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Journal of Thoracic Disease Jun 2022The prevalence of hypertrophic cardiomyopathy (HCM) is estimated to be 1 in 200 to 500 individuals, with systolic anterior motion (SAM) of the mitral valve (MV) and left... (Review)
Review
BACKGROUND AND OBJECTIVE
The prevalence of hypertrophic cardiomyopathy (HCM) is estimated to be 1 in 200 to 500 individuals, with systolic anterior motion (SAM) of the mitral valve (MV) and left ventricular outflow tract (LVOT) obstruction present in 60% to 70%. In this narrative review, we aim to elucidate the pathophysiology of SAM-septal contact and LVOT obstruction in HCM by presenting a detailed review on the anatomy of the MV apparatus in HCM, examining the various existing theories pertaining to the SAM phenomenon as supported by cardiac imaging, and providing a critical assessment of management strategies for SAM in HCM.
METHODS
A literature review was performed using PubMed, EMBASE, Ovid, and the Cochrane Library, of all scientific articles published through December 2021. A focus was placed on descriptive studies, reports correlating echocardiographic findings with pathologic diagnosis, and outcomes studies.
KEY CONTENT AND FINDINGS
The pathophysiology of SAM involves the complex interplay between HCM morphology, MV apparatus anatomic abnormalities, and labile hemodynamic derangements. Echocardiography and cardiac magnetic resonance (CMR) vector flow mapping have identified drag forces, as opposed to the "Venturi effect", as the main hydraulic forces responsible for SAM. The degree of mitral regurgitation with SAM is variable, and its severity is correlated with degree of LVOT obstruction and outcomes. First line therapy for the amelioration of SAM and LVOT obstruction is medical therapy with beta-blockers, non-dihydropyridine calcium-channel blockers, and disopyramide, in conjunction with lifestyle modifications. In refractory cases septal reduction therapy is performed, which may be combined with a 'resect-plicate-release' procedure, anterior mitral leaflet extension, surgical edge-to-edge MV repair, anterior mitral leaflet retention plasty, or secondary chordal cutting.
CONCLUSIONS
Recent scientific advances in the field of HCM have allowed for a maturation of our understanding of the SAM phenomenon. Cardiac imaging plays a critical role in its diagnosis, treatment, and surveillance, and in our ability to apply the appropriate therapeutic regimens. The increasing prevalence of HCM places an emphasis on continued basic and clinical research to further improve outcomes for this challenging population.
PubMed: 35813751
DOI: 10.21037/jtd-22-182 -
Journal of Clinical Medicine Apr 2023Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic...
Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1-4.5), = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile.
PubMed: 37048808
DOI: 10.3390/jcm12072725 -
Journal of Cardiac Failure Nov 2023
Topics: Humans; Disopyramide; Sequoia; Heart Failure; Anti-Arrhythmia Agents; Cardiomyopathy, Hypertrophic
PubMed: 37473912
DOI: 10.1016/j.cardfail.2023.07.003 -
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 -
Cardiology and Therapy Jun 2022There is limited evidence on therapies for obstructive hypertrophic cardiomyopathy (HCM), and data regarding treatment patterns and cost are scarce. This study assessed...
INTRODUCTION
There is limited evidence on therapies for obstructive hypertrophic cardiomyopathy (HCM), and data regarding treatment patterns and cost are scarce. This study assessed treatment patterns and economic outcomes in patients with symptomatic obstructive HCM.
METHODS
Adults with symptomatic obstructive HCM as per study design and treated with pharmacotherapies [beta blockers (BBs), calcium channel blockers (CCBs), BB + CCB, or disopyramide] or procedures (septal reduction therapy, heart transplantation, implantable cardioverter-defibrillator, and pacemaker implantation) were identified from the IBM® MarketScan® Commercial and Medicare Supplemental database (January 2009-March 2019). Patients had 12-month continuous eligibility before and after (study period) treatment initiation (index treatment). Healthcare resource utilization (HRU), costs, and treatment changes were assessed.
RESULTS
Of the 4883 patients included in the analysis, 85% received pharmacotherapies (BB 52.5%; CCB 11.7%; BB + CCB 17.7%; disopyramide 2.4%) and 15.7% underwent procedures. During the study period, 38, 34, and 100% of all patients had ≥ 1 inpatient stay, emergency room (ER) visit, and outpatient visit, respectively; mean total healthcare costs were US$53,053. Patients undergoing procedures had the highest HRU and costs across groups. Among patients receiving pharmacotherapies, HRU was lowest with BBs and highest with disopyramide. Treatment changes were observed in 43.8% of patients receiving pharmacotherapies.
CONCLUSIONS
Patients experienced high rates of treatment changes, and the economic burden associated with symptomatic obstructive HCM increased as therapy escalated. More effective therapies are needed to stabilize or decrease the economic burden of obstructive HCM.
PubMed: 35230625
DOI: 10.1007/s40119-022-00257-7 -
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 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 -
Drugs Jun 2022Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare... (Review)
Review
Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from "old" established agents up to novel selective drugs that have been recently trialed in patients.
Topics: Adrenergic beta-Antagonists; Cardiomyopathy, Hypertrophic; Humans
PubMed: 35696053
DOI: 10.1007/s40265-022-01728-w -
JACC. Basic To Translational Science Nov 2019Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We...
Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We tested disopyramide in cardiomyocytes from the septum of surgical myectomy patients: disopyramide inhibits multiple ion channels, leading to lower Ca transients and force, and shortens action potentials, thus reducing cellular arrhythmias. The electrophysiological profile of disopyramide explains the efficient reduction of outflow gradients but also the limited prolongation of the QT interval and the absence of arrhythmic side effects observed in 39 disopyramide-treated patients. In conclusion, our results support the idea that disopyramide is safe for outpatient use in obstructive patients.
PubMed: 31998849
DOI: 10.1016/j.jacbts.2019.06.004 -
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