-
Pharmaceutics Feb 2023Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and...
Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Computational modeling and drug design approaches can speed up the drug discovery and significantly reduce expenses aiming to improve the treatment of cardiomyopathy. In the SILICOFCM project, a multiscale platform is developed using coupled macro- and microsimulation through finite element (FE) modeling of fluid-structure interactions (FSI) and molecular drug interactions with the cardiac cells. FSI was used for modeling the left ventricle (LV) with a nonlinear material model of the heart wall. Simulations of the drugs' influence on the electro-mechanics LV coupling were separated in two scenarios, defined by the principal action of specific drugs. We examined the effects of Disopyramide and Dygoxin which modulate Ca transients (first scenario), and Mavacamten and 2-deoxy adenosine triphosphate (dATP) which affect changes of kinetic parameters (second scenario). Changes of pressures, displacements, and velocity distributions, as well as pressure-volume (P-V) loops in the LV models of HCM and DCM patients were presented. Additionally, the results obtained from the SILICOFCM Risk Stratification Tool and PAK software for high-risk HCM patients closely followed the clinical observations. This approach can give much more information on risk prediction of cardiac disease to specific patients and better insight into estimated effects of drug therapy, leading to improved patient monitoring and treatment.
PubMed: 36986654
DOI: 10.3390/pharmaceutics15030793 -
Molecular Psychiatry Jul 2023Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed...
Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.
Topics: Humans; Female; Precision Medicine; Pharmacogenetics; Quality of Life; Anxiety Disorders; Biomarkers; Risk Assessment; Benzodiazepines; Serotonin Plasma Membrane Transport Proteins
PubMed: 36878964
DOI: 10.1038/s41380-023-01998-0 -
Journal of Cardiovascular Pharmacology May 2023The pathophysiology of hypertrophic cardiomyopathy is primarily comprised of dynamic left ventricular outflow tract obstruction, mitral regurgitation, and diastolic... (Review)
Review
The pathophysiology of hypertrophic cardiomyopathy is primarily comprised of dynamic left ventricular outflow tract obstruction, mitral regurgitation, and diastolic dysfunction. Symptoms such as dyspnea, angina, or syncope can occur because of left ventricular (LV) hypertrophy and reduced LV cavity size. Currently, focus on symptom relief through optimizing LV preload and reducing inotropy is the mainstay of therapy through the use of β-blockers, nondihydropyridine calcium channel blockers, and disopyramide. Mavacamten is a novel cardiac myosin inhibitor recently approved by the Food and Drug Administration for the treatment of obstructive hypertrophic cardiomyopathy. Mavacamten normalizes myosin and actin cross-bridging to decrease contractility and ultimately reduce LV outflow tract gradients to maximize cardiac output. In this review, we report on the mechanism of action of mavacamten, safety profile, and phase 2 and 3 clinical trial data. Because of the risk of heart failure resulting from systolic dysfunction, careful patient selection and close monitoring are key for implementing this therapy into cardiovascular practice.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Hypertrophy, Left Ventricular
PubMed: 36878205
DOI: 10.1097/FJC.0000000000001416 -
Hospital Practice (1995) Feb 2023Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition defined by left ventricular wall thickness greater than 15 mm in the absence of other... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition defined by left ventricular wall thickness greater than 15 mm in the absence of other conditions that could explain that degree of hypertrophy. Obstructive HCM associated with left ventricular outflow tract obstruction is defined by an intraventricular systolic pressure gradient greater than or equal to 30 mm Hg. Over the past couple of decades, there has been an expansion of both invasive and pharmacotherapeutic options for patients with HCM, with recent guidelines calling for a melody of invasive and non-invasive treatment strategies. There are several invasive therapies including proven therapies such as alcohol septal ablation and septal myectomy. Novel invasive therapies such as MitraClip, radiofrequency septal ablation and SESAME procedure have more recently been promoted. Pharmacological therapy has also dramatically evolved and includes conventional medications such as beta-blockers, calcium channel blockers, and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, may significantly change management. Other myosin inhibitors and modulators are also being developed and tested in large clinical trials. Given significant phenotypical variability in patients with HCM, clinical management can be challenging, and often requires an individualized approach with a combination of invasive and non-invasive options.
Topics: Humans; Cardiomyopathy, Hypertrophic; Treatment Outcome
PubMed: 36598161
DOI: 10.1080/21548331.2022.2162297 -
Biological & Pharmaceutical Bulletin 2023The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the...
The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC values to block the L-type Ca channel rather than the Na channel. The effects of drugs were roughly the same when examined under a high extracellular K solution, which inactivates the Na channel. Furthermore, the attenuation of the extracellular Ca-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca channel.
Topics: Guinea Pigs; Animals; Anti-Arrhythmia Agents; Propafenone; Myocardium; Lidocaine; Papillary Muscles
PubMed: 36596522
DOI: 10.1248/bpb.b22-00644 -
Journal of Clinical Medicine Dec 2022Background: Disopyramide is a class Ia antiarrhythmic drug that has been used for the second-line treatment of symptomatic hypertrophic obstructive cardiomyopathy...
Background: Disopyramide is a class Ia antiarrhythmic drug that has been used for the second-line treatment of symptomatic hypertrophic obstructive cardiomyopathy (HOCM). The aim of the study was to assess the impact of short-acting disopyramide in patients with hypertrophic obstructive cardiomyopathy (HOCM) using two-dimensional speckle-tracking echocardiography. Methods: This prospective study included patients with HOCM on chronic treatment with short-acting disopyramide. Two sequential comprehensive echocardiographic examinations were performed: after temporary disopyramide suspension and 2.5 h after disopyramide intake. Results: 19 patients were included in the study. The effect of disopyramide on the left ventricle was not uniform. After the intake of disopyramide, the mean global strain peak was −17 ± 2% before disopyramide intake and −14 ± 2% after (p < 0.0001). There was a significant reduction in strain in the basal septal (p = 0.015), basal inferior (p = 0.019), basal posterior (p = 0.05), apical anterior (p = 0.0001), and apical lateral segments (p = 0.021). In all other segments, there was no significant change. Disopyramide also caused a significant accentuation of the base-apex strain gradients (p = 0.036). No change was noted in circumferential and left atrial strain. While the left ventricular ejection fraction and outflow gradients did not change, the significant reduction in global and segmental longitudinal strain demonstrated the acute negative inotropic effect of disopyramide on the myocardium in patients with HOCM. Conclusion: A strain analysis may be a useful tool to assess the negative inotropic effect of cardiovascular medication on the left ventricle in patients with HOCM.
PubMed: 36555940
DOI: 10.3390/jcm11247325 -
Expert Review of Cardiovascular Therapy Jan 2023Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading to hypertrophy of the left ventricle excluding other etiologies. Patients can experience... (Review)
Review
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading to hypertrophy of the left ventricle excluding other etiologies. Patients can experience exertional chest pain, dyspnea, syncope or even sudden cardiac death (SCD). Traditional medical management consists of beta blockers (BB), nondihydropyridine calcium channel blockers and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, has recently been shown to improve both quantitative and qualitative measures of obstructive HCM allowing some patients to defer septal reduction therapy.
AREAS COVERED
This review delves into the pharmacotherapy of mavacamten, the evidence behind this first-in-class drug for HCM, guidance for clinical usage, and possible future uses for cardiac myosin inhibitors.
EXPERT OPINION
Mavacamten should be incorporated into the standard armamentarium of medications used to treat obstructive HCM. PIONEER-HCM, EXPLORER-HCM and VALOR-HCM demonstrated improvements in peak LVOT gradient both at rest and post-exercise, cardiac biomarkers, New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Unlike other medications utilized for treatment, mavacamten can delay or even obviate the need for septal reduction therapy.
Topics: Humans; Adult; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Cardiac Myosins
PubMed: 36522857
DOI: 10.1080/14779072.2023.2159811 -
Frontiers in Cardiovascular Medicine 2022Brugada syndrome (BrS) is associated with ventricular tachyarrhythmias. However, the presence of electrical strom (ES) and its management still debated.
BACKGROUND
Brugada syndrome (BrS) is associated with ventricular tachyarrhythmias. However, the presence of electrical strom (ES) and its management still debated.
OBJECTIVES
We present the outcome and management of 44 BrS patients suffering from ES.
METHODS
A systematic literature review and pooled analysis Through database review including PubMed, Web of Science, Cochrane Libary and Cinahl studies were analyzed. Evidence from 7 reports of 808 BrS patients was identified.
RESULTS
The mean age of patients suffering from ES was 34 ± 9.5 months (94.7% males, 65.8% spontaneous BrS type I). Using electrophysiological study ventricular tachycardia/ventricular fibrillation were inducible in 12/23 (52.2%). Recurrence of ES was documented in 6.1%. Death from ES was 8.2% after a follow-up of 83.5 ± 53.4. In up to 27 ES resolved without treatment. External shock was required in 35.6%, internal ICD shock in 13.3%, Overdrive pacing, left cardiac sympathetic block and atropin in 2.2%. Short-term antiarrhythmic management was as the following: Isopreterenol or Isopreterenol in combination with quinidine 35.5%, orciprenaline in 2.2%, quinidine 2.2%, disopyramide 2.2% or denopamide 2.2%. However, lidocaine, magensium sulfate, mexiletine and propanolol failed to control ES.
CONCLUSION
Although ES is rare in BrS, this entity challenges physicians. Despite its high mortality rate, spontaneous termination is possible. Short-term management using Isoproterenol and/or quinidine might be safe. Prospective studies on management of ES are warranted.
PubMed: 36386327
DOI: 10.3389/fcvm.2022.981715 -
Cardiology and Therapy Dec 2022Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by pathogenic variants in sarcomeric genes, leading to left ventricular hypertrophy and complex phenotypic... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by pathogenic variants in sarcomeric genes, leading to left ventricular hypertrophy and complex phenotypic heterogeneity. While HCM is the most common inherited cardiomyopathy, pharmacological treatment options have previously been limited and were predominantly directed towards symptom control owing to left ventricular outflow obstruction. These therapies, including beta blockers, calcium channel blockers, and disopyramide, have not been shown to affect the natural history of the disease, which is of particular concern for younger patients who have an increased lifetime risk of experiencing arrhythmias, heart failure, and sudden cardiac death. Increased knowledge of the genetic mechanisms underlying this disease in recent years has led to the development of targeted, potentially disease-modifying therapies for both obstructive and nonobstructive phenotypes that may help to prevent or ameliorate left ventricular hypertrophy. In this review article, we will define the etiology and clinical phenotypes of HCM, summarize the conventional therapies for obstructive HCM, discuss the emerging targeted therapies as well as novel invasive approaches for obstructive HCM, describe the therapeutic advances for nonobstructive HCM, and outline the future directions for the treatment of HCM.
PubMed: 36243823
DOI: 10.1007/s40119-022-00283-5 -
International Journal of Cardiology Jan 2023We assessed the efficacy and safety of ranolazine in real-world patients with hypertrophic cardiomyopathy (HCM).
OBJECTIVES
We assessed the efficacy and safety of ranolazine in real-world patients with hypertrophic cardiomyopathy (HCM).
BACKGROUND
Ranolazine is an anti-anginal drug that inhibits the late phase of the inward sodium current. In a small prospective trial, ranolazine reduced the arrhythmic burden and improved biomarker profile in HCM patients. However, systematic reports reflecting real-world use in this setting are lacking.
METHODS
Changes in clinical and instrumental features, symptoms and arrhythmic burden were evaluated in 119 patients with HCM before and during treatment with ranolazine at a national referral centre for HCM.
RESULTS
Patients were treated with ranolazine for 2 [1-4] years; 83 (70%) achieved a dosage ≥1000 mg per day. Treatment interruption was necessary in 24 patients (20%) due to side effects (n = 10, 8%) or disopyramide initiation (n = 8, 7%). Seventy patients (59%) were treated with ranolazine for relief of angina. Among them, 51 (73%) had total symptomatic relief and 47 patients (67%) showed ≥2 Canadian Cardiovascular society (CCS) angina grade improvement. Sixteen patients (13%) were treated for recurrent ventricular arrhythmias, including 4 with a clear ischemic trigger, who experienced no further arrhythmic episodes while on ranolazine. Finally, 33 patients (28%) were treated for heart failure associated with severe diastolic dysfunction: no symptomatic benefit could be observed in this group.
CONCLUSION
Ranolazine was safe and well tolerated in patients with HCM. The use of ranolazine may be considered in patients with HCM and microvascular angina.
Topics: Humans; Ranolazine; Prospective Studies; Canada; Cardiomyopathy, Hypertrophic; Angina Pectoris; Treatment Outcome; Acetanilides
PubMed: 36228766
DOI: 10.1016/j.ijcard.2022.10.014