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Jamil A Tajik - One of the best experts on this subject based on the ideXlab platform.

Allan L Klein - One of the best experts on this subject based on the ideXlab platform.

  • biventricular mechanics in constrictive pericarditis comparison with Restrictive Cardiomyopathy and impact of pericardiectomy
    Circulation-cardiovascular Imaging, 2013
    Co-Authors: Kenya Kusunose, Arun Dahiya, Zoran B Popovic, Hirohiko Motoki, Chadi M Alraies, Andrew O Zurick, Michael A Bolen, Deborah H Kwon, Scott D Flamm, Allan L Klein
    Abstract:

    Background— The aim of our study was to compare myocardial mechanics of constrictive pericarditis (CP) with Restrictive Cardiomyopathy (RCM), or healthy controls; to assess the impact of pericardial thickening detected by cardiac magnetic resonance on regional myocardial mechanics in CP; and to quantitate the effect of pericardiectomy on myocardial mechanics in CP. Methods and Results— Myocardial mechanics were evaluated by 2-dimensional speckle tracking in 52 consecutive patients with CP who underwent cardiac magnetic resonance examination before pericardiectomy, 35 patients with RCM, and 26 control subjects. CP patients had selectively depressed left ventricular (LV) anterolateral wall strain (LWS) and right ventricular (RV) free wall longitudinal systolic strain (FWS) but preserved LV septal wall systolic strain (SWS). In a comparison of RCM and normals, CP patients had significantly lower regional longitudinal systolic strain ratios (CP versus RCM and normal; LVLWS/LVSWS: 0.8±0.2 versus 1.1±0.2 and 1.0±0.2; P P =0.011). There was a significant inverse correlation between pericardial thickness and respective ventricular strains ( P =0.001). Pericardiectomy resulted in the improvement of the depressed LVLWS/LVSWS (0.83±0.18–0.95±0.12; P Conclusions— Regional longitudinal systolic strain ratios are robust novel diagnostic tools for CP. Regional myocardial mechanics inversely correlates with adjacent pericardial segment thickness detected by cardiac magnetic resonance, and pericardiectomy leads to systolic strain improvement, which is more pronounced in right ventricular and LV free walls.

  • hydroxychloroquine induced Restrictive Cardiomyopathy
    European Journal of Echocardiography, 2007
    Co-Authors: John Cotroneo, Khaled M Sleik, Rene E Rodriguez, Allan L Klein
    Abstract:

    Chloroquine (Hydroxychloroquine)-induced Cardiomyopathy is a rare but potentially life-threatening condition. Cessation of the culprit drug, along with aggressive afterload reduction therapy, has been associated with halting of disease progress and even improvement in patients' clinical and histologic status. Echocardiography is a fundamental tool in the identification and assessment of patients with Cardiomyopathy, with particular utility in the detailed assessment of biventricular systolic and diastolic function. It also provides an objective and non-invasive means of assessing treatment response. We present a case of a 51-year-old woman with hydroxychloroquine-induced Restrictive Cardiomyopathy and correlate clinical, echocardiographic and anatomic pathologic findings both at initial presentation and following treatment.

  • diastolic heart failure Restrictive Cardiomyopathy constrictive pericarditis and cardiac tamponade clinical and echocardiographic evaluation
    Cardiology in Review, 2002
    Co-Authors: Craig R Asher, Allan L Klein
    Abstract:

    An understanding of the basic principles of diastolic function is important in order to recognize diseases that may result in diastolic dysfunction and diastolic heart failure. Although uncommon, Restrictive Cardiomyopathy, constrictive pericarditis, and cardiac tamponade are among the disorders that may affect primarily diastolic function with preservation of systolic function. Diastolic heart failure may manifest with chronic nonspecific symptoms or may present with acute hemodynamic compromise. Echocardiography plays a vital role in the diagnosis of diastolic dysfunction and differentiation of these disease processes. It also provides a basis for clinical decisions regarding management and surgical referral. This review summarizes the clinical features, pathophysiology, and hemodynamic and echocardiographic signs of Restrictive Cardiomyopathy, constrictive pericarditis, and cardiac tamponade.

  • comparison of new doppler echocardiographic methods to differentiate constrictive pericardial heart disease and Restrictive Cardiomyopathy
    American Journal of Cardiology, 2001
    Co-Authors: Navin Rajagopalan, Mario J Garcia, Leonardo L Rodriguez, James D Thomas, Daniel R Murray, Carolyn Appersonhansen, Marie Stugaard, Allan L Klein
    Abstract:

    Abstract This study assesses how the newer modalities of tissue Doppler echocardiography and color M-mode flow propagation compare with respiratory variation of Doppler flow in distinguishing between constrictive pericarditis and Restrictive Cardiomyopathy. We studied 30 patients referred for further evaluation of diastolic function who had a diagnosis of constrictive pericarditis or Restrictive Cardiomyopathy established by diagnostic tests, including clinical assessment, magnetic resonance imaging, cardiac catheterization, endomyocardial biopsy, and surgical findings. Nineteen patients had constrictive pericarditis and 11 had Restrictive Cardiomyopathy. We performed 2-dimensional transesophageal echocardiography combined with pulsed-wave Doppler of the pulmonary veins and mitral inflow with respiratory monitoring, tissue Doppler echocardiography of the lateral mitral annulus, and color M-mode flow propagation of left ventricular filling. Respiratory variation of the mitral inflow peak early (peak E) velocity of ≥10% predicted constrictive pericarditis with 84% sensitivity and 91% specificity and variation in the pulmonary venous peak diastolic (peak D) flow velocity of ≥18% distinguished constriction with 79% sensitivity and 91% specificity. Using tissue Doppler echocardiography, a peak early velocity of longitudinal expansion (peak E a ) of ≥8.0 cm/s differentiated patients with constriction from restriction with 89% sensitivity and 100% specificity. A slope of ≥100 cm/s for the first aliasing contour in color M-mode flow propagation predicted patients with constriction with 74% sensitivity and 91% specificity. Thus, the newer methods of tissue Doppler echocardiography and color M-mode flow propagation are equivalent and complimentary with Doppler respiratory variation in distinguishing between constrictive pericarditis and Restrictive Cardiomyopathy. The additive role of the new methods needs to be established in difficult cases of constrictive pericarditis where respiratory variation may be absent or decreased.

  • differentiation of constrictive pericarditis from Restrictive Cardiomyopathy assessment of left ventricular diastolic velocities in longitudinal axis by doppler tissue imaging
    Journal of the American College of Cardiology, 1996
    Co-Authors: Mario J Garcia, Leonardo L Rodriguez, Miguel Ares, Brian P Griffin, James D Thomas, Allan L Klein
    Abstract:

    Objectives. We sought to determine the utility of left ventricular expansion velocities in differentiating constrictive pericarditis from Restrictive Cardiomyopathy. Background. Several studies have shown that left ventricular diastolic expansion is influenced by the elastic recoil forces of the myocardium. These forces are affected by intrinsic myocardial disease but should be preserved when diastole is impaired as a result of extrinsic causes. Methods. Using Doppler tissue imaging, we measured peak early velocity of longitudinal axis expansion (Ea) in 8 patients with constrictive pericarditis, 7 patients with restriction and 15 normal volunteers. Transmitral early (E) and late (A) Doppler flow velocities, left ventricular systolic and diastolic volumes, ejection fraction and mitral annular M-mode displacement were also compared between the groups. Results. The Eavalue was significantly higher in normal subjects (14.5 ± 4.7 cm/s [mean ±SD]) and in patients with constriction (14.8 ± 4.8 cm/s) than in those with restriction (5.1 ± 1.4 cm/s, p Conclusions. Our study indicates that longitudinal axis expansion velocities are markedly reduced in patients with Restrictive Cardiomyopathy. The poor correlation found with transvalvular flow velocities suggests that Eamay be relatively preload independent. The measurement of longitudinal axis expansion velocities provides a clinically useful distinction between constrictive pericarditis and Restrictive Cardiomyopathy and may prove to be valuable in the study of diastolic function.

James B Seward - One of the best experts on this subject based on the ideXlab platform.

  • comparison of usefulness of tissue doppler imaging versus brain natriuretic peptide for differentiation of constrictive pericardial disease from Restrictive Cardiomyopathy
    American Journal of Cardiology, 2008
    Co-Authors: Partho P Sengupta, Vijay K Krishnamoorthy, Josef Korinek, Krishnaswamy Chandrasekaran, Walter P. Abhayaratna, Marek Belohlavek, Jamil A Tajik, James B Seward, Thoralf M Sundt, Bijoy K Khandheria
    Abstract:

    Brain (B-type) natriuretic peptide (BNP) and tissue Doppler imaging may distinguish Restrictive Cardiomyopathy (RCMP) from idiopathic constrictive pericardial disease (CP). However, their comparative efficacy is unknown for patients with CP from secondary causes (e.g., surgery or radiotherapy). We compared the efficacy of tissue Doppler imaging and BNP for differentiation of RCMP (n = 15) and CP (n = 16). BNP was higher in patients with RCMP than CP (p = 0.008), but the groups overlapped, particularly for BNP

  • disparate patterns of left ventricular mechanics differentiate constrictive pericarditis from Restrictive Cardiomyopathy
    Jacc-cardiovascular Imaging, 2008
    Co-Authors: Partho P Sengupta, Vijay K Krishnamoorthy, Josef Korinek, Krishnaswamy Chandrasekaran, Walter P. Abhayaratna, Marek Belohlavek, James B Seward, Thoralf M Sundt, Farouk Mookadam, Jamil A Tajik
    Abstract:

    Objectives The purpose of this study was to compare the longitudinal, circumferential, and radial mechanics of the left ventricle (LV) in patients with constrictive pericarditis (CP) and Restrictive Cardiomyopathy (RCM). Background Diastolic dysfunction in CP is related to epicardial tethering and pericardial constraint, whereas in RCM it is predominantly characterized by subendocardial dysfunction. Assessment of variations in longitudinal and circumferential deformation of LV might be useful to distinguish these 2 conditions. Methods Longitudinal, radial, and circumferential mechanics of the LV were quantified by 2-dimensional speckle tracking of B-mode cardiac ultrasound images in 26 patients with CP, 19 patients with RCM, and 21 control subjects. Results In comparison with control subjects, patients with CP had significantly reduced circumferential strain (base; −16 ± 6% vs. −9 ± 6%; p Conclusions Deformation of the LV is constrained in the circumferential direction in CP and in the longitudinal direction in RCM. Subsequent early diastolic recoil of LV is also attenuated in each of the 2 directions, respectively, uniquely differentiating the abnormal diastolic restoration mechanics of the LV seen in CP and RCM.

  • differentiation of constrictive pericarditis from Restrictive Cardiomyopathy using mitral annular velocity by tissue doppler echocardiography
    American Journal of Cardiology, 2004
    Co-Authors: Jongwon Ha, Steve R Ommen, Jamil A Tajik, Marion E Barnes, Naser M Ammash, Morie A Gertz, James B Seward, Jae K Oh
    Abstract:

    Abstract This study evaluated the diagnostic role of early diastolic mitral annular velocity (E′) by tissue Doppler echocardiography for differentiating constrictive pericarditis from Restrictive Cardiomyopathy (primary Restrictive Cardiomyopathy and cardiac amyloidosis). The study group consisted of 75 patients (53 men, 22 women; mean age 62 years, range 27 to 87). Of these, 23 patients had surgically confirmed constrictive pericarditis, 38 had biopsy-proved systemic amyloidosis and typical echocardiographic features of cardiac involvement, and 14 had primary Restrictive Cardiomyopathy. Standard mitral inflow characteristics were measured. Tissue Doppler echocardiography was used to measure E′ at the septal annulus. E′ was significantly higher in patients with constrictive pericarditis than in those with primary Restrictive Cardiomyopathy or cardiac amyloidosis (12.3 vs 5.1 cm/second, p

  • differentiation of constrictive pericarditis from Restrictive Cardiomyopathy using mitral annular velocity by tissue doppler echocardiography
    American Journal of Cardiology, 2004
    Co-Authors: Steve R Ommen, Jamil A Tajik, Marion E Barnes, Naser M Ammash, Morie A Gertz, James B Seward
    Abstract:

    This study evaluated the diagnostic role of early diastolic mitral annular velocity (E') by tissue Doppler echocardiography for differentiating constrictive pericarditis from Restrictive Cardiomyopathy (primary Restrictive Cardiomyopathy and cardiac amyloidosis). The study group consisted of 75 patients (53 men, 22 women; mean age 62 years, range 27 to 87). Of these, 23 patients had surgically confirmed constrictive pericarditis, 38 had biopsy-proved systemic amyloidosis and typical echocardiographic features of cardiac involvement, and 14 had primary Restrictive Cardiomyopathy. Standard mitral inflow characteristics were measured. Tissue Doppler echocardiography was used to measure E' at the septal annulus. E' was significantly higher in patients with constrictive pericarditis than in those with primary Restrictive Cardiomyopathy or cardiac amyloidosis (12.3 vs 5.1 cm/second, p or =8 cm/second resulted in 95% sensitivity and 96% specificity for the diagnosis of constrictive pericarditis. There was no overlap of E' between patients who had constrictive pericarditis and those who had cardiac amyloidosis. In a subgroup analysis of Restrictive Cardiomyopathy, E' of patients who had cardiac amyloidosis was significantly lower than that of patients who had primary Restrictive Cardiomyopathy (4.6 vs 6.3 cm/second, p <0.001). Thus, E' velocity can distinguish between constrictive pericarditis and Restrictive Cardiomyopathy with a specific cut-off value in patients with clinical and echocardiographic evidence of diastolic heart failure.

  • clinical profile and outcome of idiopathic Restrictive Cardiomyopathy
    Circulation, 2000
    Co-Authors: Naser M Ammash, James B Seward, Kent R Bailey, William D Edwards, Jamil A Tajik
    Abstract:

    Background—Idiopathic Restrictive Cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function. Methods and Results—Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic Restrictive Cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years’ duration, or cardiac or systemic conditions associated with Restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actu...

Partho P Sengupta - One of the best experts on this subject based on the ideXlab platform.

  • new cardiac imaging algorithms to diagnose constrictive pericarditis versus Restrictive Cardiomyopathy
    Current Cardiology Reports, 2017
    Co-Authors: Ahmad Mahmoud, Manish Bansal, Partho P Sengupta
    Abstract:

    Echocardiography is the mainstay in the diagnostic evaluation of constrictive pericarditis (CP) and Restrictive Cardiomyopathy (RCM), but no single echocardiographic parameter is sufficiently robust to accurately distinguish between the two conditions. The present review summarizes the recent advances in echocardiography that promise to improve its diagnostic performance for this purpose. The role of other imaging modalities such as cardiac computed tomography, magnetic resonance imaging, and invasive hemodynamic assessment in the overall diagnostic approach is also discussed briefly. A recent study has demonstrated improved diagnostic accuracy of echocardiography with integration of multiple conventional echocardiographic parameters in to a step-wise algorithm. Concurrently, the studies using speckle-tracking echocardiography have revealed distinct and disparate patterns of myocardial mechanical abnormalities in CP and RCM with their ability to distinguish between the two conditions. The incorporation of machine-learning algorithms into echocardiography workflow permits easy integration of the wealth of the diagnostic data available and promises to further enhance the diagnostic accuracy of echocardiography. New imaging algorithms are continuously being evolved to permit accurate distinction between CP and RCM. Further research is needed to validate the accuracy of these newer algorithms and to define their place in the overall diagnostic approach for this purpose.

  • cognitive machine learning algorithm for cardiac imaging a pilot study for differentiating constrictive pericarditis from Restrictive Cardiomyopathy
    Circulation-cardiovascular Imaging, 2016
    Co-Authors: Partho P Sengupta, Yenmin Huang, Manish Bansal, Ali Ashrafi, Matt Fisher, Khader Shameer, Walt Gall, Joel T Dudley
    Abstract:

    Background— Associating a patient’s profile with the memories of prototypical patients built through previous repeat clinical experience is a key process in clinical judgment. We hypothesized that a similar process using a cognitive computing tool would be well suited for learning and recalling multidimensional attributes of speckle tracking echocardiography data sets derived from patients with known constrictive pericarditis and Restrictive Cardiomyopathy. Methods and Results— Clinical and echocardiographic data of 50 patients with constrictive pericarditis and 44 with Restrictive Cardiomyopathy were used for developing an associative memory classifier–based machine-learning algorithm. The speckle tracking echocardiography data were normalized in reference to 47 controls with no structural heart disease, and the diagnostic area under the receiver operating characteristic curve of the associative memory classifier was evaluated for differentiating constrictive pericarditis from Restrictive Cardiomyopathy. Using only speckle tracking echocardiography variables, associative memory classifier achieved a diagnostic area under the curve of 89.2%, which improved to 96.2% with addition of 4 echocardiographic variables. In comparison, the area under the curve of early diastolic mitral annular velocity and left ventricular longitudinal strain were 82.1% and 63.7%, respectively. Furthermore, the associative memory classifier demonstrated greater accuracy and shorter learning curves than other machine-learning approaches, with accuracy asymptotically approaching 90% after a training fraction of 0.3 and remaining flat at higher training fractions. Conclusions— This study demonstrates feasibility of a cognitive machine-learning approach for learning and recalling patterns observed during echocardiographic evaluations. Incorporation of machine-learning algorithms in cardiac imaging may aid standardized assessments and support the quality of interpretations, particularly for novice readers with limited experience.

  • diagnostic concordance of echocardiography and cardiac magnetic resonance based tissue tracking for differentiating constrictive pericarditis from Restrictive Cardiomyopathy
    Circulation-cardiovascular Imaging, 2014
    Co-Authors: Makoto Amaki, John Savino, David L Ain, Javier Sanz, Gianni Pedrizzetti, Hemant Kulkarni, Jagat Narula, Partho P Sengupta
    Abstract:

    Background—Variations in longitudinal deformation of the left ventricle have been suggested to be useful for differentiating chronic constrictive pericarditis (CP) and Restrictive Cardiomyopathy (R...

  • comparison of usefulness of tissue doppler imaging versus brain natriuretic peptide for differentiation of constrictive pericardial disease from Restrictive Cardiomyopathy
    American Journal of Cardiology, 2008
    Co-Authors: Partho P Sengupta, Vijay K Krishnamoorthy, Josef Korinek, Krishnaswamy Chandrasekaran, Walter P. Abhayaratna, Marek Belohlavek, Jamil A Tajik, James B Seward, Thoralf M Sundt, Bijoy K Khandheria
    Abstract:

    Brain (B-type) natriuretic peptide (BNP) and tissue Doppler imaging may distinguish Restrictive Cardiomyopathy (RCMP) from idiopathic constrictive pericardial disease (CP). However, their comparative efficacy is unknown for patients with CP from secondary causes (e.g., surgery or radiotherapy). We compared the efficacy of tissue Doppler imaging and BNP for differentiation of RCMP (n = 15) and CP (n = 16). BNP was higher in patients with RCMP than CP (p = 0.008), but the groups overlapped, particularly for BNP

  • disparate patterns of left ventricular mechanics differentiate constrictive pericarditis from Restrictive Cardiomyopathy
    Jacc-cardiovascular Imaging, 2008
    Co-Authors: Partho P Sengupta, Vijay K Krishnamoorthy, Josef Korinek, Krishnaswamy Chandrasekaran, Walter P. Abhayaratna, Marek Belohlavek, James B Seward, Thoralf M Sundt, Farouk Mookadam, Jamil A Tajik
    Abstract:

    Objectives The purpose of this study was to compare the longitudinal, circumferential, and radial mechanics of the left ventricle (LV) in patients with constrictive pericarditis (CP) and Restrictive Cardiomyopathy (RCM). Background Diastolic dysfunction in CP is related to epicardial tethering and pericardial constraint, whereas in RCM it is predominantly characterized by subendocardial dysfunction. Assessment of variations in longitudinal and circumferential deformation of LV might be useful to distinguish these 2 conditions. Methods Longitudinal, radial, and circumferential mechanics of the LV were quantified by 2-dimensional speckle tracking of B-mode cardiac ultrasound images in 26 patients with CP, 19 patients with RCM, and 21 control subjects. Results In comparison with control subjects, patients with CP had significantly reduced circumferential strain (base; −16 ± 6% vs. −9 ± 6%; p Conclusions Deformation of the LV is constrained in the circumferential direction in CP and in the longitudinal direction in RCM. Subsequent early diastolic recoil of LV is also attenuated in each of the 2 directions, respectively, uniquely differentiating the abnormal diastolic restoration mechanics of the LV seen in CP and RCM.

Nikita Sinha - One of the best experts on this subject based on the ideXlab platform.

  • allele specific silencing ameliorates Restrictive Cardiomyopathy attributable to a human myosin regulatory light chain mutation
    Circulation, 2019
    Co-Authors: Kathia Zaletarivera, Alexandra Dainis, Alexandre J S Ribeiro, Gabriel Rubio, Ching Shang, Thomas Finsterbach, Pablo Cordero, Victoria N Parikh, Shirley Sutton, Nikita Sinha
    Abstract:

    Background: Restrictive Cardiomyopathy is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic Cardiomyopathy. There is no approved thera...

  • allele specific silencing ameliorates Restrictive Cardiomyopathy due to a human myosin regulatory light chain mutation
    bioRxiv, 2019
    Co-Authors: Kathia Zaleta, Alexandra Dainis, Alexandre J S Ribeiro, Pablo Sanchezcordero, Gabriel Rubio, Ching Shang, Thomas Finsterbach, Nikita Sinha, Nikhil A Jain, Roger J Hajjar
    Abstract:

    Background: Restrictive Cardiomyopathy (RCM) is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic Cardiomyopathy. There is no approved therapy. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of Restrictive Cardiomyopathy in a mouse model. Methods: AAV9-M7.8L shRNA was selected from a pool of RNAi oligonucleotides containing the SNV in different positions to specifically target the mutated allele causative of RCM by FACS screening. Two groups of RLC-N47K transgenic mice were injected with a single dose of AAV9-M7.8L shRNA at 3 days of age and at 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine VO2max and left ventricular mass. At the end of treatment, heart, lung, liver and kidney tissue was harvested to determine viral tropism and for transcriptome and proteomic analysis. Cardiomyocytes were isolated for single cell studies. Results: One time injection of AAV9-M7.8L RNAi in 3-day-old humanized RLC mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed 16 weeks post-injection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight and attenuated a pathological increase in left ventricular mass (LVM). Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of the maximal contraction velocity with marked reduction in hypercontractility as well as relaxation kinetics and improved time to maximal calcium reuptake velocity. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II (CAMKII) and the transcription activator Brg1 were reduced suggesting recovery towards a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts while endogenous microRNAs were preserved suggesting the RNAi pathway was not saturated. Conclusions: Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed at human Restrictive Cardiomyopathy. This is a promising step towards targeted therapy for a prevalent human disease.

  • allele specific silencing ameliorates Restrictive Cardiomyopathy due to a human myosin regulatory light chain mutation
    bioRxiv, 2019
    Co-Authors: Kathia Zaletarivera, Alexandra Dainis, Alexandre J S Ribeiro, Pablo Sanchezcordero, Gabriel Rubio, Ching Shang, Thomas Finsterbach, Nikita Sinha, Jing Liu, Nikhil A Jain
    Abstract:

    Abstract Background Restrictive Cardiomyopathy (RCM) is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic Cardiomyopathy. There is no approved therapy. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of Restrictive Cardiomyopathy in a mouse model. Methods AAV9-M7.8L shRNA was selected from a pool of RNAi oligonucleotides containing the SNV in different positions to specifically target the mutated allele causative of RCM by FACS screening. Two groups of RLC-N47K transgenic mice were injected with a single dose of AAV9-M7.8L shRNA at 3 days of age and at 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine VO2max and left ventricular mass. At the end of treatment, heart, lung, liver and kidney tissue was harvested to determine viral tropism and for transcriptome and proteomic analysis. Cardiomyocytes were isolated for single cell studies. Results One time injection of AAV9-M7.8L RNAi in 3-day-old humanized RLC mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed 16 weeks post-injection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight and attenuated a pathological increase in left ventricular mass (LVM). Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of the maximal contraction velocity with marked reduction in hypercontractility as well as relaxation kinetics and improved time to maximal calcium reuptake velocity. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II (CAMKII) and the transcription activator Brg1 were reduced suggesting recovery towards a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts while endogenous microRNAs were preserved suggesting the RNAi pathway was not saturated. Conclusions Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed at human Restrictive Cardiomyopathy. This is a promising step towards targeted therapy for a prevalent human disease. Clinical Perspective What is new? Restrictive Cardiomyopathy due to a mutation of human MYL2 modeled in cells and mice can be treated with RNA interference Reduction of disease-causing allele improves function at the cellular and organ level Off target effects evaluated and not found to be significant What are the clinical implications? Allele-specific RNA silencing of human alleles may be effective in treating inherited Restrictive Cardiomyopathy RNA therapies targeting individual mutations may need to be developed prior to consideration of clinical translation