Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling. Methods A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV). Results A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling. Conclusions Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia

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Effects of candesartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy

European Heart Journal ◽

10.1093/ehjci/ehaa946.3360 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Maqsood ◽

H.A Shakeel ◽

H.F Shoukat ◽

M.D Khan ◽

S.A.Y Shah ◽

...

Keyword(s):

Late Gadolinium Enhancement ◽

Hypertrophic Cardiomyopathy ◽

Interstitial Fibrosis ◽

Angiotensin Receptor Blockers ◽

Left Ventricular ◽

Funding Source ◽

Gadolinium Enhancement ◽

Percent Change ◽

Lv Mass ◽

Significant Difference

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular (LV) hypertrophy in the absence of pressure overload. Manifestations of the disease include heart failure associated with diastolic dysfunction and atrial and ventricular tachyarrhythmias. Pathological features of HCM include myocyte hypertrophy, interstitial fibrosis, and myocyte disarray and are mediated by angiotensin II. Purpose This study aimed to evaluate the effects of candesartan on left ventricular (LV) hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy (HCM). Methods In double-blind fashion, 30 patients (6 women, 24 men; age: 55±11 years) with HCM were randomly assigned to receive placebo (n=13) or candesartan 50 mg twice a day (n=17) for 1 year. To measure LV mass and extent of fibrosis, cardiac magnetic resonance imaging was performed at baseline and 1 year as assessed by late gadolinium enhancement. Results There was a trend toward a significant difference in the percent change in LV mass (median: +5% with placebo vs. −5% with candesartan; p=0.06). There was a significant difference in the percent change in the extent of late gadolinium enhancement, with the placebo group experiencing a larger increase (+30±27% with placebo vs. −22±44% with candesartan; p=0.03). Conclusion Our study concludes reduction of the progression of myocardial hypertrophy and fibrosis with candesartan in patients with hypertrophic cardiomyopathy. Our study population was limited so we warrant larger trials to confirm a place for angiotensin receptor blockers in the management of patients with hypertrophic cardiomyopathy. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): Self funding

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Assessment of Diastolic Function in Hypertrophic Cardiomyopathy by Computed Tomography–Derived Analysis of Left Ventricular Filling

Journal of Computer Assisted Tomography ◽

10.1097/rct.0000000000000533 ◽

2017 ◽

Vol 41 (3) ◽

pp. 339-343

Author(s):

Itai Ghersin ◽

Eduard Ghersin ◽

Sobhi Abadi ◽

Jennifer E. Runco Therrien ◽

Tanyanan Tanawuttiwat ◽

...

Keyword(s):

Computed Tomography ◽

Hypertrophic Cardiomyopathy ◽

Diastolic Function ◽

Left Ventricular ◽

Left Ventricular Filling ◽

Ventricular Filling

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Doppler Estimation of Left Ventricular Filling Pressures in Patients With Hypertrophic Cardiomyopathy

Circulation ◽

10.1161/01.cir.99.2.254 ◽

1999 ◽

Vol 99 (2) ◽

pp. 254-261 ◽

Cited By ~ 341

Author(s):

Sherif F. Nagueh ◽

Nasser M. Lakkis ◽

Katherine J. Middleton ◽

William H. Spencer ◽

William A. Zoghbi ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Left Ventricular ◽

Left Ventricular Filling ◽

Ventricular Filling

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Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1016/s1053-0770(99)90241-0 ◽

1999 ◽

Vol 13 (4) ◽

pp. 503

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Left Ventricular ◽

Left Ventricular Filling ◽

Ventricular Filling

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Caregiver burden of patients with heart failure with a left-ventricular ejection fraction (LVEF) less than or equal to 60%: a cross-sectional survey in the EU

European Heart Journal ◽

10.1093/ehjci/ehaa946.0978 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R Lahoz ◽

S Corda ◽

C Proudfoot ◽

A.F Fonseca ◽

S Cotton ◽

...

Keyword(s):

Heart Failure ◽

Caregiver Burden ◽

Nyha Class ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Funding Source ◽

Cross Sectional Survey ◽

Private Company ◽

Cross Sectional ◽

Patients With Heart Failure

Abstract Background and purpose The majority of patients with heart failure (HF) have difficulties in independently carrying out activities of daily living and hence, require support from caregivers (CGs). This study assessed the quality of life (QoL) of CGs of HF patients with sub-normal LVEF (≤60%). Methods A cross-sectional survey of HF patients and their CGs was conducted in France, Germany, Italy, Spain and the UK. Cardiologists and primary care physicians completed patient record forms (PRF) between June and November 2019. Caregivers of the same patients were invited to complete a caregiver self-completion survey, which included the Family Caregiver QoL Scale (FAMQOL) and EQ-5D. Patient demographics were derived from PRFs. Results 361 CGs (73.1% female, mean age: 58.8 yrs) and HF patients (39.9% female, mean age: 71.2 yrs) were included. 58.2% of the CGs were spouses, 23.4% a child of the patient. On average, CGs devoted 20 hrs/week in the care of HF patients; this CG time increased from 12 to 26 hrs/week with NYHA class I to III/IV of the HF patient. Further, anxiety/stress was experienced overall by 29/31% of CGs which increased from 27/17% for NYHA I to 40/41% for NYHA III/IV of the HF patient (Table 1). Conclusions Caregivers of patients with HF and LVEF ≤60% spend a significant amount of time to provide daily support to HF patients. Patients with progressive disease were older, more polymorbid and had a higher disease duration. These factors likely contributed towards increased caregiver burden of HF patients with increased NYHA class. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis Pharma AG

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Right ventricular speckle tracking in patients with heart failure – a comparison of right ventricular measures

European Heart Journal ◽

10.1093/ehjci/ehaa946.0145 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

I.J Lundorff ◽

M Sengeloev ◽

S Pedersen ◽

D Modin ◽

N.E Bruun ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Right Ventricular ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Funding Source ◽

Private Company ◽

Ventricular Ejection Fraction ◽

Risk Of Mortality ◽

Patients With Heart Failure

Abstract Background RV dysfunction is associated with increased mortality and morbidity in patients with heart failure. Due to the complex shape and position of the RV, assessing RV function from echocardiographic images remains a challenge. Purpose We have previously found that global longitudinal strain from 2DSTE is superior to left ventricular ejection fraction (LVEF) in identifying HFrEF patients with high risk of mortality. In this study we wanted to examine RV 2DSTE in patients with HFrEF and compare its prognostic value to conventional RV measures. Methods and results Echocardiographic examinations were retrieved from 701 patients with HFrEF. RV estimates were analysed offline, and end point was all-cause mortality. During follow-up (median 39 months) 118 patients (16.8%) died. RV GLS and RV FWS remained associated with mortality after multivariable adjustment, independent of TAPSE (RV GLS: HR 1.07, 95% CI 1.02–1.13, p=0.010, per 1% decrease) (RV FWS: HR 1.05, 95% CI 1.01–1.09, p=0.010, per 1% decrease). This seemed to be caused by significant associations in men as TAPSE remained as the only independent prognosticator in women. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics (TAPSE: 0.74 to 0.75; RVFAC: 0.74 to 0.75; RVFWS: 0.74 to 0.77; RVGLS: 0.74 to 0.77). Conclusions RV strain from 2DSTE was associated with mortality in patients with HFrEF, independent of TAPSE and established risk factors. Our results indicate that RV strain is particularly valuable in male patients, whereas in women TAPSE remains a stronger prognosticator. RV GLS and the risk of mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PGJ reports receiving lecture fee from Novo Nordisk.

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