proficient in emergency ultrasound, facilitating the education and training of more clinicians in POCUS, and ultimately enhancing healthcare outcomes in resource-limited environments.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H1-Histamine Receptor on the Heart.

There is a debate on whether H1-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H1-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H1-histamine receptors (H1-TG) and compared these findings with those in littermate wild-type mice (WT). In H1-TG mice, we studied the presence of H1-histamine receptors by autoradiography of the atrium and ventricle using [3H]mepyramine. The messenger RNA for human H1-histamine receptors was present in the heart from H1-TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H1-histamine receptor in cardiac cells from H1-TG. We noted that histamine (1 nM-10 µM) in paced (1 Hz) left atrial preparations from H1-TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H1-TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H1-TG were attenuated by the H1-histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H1-histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H1-histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H1-histamine receptor to contribute to the clarification of the controversy on whether H1-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H1-histamine receptors first decrease and then raise contractile force in the mammalian heart but exert solely negative chronotropic effects.

Use of Inotropes and vasopressors in Septic Shock: When, Why, and How?

Septic shock, a severe and sometimes fatal condition caused by systemic infection, demands immediate and focused therapies to restore hemodynamic stability and prevent organ failure. The use of vasopressors and inotropes has become the foundation in the treatment of septic shock, with the goal of reversing the vasodilatory condition and increasing cardiac contractility.&#x0D; Vasopressors are an effective class of medications that cause vasoconstriction and hence increase mean arterial pressure (MAP). Norepinephrine is recommended as the first-line agent to use in septic shock. However, many medications have both vasopressor and inotropic actions, distinguishing them from inotropes, which increase heart contractility.&#x0D; Inotropes work by increasing cardiac contractility and thereby increasing cardiac output. Dobutamine is still the mainstay of treatment based on the latest SCCM guidelines.&#x0D; This review provides a comprehensive overview of the rationale, indications, doses and major side effects surrounding the administration of these pharmacological agents in septic shock.&#x0D; Our team extensively explored various databases regarding this subject. We concluded that the most trustworthy sources for our study were articles indexed in PubMed. We thoroughly examined these articles and synthesized the information within our review.&#x0D; We recommend that more trials are needed to compare the effectivity of dobutamine compared to other inotropes in the setting of septic shock as the latest guidelines are based on a shortage of randomized control trials. Also the literature should emphasize the importance of continuous hemodynamic monitoring during vasopressor therapy, highlighting the necessity for personalized changes to reach and maintain target blood pressure targets.

Targeted Gene Deletion or Antagonism of the Prostaglandin E2 EP3 Receptor Protects Against Cardiac Injury Postmyocardial Infarction.

Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI. To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI. CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice. Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.

A Comprehensive Review on Unveiling the Journey of Digoxin: Past, Present, and Future Perspectives.

Digoxin, a cardiac glycoside derived from the foxglove plant (Digitalis spp.), has been utilized for centuries in managing various cardiac conditions due to its ability to increase myocardial contractility and regulate heart rate. This comprehensive review explores the historical context, pharmacological properties, clinical applications, efficacy, safety profile, challenges, and future perspectives of digoxin. Tracing its journey from traditional medicine to modern cardiovascular therapeutics, we delve into its mechanism of action, therapeutic indications, and clinical guidelines. While digoxin remains a cornerstone therapy for heart failure and atrial fibrillation, its narrow therapeutic index and individual variability in response pose challenges in clinical practice. Nevertheless, ongoing research efforts aim to elucidate its role in emerging therapeutic areas and technological advancements in drug delivery. Despite the advent of newer pharmacological agents, digoxin's enduring relevance lies in its established efficacy, affordability, and global accessibility. This review underscores the symbiotic relationship between tradition and progress in cardiovascular medicine, highlighting the timeless pursuit of medical innovation to optimize patient care.

Retracted: Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway.

[This retracts the article DOI: 10.1155/2020/1625362.].

PLEKHM2 deficiency induces impaired mitochondrial clearance and elevated ROS levels in human iPSC-derived cardiomyocytes

Pleckstrin homology domain-containing family M member 2 (PLEKHM2) is an essential adaptor for lysosomal trafficking and its homozygous truncation have been reported to cause early onset dilated cardiomyopathy (DCM). However, the molecular mechanism of PLEKHM2 deficiency in DCM pathogenesis and progression is poorly understood. Here, we generated an in vitro model of PLEKHM2 knockout (KO) induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the potential pathogenic mechanism of PLEKHM2-deficient cardiomyopathy. PLEKHM2-KO hiPSC-CMs developed disease phenotypes with reduced contractility and impaired calcium handling. Subsequent RNA sequencing (RNA-seq) analysis revealed altered expression of genes involved in mitochondrial function, autophagy and apoptosis in PLEKHM2-KO hiPSC-CMs. Further molecular experiments confirmed PLEKHM2 deficiency impaired autophagy and resulted in accumulation of damaged mitochondria, which triggered increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (Δψm). Importantly, the elevated ROS levels caused oxidative stress-induced damage to nearby healthy mitochondria, resulting in extensive Δψm destabilization, and ultimately leading to impaired mitochondrial function and myocardial contractility. Moreover, ROS inhibition attenuated oxidative stress-induced mitochondrial damage, thereby partially rescued PLEKHM2 deficiency-induced disease phenotypes. Remarkably, PLEKHM2-WT overexpression restored autophagic flux and rescued mitochondrial function and myocardial contractility in PLEKHM2-KO hiPSC-CMs. Taken together, these results suggested that impaired mitochondrial clearance and increased ROS levels play important roles in PLEKHM2-deficient cardiomyopathy, and PLEKHM2-WT overexpression can improve mitochondrial function and rescue PLEKHM2-deficient cardiomyopathy.

Circadian Rhythms in Cardiovascular Metabolism.

Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake and fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations in numerous cardiovascular functional parameters, including blood pressure, heart rate, and myocardial contractility. It is, therefore, not surprising that metabolic processes also fluctuate over the course of the day, to ensure temporal needs for ATP, building blocks, and metabolism-based signaling molecules are met. What has become increasingly clear is that in addition to classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks to temporally orchestrate metabolic pathways in preparation for predicted stimuli/stresses (termed anticipatory mechanisms). Here, we review current knowledge regarding circadian regulation of metabolism, how metabolic rhythms are synchronized with cardiovascular function, and whether circadian misalignment/disruption of metabolic processes contribute toward the pathogenesis of cardiovascular disease.

Myosin folding boosts solubility in cardiac muscle sarcomeres.

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected > 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility.

The Effect of Cardiovascular Medication on Heart Rate Variability in Patients Presenting with Early Sepsis at the Emergency Department: A Prospective Cohort Study

Our SepsiVit study showed that long-term, automatically analyzed ECG recordings can be used to determine heart rate variability (HRV) features associated with the clinical deterioration of early septic patients at the ED. This study focus on the influence of cardiovascular medication on HRV in patients with early sepsis at the ED. This study is an exploratory post-hoc analysis of our SepsiVit study. Eligible patients were connected to a mobile bedside monitor for continuously ECG measurements. The first 3 hours were analyzed for this study. Between January 2017 and December 2018, 171 patients were included with early sepsis, defined as infection and two or more systemic inflammatory response syndrome criteria. We excluded sixteen patients because of insufficient measurements. Therefore, we included 155 patients in the final analysis: 72.9% with sepsis, 2.6% with septic shock, and 24.5% classified as infection. In 9.0% of the patients, medication directly impacting cardiac contractility was administered, while 22.6% received medication with an indirect effect. A combination of both types of medication was prescribed to 17.4% of the patients. The majority of patients (51.0%) did not utilize any cardiovascular medication. Patients using both medication with direct and indirect effect were on average 10 years older than patients using no cardiovascular medication (p 0.037). No differences in vital signs or HRV parameters were found in patients using cardiovascular medication. Our results showed that HRV is not influenced by cardiovascular medication. Consequently, the correction of HRV features for the use of cardiovascular medication is unnecessary when analyzing, modelling, and interpreting these signals.

A computational study of right ventricular mechanics in a rat model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) presents a significant challenge to right ventricular (RV) function due to progressive pressure overload, necessitating adaptive remodeling in the form of increased wall thickness, enhanced myocardial contractility and stiffness to maintain cardiac performance. However, the impact of these remodeling mechanisms on RV mechanics in not clearly understood. In addition, there is a lack of quantitative understanding of how each mechanism individually influences RV mechanics. Utilizing experimental data from a rat model of PAH at three distinct time points, we developed biventricular finite element models to investigate how RV stress and strain evolved with PAH progression. The finite element models were fitted to hemodynamic and morphological data to represent different disease stages and used to analyze the impact of RV remodeling as well as the altered RV pressure. Furthermore, we performed a number of theoretical simulation studies with different combinations of morphological and physiological remodeling, to assess and quantify their individual impact on overall RV load and function. Our findings revealed a substantial 4-fold increase in RV stiffness and a transient 2-fold rise in contractility, which returned to baseline by week 12. These changes in RV material properties in addition to the 2-fold increase in wall thickness significantly mitigated the increase in wall stress and strain caused by the progressive increase in RV afterload. Despite the PAH-induced cases showing increased wall stress and strain at end-diastole and end-systole compared to the control, our simulations suggest that without the observed remodeling mechanisms, the increase in stress and strain would have been much more pronounced. Our model analysis also indicated that while changes in the RV's material properties-particularly increased RV stiffness - have a notable effect on its mechanics, the primary compensatory factor limiting the stress and strain increase in the early stages of PAH was the significant increase in wall thickness. These findings underscore the importance of RV remodeling in managing the mechanical burden on the right ventricle due to pressure overload.

The role of protein kinase A signaling in cardiomyopathy

Cardiomyopathy, a diverse group of heart muscle diseases, poses a significant challenge to global cardiovascular health. However, the intricate molecular mechanisms underlying cardiomyopathy, especially the pivotal role of protein kinase A (PKA) signaling pathways in its pathogenesis, remains unclear. The review synthesizes current research findings and highlights the multifaceted interactions between PKA and key cellular components implicated in cardiomyopathy progression. Moreover, this paper unfolds with an exploration of the normal physiological functions of PKA in cardiac cells, emphasizing its role in regulating crucial processes such as excitation-contraction coupling and cellular energy homeostasis. The article navigates through the dysregulation of PKA signaling observed in various forms of cardiomyopathy, including hypertrophic, dilated, and restrictive subtypes. Insightful analyses into the impact of PKA-mediated phosphorylation events on cardiac contractility, ion channel function, and mitochondrial dynamics shed light on the intricate interplay between signaling cascades and disease manifestation. Future clinical trials targeting the PKA signaling pathway are required to seek more effective and precise therapeutic approaches of cardiomyopathy.