Assessment of Diastolic Function With Doppler Tissue Imaging to Predict Genotype in Preclinical Hypertrophic Cardiomyopathy

Ho, Carolyn Y.; Sweitzer, Nancy K.; McDonough, Barbara; Maron, Barry J.; Casey, Susan A.; Seidman, J. G.; Seidman, Christine E.; Solomon, Scott D.

doi:10.1161/01.cir.0000019070.70491.6d

Cited by 377 publications

(245 citation statements)

References 33 publications

(33 reference statements)

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“…Instead, we suggest that there is insidious proliferation of non-myocyte cells in untreated HCM mice and human patients. Moreover, transcriptional profiling of non-myocyte cells indicated that proliferation was coupled to increased expression of profibrotic molecules (including collagens, periostin, elastin; Supplemental Table 2), a sequence that could readily expand the extracellular matrix in HCM hearts ( Figure 6) and contribute to the progressive diminution of diastolic function observed in human HCM (44). Our studies did not address whether resident or newly recruited cells become activated in HCM.…”

Section: Discussionmentioning

confidence: 90%

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Teekakirikul¹,

Eminaga²,

Toka³

et al. 2010

J. Clin. Invest.

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Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophynegative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce nonmyocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.

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Section: Discussionmentioning

confidence: 90%

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Teekakirikul¹,

Eminaga²,

Toka³

et al. 2010

J. Clin. Invest.

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404

342

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“…For example, several studies have evaluated the presence or absence of rejection after heart transplantation using TDI [91,92]. Several studies have evaluated abnormalities in myocardial structure in patients with hypertrophic cardiomyopathy, amyloidosis, or Friedreich's ataxia [93][94][95][96] (Figure 7). One study investigated the relationship between ß-adrenergic receptor density and TDI variables in patients with ischemic heart disease [97].…”

Section: Future Directionsmentioning

confidence: 99%

The Role of Tissue Doppler Imaging as a New Diagnostic Option in Evaluating Left Ventricular Function

Oki

2003

J Echocardiogr

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In general, pump function and myocardial contractility should be assessed when evaluating left ventricular (LV) systolic function. Ejection fraction obtained from left ventriculography is routinely used as an index of pump function, and the maximum value of the first derivative of LV pressure curve (peak dP/dt) has been used as an index of myocardial contractility. On the other hand, active relaxation of the LV myocardium during early diastole and LV passive filling or compliance during mid-to late diastole are important factors in evaluating LV diastolic function. To obtain this information, the time constant of the LV pressure decay during isovolumic diastole (tau) and LV end-diastolic pressure, which are calculated from the LV pressure curve recorded during cardiac catheterization, is used. However, invasive hemodynamic measurements cannot be performed in all patients, nor are they appropriate for follow-up evaluation involving repeated examinations.Recently, routine echocardiography has facilitated the noninvasive evaluation of LV systolic and diastolic function. The percent fractional shortening of the LV based on M-mode echocardiography and the LV ejection fraction determined by two-dimensional echocardiography are indices of LV pump function, and therefore cannot accurately evaluate LV myocardial contractility. On the other hand, "diastology" has become an important clinical topic [1]. There are several reasons why assessment of diastolic function is important: 1) 30 to 40% of patients evaluated for congestive heart failure have normal LV pump function [2,3]; 2) the transmitral flow velocity pattern, which is recorded using the pulsed Doppler method, may be an index for noninvasive evaluation of LV diastolic function [4]; and 3) the prognosis is poor in patients with LV systolic dysfunction and pseudonormalization or restrictive pattern of the transmitral flow velocity [5,6]. However, it has been shown that the diastolic indices obtained from transmitral and pulmonary venous flow velocities are influenced by loading conditions, especially by the pre- The Role of Tissue Doppler Imaging as a New Diagnostic Option in Evaluating Left AbstractThe widespread use of the pulsed Doppler echocardiography has facilitated the noninvasive evaluation of hemodynamic abnormalities of the left atrium and left ventricle (LV) based on transmitral and pulmonary venous flow velocity patterns. However, it has been shown that loading conditions, especially preload, influence the indices obtained from these velocity patterns. Recently, tissue Doppler imaging (TDI) has been applied to the clinical setting to assess LV myocardial function. In particular, this procedure has the following characteristics: 1) it can provide circumferential and longitudinal information for the LV myocardium; 2) the early diastolic LV myocardial parameters determined by TDI are not influenced by preload; 3) LV myocardial contractility can be evaluated from the early systolic parameters; 4) LV systolic and diastolic asynchrony can be detected; 5) myoca...

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“…Phenotypically, HCM is characterized by varying degrees of cardiac remodeling that ultimately leads to asymmetrical thickening of the left ventricular wall and can potentially cause sudden cardiac death 1, 2. At the whole heart level, HCM is characterized by hypercontractility, as indicated by an increased left ventricular ejection fraction3 and power output,4 and also diastolic dysfunction 5, 6. At the myofilament level, HCM‐related hypercontractility is often linked to enhanced sensitivity of the contractile apparatus to Ca 2+ ,7, 8 and accelerated rates of cross‐bridge (XB) cycling 9…”

Section: Introductionmentioning

confidence: 99%

“…Missense mutations in human cardiac β‐MHC result in variable effects on contractile function including reduced13, 14 or enhanced intrinsic force generation15, 16; decreased14, 16 or enhanced15 myosin ATPase activity; and accelerated13, 15, 17 or slowed16 actin sliding velocities. Importantly, recent data show that HCM‐causing mutations in β‐MHC that cause hypercontractility weaken myosin's S1‐S2 intradomain interactions, thus effectively increasing the total number of myosin heads that can interact with actin during systole,11 thereby chronically elevating left ventricular ejection fraction 5, 18. Thus, recent studies have attempted to normalize HCM‐related hypercontractility by directly targeting the myosin motor rather than using β‐blockers and calmodulin antagonists, which may trigger the activation of unwanted signaling pathways 19, 20.…”

Section: Introductionmentioning

confidence: 99%

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Mamidi

Doh

et al. 2018

JAHA

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BackgroundRecent studies suggest that mavacamten (Myk461), a small myosin‐binding molecule, decreases hypercontractility in myocardium expressing hypertrophic cardiomyopathy‐causing missense mutations in myosin heavy chain. However, the predominant feature of most mutations in cardiac myosin binding protein‐C (cMyBPC) that cause hypertrophic cardiomyopathy is reduced total cMyBPC expression, and the impact of Myk461 on cMyBPC‐deficient myocardium is currently unknown.Methods and ResultsWe measured the impact of Myk461 on steady‐state and dynamic cross‐bridge (XB) behavior in detergent‐skinned mouse wild‐type myocardium and myocardium lacking cMyBPC (knockout (KO)). KO myocardium exhibited hypercontractile XB behavior as indicated by significant accelerations in rates of XB detachment (krel) and recruitment (kdf) at submaximal Ca2+ activations. Incubation of KO and wild‐type myocardium with Myk461 resulted in a dose‐dependent force depression, and this impact was more pronounced at low Ca2+ activations. Interestingly, Myk461‐induced force depressions were less pronounced in KO myocardium, especially at low Ca2+ activations, which may be because of increased acto‐myosin XB formation and potential disruption of super‐relaxed XBs in KO myocardium. Additionally, Myk461 slowed krel in KO myocardium but not in wild‐type myocardium, indicating increased XB “on” time. Furthermore, the greater degree of Myk461‐induced slowing in kdf and reduction in XB recruitment magnitude in KO myocardium normalized the XB behavior back to wild‐type levels.ConclusionsThis is the first study to demonstrate that Myk461‐induced force depressions are modulated by cMyBPC expression levels in the sarcomere, and emphasizes that clinical use of Myk461 may need to be optimized based on the molecular trigger that underlies the hypertrophic cardiomyopathy phenotype.

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Assessment of Diastolic Function With Doppler Tissue Imaging to Predict Genotype in Preclinical Hypertrophic Cardiomyopathy

Cited by 377 publications

References 33 publications

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

The Role of Tissue Doppler Imaging as a New Diagnostic Option in Evaluating Left Ventricular Function

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

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