Professional Education

  • Doctor of Philosophy, Kyoto University (2017)
  • PhD, Kyoto University, Cardiovascular Medicine (2017)
  • DVM, Tokyo University of Agriculture and Technology, Veterinary Medicine (2013)

Stanford Advisors

All Publications

  • Electrophysiological Analysis of hiPSC-Derived Cardiomyocytes Using a Patch-Clamp Technique. Methods in molecular biology (Clifton, N.J.) Yamamoto, Y., Hirose, S., Wuriyanghai, Y., Yoshinaga, D., Makiyama, T. 2021; 2320: 121-133


    Electrophysiological analysis of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using a patch-clamp technique enables the most precise evaluation of electrophysiological properties in single cells. Compared to multielectrode array (MEA) and membrane voltage imaging, patch-clamp recordings offer quantitative measurements of action potentials, and the relevant ionic currents which are essential for the research of disease modeling of inherited arrhythmias, safety pharmacology, and drug discovery using hiPSC-CMs. In this chapter, we describe the detail flow of patch-clamp recordings in hiPSC-CMs.

    View details for DOI 10.1007/978-1-0716-1484-6_13

    View details for PubMedID 34302654

  • Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation HUMAN MOLECULAR GENETICS Yamamoto, Y., Makiyama, T., Harita, T., Sasaki, K., Wuriyanghai, Y., Hayano, M., Nishiuchi, S., Kohjitani, H., Hirose, S., Chen, J., Yokoi, F., Ishikawa, T., Ohno, S., Chonabayashi, K., Motomura, H., Yoshida, Y., Horie, M., Makita, N., Kimura, T. 2017; 26 (9): 1670-1677


    Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3. Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15. We generated LQT15-hiPSCs from a 12-year-old boy with LQTS carrying a CALM2-N98S mutation and differentiated these hiPSCs into cardiomyocytes (LQT15-hiPSC-CMs). Action potentials (APs) and L-type Ca2+ channel (LTCC) currents in hiPSC-CMs were analyzed by the patch-clamp technique and compared with those of healthy controls. Furthermore, we performed mutant allele-specific knockout using a CRISPR-Cas9 system and analyzed electrophysiological properties. Electrophysiological analyses revealed that LQT15-hiPSC-CMs exhibited significantly lower beating rates, prolonged AP durations, and impaired inactivation of LTCC currents compared with control cells, consistent with clinical phenotypes. Notably, ablation of the mutant allele rescued the electrophysiological abnormalities of LQT15-hiPSC-CMs, indicating that the mutant allele caused dominant-negative suppression of LTCC inactivation, resulting in prolonged AP duration. We successfully recapitulated the disease phenotypes of LQT15 and revealed that inactivation of LTCC currents was impaired in CALM2-N98S hiPSC model. Additionally, allele-specific ablation using the latest genome-editing technology provided important insights into a promising therapeutic approach for inherited cardiac diseases.

    View details for DOI 10.1093/hmg/ddx073

    View details for Web of Science ID 000400912200007

    View details for PubMedID 28335032

  • Effects of a Sustained-Release Form of Isosorbide Dinitrate on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation JOURNAL OF VETERINARY INTERNAL MEDICINE Yamamoto, Y., Suzuki, S., Hamabe, L., Aytemiz, D., Huai-Che, H., Kim, S., Yoshiyuki, R., Fukayama, T., Fukushima, R., Tanaka, R. 2013; 27 (6): 1421-1426


    The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR).The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR.Six healthy Beagles weighing 11.2 ± 2.2 kg (2 years of age; 2 males and 4 females) were used.Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration.LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001).Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

    View details for DOI 10.1111/jvim.12184

    View details for Web of Science ID 000326972600017

    View details for PubMedID 24010635

  • Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Hirose, S., Makiyama, T., Melgari, D., Yamamoto, Y., Wuriyanghai, Y., Yokoi, F., Nishiuchi, S., Harita, T., Hayano, M., Kohjitani, H., Gao, J., Kashiwa, A., Nishikawa, M., Wu, J., Yoshimoto, J., Chonabayashi, K., Ohno, S., Yoshida, Y., Horie, M., Kimura, T. 2020; 8: 761


    Long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the SCN5A gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of β-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that β-blocker therapy reduced the risk of life-threatening cardiac events in female patients; however, the detailed mechanism of action remains unclear.This study aimed to establish LQT3-human induced pluripotent stem cells (hiPSCs) and to investigate the effect of propranolol in this model.An hiPSCs cell line was established from peripheral blood mononuclear cells of a boy with LQT3 carrying the SCN5A-N1774D mutation. He had suffered from repetitive torsades de pointes (TdPs) with QT prolongation since birth (QTc 680 ms), which were effectively treated with propranolol, as it suppressed lethal arrhythmias. Furthermore, hiPSCs were differentiated into cardiomyocytes (CMs), on which electrophysiological functional assays were performed using the patch-clamp method.N1774D-hiPSC-CMs exhibited significantly prolonged action potential durations (APDs) in comparison to those of the control cells (N1774D: 440 ± 37 ms vs. control: 272 ± 22 ms; at 1 Hz pacing; p < 0.01). Furthermore, N1774D-hiPSC-CMs presented gain-of-function features: a hyperpolarized shift of steady-state activation and increased late sodium current compared to those of the control cells. 5 μM propranolol shortened APDs and inhibited late sodium current in N1774D-hiPSC-CMs, but did not significantly affect in the control cells. In addition, even in the presence of intrapipette guanosine diphosphate βs (GDPβs), an inhibitor of G proteins, propranolol reduced late sodium current in N1774D cells. Therefore, these results suggested a unique inhibitory effect of propranolol on late sodium current unrelated to β-adrenergic receptor block in N1774D-hiPSC-CMs.We successfully recapitulated the clinical phenotype of LQT3 using patient-derived hiPSC-CMs and determined that the mechanism, by which propranolol inhibited the late sodium current, was independent of β-adrenergic receptor signaling pathway.

    View details for DOI 10.3389/fcell.2020.00761

    View details for Web of Science ID 000566255400001

    View details for PubMedID 32903469

    View details for PubMedCentralID PMC7438478

  • Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells STEM CELL REPORTS Yoshinaga, D., Baba, S., Makiyama, T., Shibata, H., Hirata, T., Akagi, K., Matsuda, K., Kohjitani, I., Wuriyanghai, Y., Umeda, K., Yamamoto, Y., Conklin, B. R., Horie, M., Takita, J., Heike, T. 2019; 13 (2): 394-404


    For long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients.

    View details for DOI 10.1016/j.stemcr.2019.06.007

    View details for Web of Science ID 000481410000013

    View details for PubMedID 31378668

    View details for PubMedCentralID PMC6700479

  • Clinical Manifestations and Long-Term Mortality in Lamin A/C Mutation Carriers From a Japanese Multicenter Registry CIRCULATION JOURNAL Nakajima, K., Aiba, T., Makiyama, T., Nishiuchi, S., Ohno, S., Kato, K., Yamamoto, Y., Doi, T., Shizuta, S., Onoue, K., Yagihara, N., Ishikawa, T., Watanabe, I., Kawakami, H., Oginosawa, Y., Murakoshi, N., Nogami, A., Aonuma, K., Saito, Y., Kimura, T., Yasuda, S., Makita, N., Shimizu, W., Horie, M., Kusano, K. 2018; 82 (11): 2707-+


    Mutation in the lamin A/C gene (LMNA) is associated with several cardiac phenotypes, such as cardiac conduction disorders (CCD), atrial arrhythmia (AA), malignant ventricular arrhythmia (MVA) and left ventricular dysfunction (LVD), leading to sudden cardiac death (SCD) and/or end-stage heart failure. We investigated how these phenotypes are associated with each other and which of them are most important for total mortality. Methods and Results: A multicenter registry included 110 LMNA mutation carriers (age, 43±15 years, male: 62%) from 60 families. After genetic diagnosis of LMNA mutation (missense: 27%, non-missense: 73%), patients or subjects were followed to evaluate the manifestations of their phenotypes and the risk of total mortality; 90 patients could be followed (median: 5 [0-35] years). Prevalence of the 4 clinical phenotypes was significantly increased during follow-up. Among these phenotypes, AA was significantly associated with MVA. CCD was significantly associated with LVD. LVD, meanwhile, was significantly associated with CCD and MVA. Male sex was significantly associated with MVA. Furthermore, during follow-up, 17 patients died: 12 end-stage heart failure, 4 SCD and 1 stroke. LVD was the only independent predictor for all-cause death (OR: 41.7, 95% CI: 4.1-422.3; P=0.0016).Several cardiac phenotypes were age-dependently increased in LMNA mutation carriers, suggesting that ICD or CRT-D could suppress SCD after middle age; however, LVD leading to end-stage heart failure was the only independent predictor for total mortality.

    View details for DOI 10.1253/circj.CJ-18-0339

    View details for Web of Science ID 000450971300006

    View details for PubMedID 30078822

  • Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation HEART RHYTHM Wuriyanghai, Y., Makiyama, T., Sasaki, K., Kamakura, T., Yamamoto, Y., Hayano, M., Harita, T., Nishiuchi, S., Chen, J., Kohjitani, H., Hirose, S., Yokoi, F., Gao, J., Chonabayashi, K., Watanabe, K., Ohno, S., Yoshida, Y., Kimura, T., Horie, M. 2018; 15 (10): 1566-1574


    Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α subunit of the slow delayed rectifier potassium current channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl, in KCNQ1 is most commonly identified in genotyped patients with LQT1 in Japan and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remain unclear.The purpose of this study was to establish and analyze patient-specific human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl.We generated hiPSCs from the peripheral blood mononuclear cells obtained from a patient with LQT1 carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiology studies.We identified 7 aberrant RNA variants in A344Aspl hiPSC-CMs, which were more complex compared with those in peripheral lymphocytes. Multielectrode array analysis revealed that 1 μM isoproterenol significantly prolonged the duration of the corrected field potential in A344Aspl hiPSC-CMs as compared with that in control hiPSC-CMs. In addition, 100 nM E-4031, which inhibits the rapid component of the delayed rectifier potassium current, was shown to induce early afterdepolarization-like waveforms in A344Aspl hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administering 500 nM isoproterenol, APDs of A344Aspl hiPSC-CMs were significantly longer than those of the controls. (R)-N-(4-(4-Methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide and phenylboronic acid, slow delayed rectifier potassium current activators, ameliorated the APDs of hiPSC-CMs.We identified complex aberrant messenger RNA variants in the A344Aspl hiPSC-CM model and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies.

    View details for DOI 10.1016/j.hrthm.2018.05.028

    View details for Web of Science ID 000445914700028

    View details for PubMedID 29857160

  • Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers CIRCULATION-CARDIOVASCULAR GENETICS Nishiuchi, S., Makiyama, T., Aiba, T., Nakajima, K., Hirose, S., Kohjitani, H., Yamamoto, Y., Harita, T., Hayano, M., Wuriyanghai, Y., Chen, J., Sasaki, K., Yagihara, N., Ishikawa, T., Onoue, K., Murakoshi, N., Watanabe, I., Ohkubo, K., Watanabe, H., Ohno, S., Doi, T., Shizuta, S., Minamino, T., Saito, Y., Oginosawa, Y., Nogami, A., Aonuma, K., Kusano, K., Makita, N., Shimizu, W., Horie, M., Kimura, T. 2017; 10 (6)


    Mutations in LMNA (lamin A/C), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored.The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end-stage heart failure (n=7) or suddenly (n=2). Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses.The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA-related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.

    View details for DOI 10.1161/CIRCGENETICS.116.001603

    View details for Web of Science ID 000418461400005

    View details for PubMedID 29237675

  • Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy CIRCULATION JOURNAL Hayano, M., Makiyama, T., Kamakura, T., Watanabe, H., Sasaki, K., Funakoshi, S., Wuriyanghai, Y., Nishiuchi, S., Harita, T., Yamamoto, Y., Kohjitani, H., Hirose, S., Yokoi, F., Chen, J., Baba, O., Horie, T., Chonabayashi, K., Ohno, S., Toyoda, F., Yoshida, Y., Ono, K., Horie, M., Kimura, T. 2017; 81 (12): 1783-+


    TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5.This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.

    View details for DOI 10.1253/circj.CJ-17-0064

    View details for Web of Science ID 000416524000009

    View details for PubMedID 28637969

  • Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia PLOS ONE Sasaki, K., Makiyama, T., Yoshida, Y., Wuriyanghai, Y., Kamakura, T., Nishiuchi, S., Hayano, M., Harita, T., Yamamoto, Y., Kohjitani, H., Hirose, S., Chen, J., Kawamura, M., Ohno, S., Itoh, H., Takeuchi, A., Matsuoka, S., Miura, M., Sumitomo, N., Horie, M., Yamanaka, S., Kimura, T. 2016; 11 (10): e0164795


    Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies.We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05).We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.

    View details for DOI 10.1371/journal.pone.0164795

    View details for Web of Science ID 000386204500066

    View details for PubMedID 27764147

    View details for PubMedCentralID PMC5072719

  • Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction HEART RHYTHM Chen, J., Makiyama, T., Wuriyanghai, Y., Ohno, S., Sasaki, K., Hayano, M., Harita, T., Nishiuchi, S., Yamamoto, Y., Ueyama, T., Shimizu, A., Horie, M., Kimura, T. 2016; 13 (1): 289-298


    Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep.The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels.LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system.We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation.We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.

    View details for DOI 10.1016/j.hrthm.2015.08.021

    View details for Web of Science ID 000367394200044

    View details for PubMedID 26282245

  • Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation BMC VETERINARY RESEARCH Suzuki, S., Fukushima, R., Ishikawa, T., Yamamoto, Y., Hamabe, L., Kim, S., Yoshiyuki, R., Machida, N., Tanaka, R. 2012; 8: 166


    One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine's effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration.Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p < .01) but not after benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p < .05) after 7 days compared to baseline. Other echocardiographic parameters did not change significantly.LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS.

    View details for DOI 10.1186/1746-6148-8-166

    View details for Web of Science ID 000311231000001

    View details for PubMedID 22989022

    View details for PubMedCentralID PMC3489586