Apoptosis as a Possible Cause of Wall Thinning in End-Stage Hypertrophic Cardiomyopathy

Ino, Toshihiro; Nishimoto, Kei; Okubo, Mataichi; Akimoto, Katsumi; Yabuta, Keijiro; Kawai, Sachio; Okada, Ryozo; Sueyoshi, Noriyoshi

doi:10.1016/s0002-9149(97)00066-0

Cited by 43 publications

(22 citation statements)

References 10 publications

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“…[1][2][3]18,24,25 A patient subset characterized by clinical progression, and largely known as the ES phase, has been described. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]26,27 Much of the prior literature about ES is, however, confined to isolated or small groups of patients. 4,6 -17 Therefore, we have revisited the ES in a multicenter cohort of Ͼ1200 HCM patients, which included the largest group of ES patients reported to date.…”

Section: Discussionmentioning

confidence: 99%

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

et al. 2006

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Background-End stage (ES) is a recognized part of the hypertrophic cardiomyopathy (HCM) disease spectrum.Frequency, clinical profile and course, and treatment strategies in these patients remain incompletely defined. Methods and Results-Three HCM cohorts comprised 1259 patients, including 44 (3.5%) characterized as ES with systolic dysfunction (ejection fraction Ͻ50% at rest; range 15% to 49%). ES developed at a wide age range (14 to 74 years), with 45% of patients Յ40 years old. Although 29 patients (66%) died of progressive heart failure, had sudden death events, or underwent heart transplantation, 15 (34%) survived with medical management over 3Ϯ3 years. Duration from onset of HCM symptoms to ES identification was considerable (14Ϯ10 years), but ES onset to death/transplantation was brief (2.7Ϯ2 years). ES occurred with similar frequency in patients with or without prior myectomy (Pϭ0.84). Appropriate defibrillator interventions were 10% per year in patients awaiting donor hearts. Most ES patients (nϭ23; 52%) showed substantial left ventricular (LV) remodeling with cavity dilatation. Less complete remodeling occurred in 21 patients (48%), including 5 with persistence of a nondilated and markedly hypertrophied LV. Pathology and magnetic resonance imaging showed extensive (transmural) fibrosis in 9 of 11 ES patients. At initial evaluation, patients who developed ES were younger with more severe symptoms, had a larger LV cavity, and more frequently had a family history of ES than other HCM patients. Conclusions-ES of nonobstructive HCM has an expanded and more diverse clinical expression than previously appreciated, including occurrence in young patients, heterogeneous patterns of remodeling, frequent association with atrial fibrillation, and impaired LV contractility that precedes cavity dilatation, wall thinning, and heart failure symptoms. ES is an unfavorable complication (mortality rate 11% per year) and a sudden death risk factor; it requires vigilance to permit timely recognition and the necessity for defibrillator implantation and heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

et al. 2006

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“…Studying apoptosis in human heart failure, however, has been difficult since data collection is limited to postmortem samples or tissue samples from heart transplant patients. [19][20][21]30,32,35,[37][38][39][40][41][42][43] The use of animal models is therefore an important avenue of inquiry in this field. The ob/ob mouse model proves valuable in providing insight into both apoptosis and cardiac hypertrophy in the context of obesity.…”

Section: Apoptosis and Heart Failurementioning

confidence: 99%

Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Trivedi¹,

Yang²,

Barouch³

2008

Cell Cycle

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Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110α) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110α catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.

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“…In fact, it was previously reported that apoptotic cardiac myocytes were identified with mononuclear cell infiltra-Vol 46 No 2 tion at the border between the fibrotic and myofibril area of an autopsy heart specimen from a DHCM patient. 8) TNF-α or IL-6, which belong to the proinflammatory cytokines family, can be expressed in the myocardium under various forms of stress and are capable of inducing left ventricular hypertrophy, cardiomyopathy and apoptosis in cardiac myocytes. [25][26][27][28][29][30][31] Furthermore, TNF-α is thought to be intimately involved in the pathogenesis of HCM.…”

Section: Discussionmentioning

confidence: 99%

“…6,7) Furthermore, pathological studies have revealed that cardiac myocyte degeneration with marked fibrosis was observed in a broad area of ventricular myocardium 3) and immunohistochemical evaluation of apoptosis showed apoptotic cells and bodies in the destroyed myocytes along the border between the fibrotic area and myofibrils in DHCM patients. 8) These findings suggest the presence of ongoing apoptotic changes in cardiac myocytes of DHCM.…”

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confidence: 88%

Analysis of Circulating Apoptosis Mediators and Proinflammatory Cytokines in Patients With Idiopathic Hypertrophic Cardiomyopathy Comparison Between Nonobstructive and Dilated-Phase Hypertrophic Cardiomyopathy

et al. 2005

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SUMMARYWe examined the plasma levels of soluble Fas (sFas) or Fas ligand (sFas-L), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in patients with idiopathic nonobstructive (HNCM) and dilated-phase (DHCM) hypertrophic cardiomyopathy.Patients with idiopathic hypertrophic cardiomyopathy (HCM) may deteriorate to DHCM and the pathogenesis is unknown.The levels of these plasma cytokines were measured by ELISA and echocardiography was performed in 38 HNCM and 11 DHCM patients, and 10 normal subjects. The followup period was three years.In HNCM, TNF-α (43.3 ± 45.2 versus 16.9 ± 4.3 pg/mL) and IL-6 (65.1 ± 86.4 versus 4.0 ± 2.1 pg/mL) were slightly higher compared to normal subjects and sFas (3.7 ± 1.2 versus 2.1 ± 0.7 ng/mL) increased significantly. sFas (3.9 ± 1.8), TNF-α (79.3 ± 72.4), and IL-6 (234.1 ± 135.2) in DHCM were significantly increased and only IL-6 was significantly different from HNCM. sFas-L (0.18 ± 0.08 versus 0.25 ± 0.05 ng/mL) in HNCM was significantly decreased, and the decrease was marked in DHCM (0.05 ± 0.02). In HNCM, TNF-α was negatively correlated with fractional shortening (r = -0.432, P = 0.0062) or positively with IL-6 (r = 0.665, P < 0.0001), while sFas-L was negatively correlated with IL-6 (r = -0.580, P < 0.0001). DHCM with high sFas had significantly higher cumulative incidences of worsening heart failure.The Fas/Fas-L system and proinflammatory cytokines may play an important role in the status of HCM and its progression to DHCM. (Int Heart J 2005; 46: 231-244)

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Apoptosis as a Possible Cause of Wall Thinning in End-Stage Hypertrophic Cardiomyopathy

Cited by 43 publications

References 10 publications

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Analysis of Circulating Apoptosis Mediators and Proinflammatory Cytokines in Patients With Idiopathic Hypertrophic Cardiomyopathy Comparison Between Nonobstructive and Dilated-Phase Hypertrophic Cardiomyopathy

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Apoptosis as a Possible Cause of Wall Thinning in End-Stage Hypertrophic Cardiomyopathy

Cited by 43 publications

References 10 publications

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

Prevalence, Clinical Profile, and Significance of Left Ventricular Remodeling in the End-Stage Phase of Hypertrophic Cardiomyopathy

Decreased p110&alpha; catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Analysis of Circulating Apoptosis Mediators and Proinflammatory Cytokines in Patients With Idiopathic Hypertrophic Cardiomyopathy Comparison Between Nonobstructive and Dilated-Phase Hypertrophic Cardiomyopathy

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Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice