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Myocardial O utilization and energetics of the left ventricle in hypertrophiccardiomyopathyGüclü, A.

2017

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citation for published version (APA)Güclü, A. (2017). Myocardial O utilization and energetics of the left ventricle in hypertrophic cardiomyopathy:Proof for gene-specific and disease-stage specific cardiac changes.

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Download date: 18. Aug. 2021

Chapter

6

A. Güçlü

P Knaapen

H.J. Harms

R.Y. Parbhudayal

M. Michels

A.A. Lammertsma

A.C. van Rossum

T. Germans

J. van der Velden

Disease stage-dependent changes in cardiac contractile performance and oxygen utilization underlie reduced myocardial efficiency in human inherited hypertrophic cardiomyopathy

Circ Cardiovasc Imaging 2017; Epub ahead of print

Abstract Background Reduced myocardial efficiency represents a target for therapy in hypertrophic cardiomyopathy (HCM), although therapeutic benefit may depend on disease stage. Here, we determined disease stage-dependent changes in myocardial efficiency and effects of myectomy surgery.

Methods and results Myocardial external efficiency (MEE) was determined in 27 asymptomatic mutation carriers (genotype-positive/phenotype-negative, G+/Ph-), 10 patients with hypertrophic obstructive cardiomyopathy (HOCM), 10 patients with aortic valve stenosis (AVS) and 14 healthy individuals using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Follow-up measurements were performed in HOCM and AVS patients 4 months after surgery. External work did not differ in HOCM compared with controls, whereas myocardial oxygen consumption (MVO2) was lower in HOCM. Because of a higher cardiac mass, total cardiac oxygen consumption was significantly higher in HOCM than in controls and G+/Ph-. MEE was significantly lower in G+/Ph- than in controls (28 ± 6 vs 42 ± 6%), and was further decreased in HOCM (22 ± 5%). In contrast to patients with AVS, MEE was not improved in patients with HOCM after surgery, which was explained by opposite changes in the septum (decrease) and lateral (increase) wall.

Conclusions Different mechanisms underlie reduced MEE at the early and advanced stage of HCM. The initial increase and subsequent reduction in MVO2 during disease progression indicates that energy deficiency is a primary mutation-related event, whereas mechanisms secondary to disease remodeling underlie low MEE in HOCM. Our data highlight that the benefit of therapies to improve energetic status of the heart may vary depending on the disease stage, and treatment should be initiated before cardiac remodeling.

Introduction

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease characterized by asymmetrical left ventricular hypertrophy, in the absence of other loading conditions.1, 2 HCM is extremely common with an estimated prevalence ranging from 1:2003 to 1:500.4 A major advancement in identification of the disease has been the implementation of genetic screening.5 To date, more than 1400 HCM-associated mutations have been identified. With these advances in genetic screening, more mutation carriers without phenotype (genotype positive/phenotype negative [G+/Ph-]) are identified, thereby increasing the number of people who are insecure about their fate as no preventive therapies are available. Disease-mediated changes in cardiac energetic state may represent a target for therapy. The phosphocreatine/ATP ratio, a cardiac marker of energetic state, is reduced in heart failure and closely correlated with patient prognosis.6, 7 In addition, in patients with manifest HCM, Crilley and colleagues reported a reduction in the phosphocreatine/ATP ratio of ~30% compared with controls.8 This energetic deficit may be caused by the mutant sarcomeric protein and/or changes in cardiac metabolism9 as part of the secondary cardiac remodeling process. Recent studies have provided evidence that ATP utilization for production of force is higher in cardiac tissue from HCM mice and human HCM patients harboring sarcomere mutations than in control tissue.10-12 Further support that the mutation itself underlies a deficiency in cardiac energetics comes from studies in asymptomatic mutation carriers without ventricular hypertrophy (G+/Ph- group), which showed reduced myocardial efficiency compared with controls, which was evident from a reduced ratio between cardiac work and oxygen consumption.12 Metabolic therapy may thus represent a preventive therapy, as it can increase energy availability.13 Metabolic agents, that are already used in clinical practice, such as anti-anginal agents may be used to improve cardiac energetics and function.14, 15 In the healthy heart, energy demand is met by oxidation of fatty acids and carbohydrates. Although fatty acids represent the predominant fuel for the heart, they provide less ATP per O2 molecule in comparison with carbohydrates.16, 17 Thus, agents that shift metabolism away from the preferred fatty acids toward carbohydrates would increase ATP supply and may prevent cardiac hypertrophy and failure. Metabolic therapy had a beneficial effect in symptomatic HCM.18 The benefit of metabolic therapy depends on the ability of the heart to shift from lipid to glucose metabolism. As cardiac metabolism may be altered during cardiac remodeling, metabolic therapy may render more benefit at an early disease stage, that is, before development of significant hypertrophy.

To establish whether it is valid to initiate metabolic therapy before onset of hypertrophy, the purpose of the present study was to investigate whether myocardial efficiency further declines in hypertrophic obstructive cardiomyopathy (HOCM) patients compared with the G+/Ph- group, and whether myectomy surgery is able to restore myocardial efficiency. The ratio between external work and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined using [11C]-acetate positron emission tomography (PET) and cardiovascular magnetic resonance (CMR) imaging. Using analysis of regional efficiency, it is possible to study whether changes are related to the degree of cardiac hypertrophy, making a comparison between G+/Ph- individuals, patients with HOCM, and patients with hypertrophy caused by aortic valve stenosis (AVS).

Methods Study population The study protocol was in agreement with principles outlined in the Declaration of Helsinki and was approved by the Medical Ethics Review Committee of the VU University Medical Center Amsterdam. Written informed consent was obtained from each patient prior to inclusion. The study population comprised 27 asymptomatic prehypertrophic mutation carriers (G+/Ph-; 6 men, mean age 37 ± 13 years), who were first-degree relatives of patients with symptomatic HOCM and were recruited after genetic testing. Fourteen carriers had a mutation in MYBPC3 and 13 in MYH7. The wall thickness in all G+/Ph- was ˂10 mm. Fourteen genotype-negative relatives of the G+/Ph- mutation carriers were included as a control group (9 men, mean age 48 ± 11 years). In addition, 10 patients with HOCM (6 men, mean age 52 ± 14 years) with maximum left ventricular (LV) wall thickness ≥15 mm in the absence of other cardiac or systemic causes of LV hypertrophy were included. All HOCM subjects reported symptoms and exhibited significant LV outflow tract (LVOT) obstruction, necessitating myectomy. Furthermore, 10 patients with AVS (7 men, mean age 62 ± 10 years), eligible for aortic valve replacement (AVR) were enrolled in the study. Inclusion criteria were the presence of symptomatic, isolated AVS with a peak transvalvular gradient of >50 mmHg (mean transvalvular gradient ranging from 34 to 68 mmHg) and an aortic valve area <1 cm2. Exclusion criteria were as follows (previously documented): aortic regurgitation more than grade 1, presence of coronary artery disease (coronary artery stenosis >30%), previous septal reduction therapy, poor LV function (ejection fraction <50%), a history of diabetes mellitus or hypertension (defined as a systemic blood pressure ≥140/90 mmHg), contraindications to magnetic resonance imaging and significant

renal dysfunction defined as an estimated glomerular filtration rate <30 mL∙min-

1∙1.73∙m-2.

Study design All patients with HOCM and AVS underwent baseline measurements (on 1 day) including transthoracic echocardiography (TTE), PET imaging using [11C]-acetate and CMR imaging within 2 weeks before septal myectomy (pre-myectomy) or AVR (pre-AVR), and follow-up measurements 4 months after surgery. The healthy control group and G+/Ph- only underwent baseline measurements and global MEE data for these groups have been published previously.12, 19

Cardiac imaging protocols Transthoracic echocardiography Echocardiography was performed according to the American Society of Echocardiography guidelines.20 Continuous wave Doppler was used to derive LVOT gradient and peak aortic valve pressure gradient. Diastolic function was assessed using a combination of early diastolic mitral annular velocity (e´) and peak early diastolic mitral E velocity, measured at the septal and lateral aspects of the mitral annulus in the apical 4-chamber view. Mitral E/e´ was calculated both septal and lateral.

CMR and PET The study protocol comprised [11C]-acetate PET and CMR imaging (Figure 1). A detailed description of the imaging protocol can be found elsewhere.12 [11C]-acetate PET imaging was performed to indirectly quantify oxygen metabolism using the rate constant k2. k2 represents the rate of transfer of radioactivity from tissue to blood, of which myocardial oxygen consumption (MVO2) can be derived as described previously.21 Data of the control group were acquired as described previously.22 For the G+/Ph-, HOCM and AVS group, [11C]-acetate scans were obtained on a Gemini TF-64 PET/CT scanner (Philips Healthcare, Best, The Netherlands). CMR was performed on a 1.5-Tesla whole body scanner (Magnetom Sonata or Avanto, Siemens, Erlangen, Germany), using a 6-channel phased-array body coil. A contiguous short-axis steady-state free precession stack was acquired extending from the mitral valve annulus to the LV apex, to obtain global LV function parameters, including ED volume (LVEDV), ES volume (LVESV), LV ejection fraction (LVEF) and LV mass (LVM).23 The forward stroke volume (SV) was obtained from the velocity-encoded phase-contrast aortic flow maps. Subsequently, a stack of 6 to 10 transversely orientated slices was planned on an end-diastolic 2-chamber view at the level of the lower leading edge of the mitral valve annulus to cover the left

atrium (LA).24 Cine imaging with myocardial tagging was applied to create noninvasive markers (tags) within the myocardium for the calculation of peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR).25, 26 Late gadolinium enhancement (LGE) images were acquired 10 to 15 minutes after intravenous administration of 0.2 mmol∙kg-1 gadolinium for quantification of myocardial fibrosis.27

Myocardial external efficiency External work (EW) was defined as the product of stroke volume (SV) derived by CMR and mean arterial pressure (MAP). In the HOCM and AVS group, individually obtained estimations of respectively LVOT gradient or aortic valve gradient were added to the MAP to ensure accurate estimations of actual LV pressures. Subsequently, myocardial external efficiency (MEE) was calculated according to the equation below:

20LVMMVO

101.33HREWMEE

2

4

where HR is the heart rate and the constants represent the caloric equivalent of 1 mmHg∙mL EW, which is 1.33∙10-4 J, whereas 1 mL O2 corresponds to 20 J.28

Regional efficiency Regional efficiency was determined in the septum and lateral wall of the LV as the ratio between regional SCS and the corresponding MVO2(beat) according to the 17-segment model of the American Heart Association.29 Less negative values indicate reduced efficiency.30

Statistics Data analyses and statistics were performed using Prism version 5.0 (Graphpad Software, Inc., La Jolla, CA, USA) and SPSS version 20 (IBM, Armonk, NY, USA). Continuous data were expressed as mean ± SD in case of a normal distribution and median [range] in case of non-normality. Normality was assessed for each individual data set (controls, G+/Ph-, HOCM and AVS patients) and variables by visual inspection of histograms. When the normality assumption was not violated, a 1-way ANOVA with Bonferroni post hoc test was performed to investigate differences among groups. When data were not normal, groups were compared using Kruskall-Wallis ANOVA and post hoc testing using separate Mann-Whitney U test for each

pair of group correcting for multiple testing. A paired 2-tailed Student t test was performed to investigate differences between baseline and follow-up measurements in case of a normal distribution. In case of non-normal distribution and for ordinal variables (New York Heart Association class) Wilcoxon signed-rank test was used. P < 0.05 was considered statistically significant.

Results Characteristics of controls, G+/Ph-, and patients with HOCM Baseline characteristics of controls, G+/Ph-, and patients with HOCM are presented in Table 1. G+/Ph- were significantly younger than both controls and patients with HOCM. In addition, more women were included in the G+/Ph- group. At baseline, heart rate was significantly lower in G+/Ph- and patients with HOCM (only patients with HOCM were on medication) than in controls. LVEDV tended to be higher in patiemts with HOCM but did not reach statistical significance. LVM, LA volume index, and NT-pro-BNP (N-terminal pro-B-type natriuretic peptide) were significantly higher, whereas global peak SCS was significantly lower in patients with HOCM than in controls and G+/Ph-, consistent with decreased myocardial function (Tables 1 and

2; Figure 1). Global e′ was significantly lower, whereas global E/e′ was significantly higher in patients with HOCM, indicating impaired diastolic function. This finding was supported by a significantly lower peak DCSR (both septal and lateral) in HOCM (Table 2). Cardiac fibrosis was present in all patients with HOCM with a median estimated percentage of 4.0% of the whole LV. In G+/Ph-, forward SV and MAP were lower compared with controls (Figure 2A and 2B), which resulted in a significantly lower external work (6537 ± 1251 versus 8794 ± 2276 mmHg·mL, P = 0.001; Figure 2E). MVO2 was higher in G+/Ph- than in controls (0.11 ± 0.03 versus 0.10 ± 0.02 mL∙min-1∙g-1, Figure 1 and 2C), whereas the total cardiac oxygen consumption did not differ (Figure 2F). This resulted in a significant decrease in MEE in G+/Ph- compared with controls (28 ± 6 versus 42 ± 6%, P < 0.001; Figure 2G). Forward SV and MAP did not differ between patients with HOCM and controls (Figure 2A-B), resulting in no difference in external work (8409 ± 2381 versus 8794 ± 2276 mmHg·mL, Figure 2E). MVO2 was lower in patients with HOCM than in controls (0.08 ± 0.02 versus 0.10 ± 0.02 mL∙min-1∙g-1; Figure 1 and 2C), whereas the total cardiac oxygen consumption was higher in HOCM because of a higher LVM (Figure 2D and 2F). As a result, MEE was significantly lower in patients with HOCM than in controls (22 ± 5 versus 42 ± 6%, P < 0.001; Figure 2G). Figure 2G illustrates also that MEE was significantly lower in HOCM than in G+/Ph-, indicating that there is further deterioration from the early to the late stage of the disease.

Noteworthy, the low MEE in G+/Ph- seemed to be caused by a relatively high O2 consumption of the heart muscle and lower external work, whereas O2 consumption was reduced (per gram tissue) and external work unchanged compared with controls in the hypertrophied muscle of patients with HOCM (Figure 1 and 2C).

Figure 1. Cardiac imaging of a control, G+/Ph- and patient with HOCM. CMR-derived cardiac 4-chamber view and parametric images of [11C]-acetate PET derived average [11C]-acetate clearance rate constant k2 with corresponding polar maps. As can be seen clearly, left ventricular remodeling occurred in patients with HOCM, evident from an increase in LVEDV, LVM and LA volume. Myocardial oxygen metabolism was lower in patients with HOCM, whereas an increase in oxygen metabolism was observed in G+/Ph- compared with controls.

Table 1: Baseline characteristics of controls, G+/Ph- and HOCM patients

Controls (n=14) G+/Ph- (n=27) HOCM (n=10)

Age (years)

Gender (male)

Body surface area

NYHA class of heart failure

I

II

III

IV

Medical treatment

β-blockers

Ca-antagonists

ACE-inhibitors

Causal gene

MYBPC3

MYH7

MYL2

SCN5A

PET & hemodynamic parameters

k2

Systolic BP (mmHg)

Diastolic BP (mmHg)

MAP (mmHg)

Heart rate (bpm)

Metabolic parameters

NT-pro-BNP (ng∙L-1)

Hb (mmol∙L-1)

Glucose (mmol∙L-1)

FFA (mmol∙L-1)

Lactate (mmol∙L-1)

Echocardiographic parameters

Global e’ (cm∙s-1)

Global E/e’

LVOT gradient (mmHg)

CMR parameters

LV septal thickness (mm)

LVEDV (mL∙m-2)

LVESV (mL∙m-2)

Forward SV (mL∙m-2)

LVEF (%)

LVM (g∙m-2)

LA max volume (mL∙m-2)

48 ± 11

9 (64)

2.0 ± 0.2

NA

NA

NA

0.08 ± 0.02

123 ± 13

71 ± 8

88 ± 8

69 ± 10

36 [14, 202]

8.3 ± 0.4

5.5 ± 0.8

0.6 ± 0.3

1.4 ± 0.6

12 ± 2

8 ± 2

NA

6.2 ± 0.8

93 ± 15

36 ± 10

49 ± 8

62 ± 5

49 ± 6

46 ± 6

37 ± 13*

7 (22)

1.8 ± 0.2*

NA

NA

14

13

-

-

0.09 ± 0.02

111 ± 14*

65 ± 7

80 ± 8*

61 ± 9*

54 [15, 205]

8.6 ± 0.9

5.1 ± 0.6

0.6 ± 0.2

1.2 ± 0.4

13 ± 3

7 ± 2

NA

6.4 ± 0.9

86 ± 11

34 ± 6

45 ± 6

60 ± 4

48 ± 7

48 ± 8

52 ± 14†

6 (60)

2.0 ± 0.2

0

4 (40%)

6 (60%)

0

8 (80)

0

1 (10)

3

1

1

1

0.06 ± 0.01†

112 ± 15

63 ± 11

92 ± 14*†

59 ± 3*

716 [238, 11428]*†

9.4 ± 0.5*†

5.5 ± 0.5

0.2 ± 0.1*†

1.4 ± 0.7

6 ± 2*†

18 ± 7*†

35 ± 26

12.9 ± 1.9*†

100 ± 24

36 ± 9

45 ± 11

64 ± 3†

102 ± 22*†

91 ± 25*†

Presence of cardiac LGE

Cardiac LGE mass, % of LV

0

0

0

0

10 (100)

4.0 [0.4, 13.4]

Data are presented as n (%) or mean ± SD or median [range]. G+/Ph-, genotype-positive/phenotype-negative; HOCM, hypertrophic obstructive cardiomyopathy; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme; k2, average [11C]-acetate clearance rate constant; BP, blood pressure; MAP, mean arterial pressure; NT-pro-BNP, NH2-terminal pro-brain natriuretic peptide; Hb, hemoglobin; FFA, free fatty acid; E, mitral peak velocity of early filling; e, early diastolic mitral annular velocity; LV, left ventricle; LVOT, LV outflow tract; LVEDV, LV end-diastolic volume; LVESV, LV end-systolic volume; SV, stroke volume; LVEF, LV ejection fraction; LVM, LV mass; LA, left atrial; LGE, late gadolinium enhancement. * P < 0.05 versus controls; † P < 0.05 HOCM versus G+/Ph-.

Figure 2. Overview of the determinants of left ventricular (LV) myocardial external efficiency for controls, G+/Ph- and patients wit HOCM. Forward stroke volume (SV, panel A) was measured by CMR. Mean arterial pressure (MAP, panel B) was approximated using systolic and diastolic blood pressures. In the HOCM and AVS group, individually obtained estimations of LVOT gradient or aortic valve gradient, respectively, were added to the MAP to ensure accurate estimations of actual LV pressures. Myocardial oxygen consumption (MVO2, panel C) was measured by [11C]-acetate PET. LV mass (LVM, panel D) was measured by CMR. External work (panel E) was defined as the product of forward SV and MAP. Total myocardial oxygen consumption (panel F) is the product of MVO2 and LVM. Myocardial external efficiency (MEE panel G) was calculated according to the equation described in the method section. Symbols of the G+/Ph- and HOCM group: Δ represents individuals with a MYBPC3 mutation; □ represents individuals with a MYH7 mutation; and ○ represents mutation unknown.

Contractile function and cardiac energetics at a regional level At a regional level, both septal and lateral SCS were significantly lower in patients with HOCM than in both G+/Ph- and controls (Table 2). Moreover, SCS was significantly lower in the septal region than in the lateral wall in all groups (P < 0.05). Both septal and lateral MVO2(beat) were significantly higher in the G+/Ph- than in the controls and patients with HOCM. In the G+/Ph- group, septal MVO2(beat) was significantly higher than in the lateral wall (P = 0.002), whereas the opposite was true for the HOCM group (P = 0.004; Table 2). In contrast, septal MVO2(beat) in the control group was comparable to MVO2(beat) of the lateral wall (P = 0.75). Both in septal and lateral walls of the LV, efficiency was significantly lower in G+/Ph- than in controls, whereas in patients with HOCM, a significantly reduced efficiency was observed only in the septum and not in the lateral wall (Table 2, Figure 3A and B). Table 2: Regional contractile function and efficiency in controls, G+/Ph- and HOCM

Controls (n=14) G+/Ph- (n=27) HOCM (n=10)

Peak SCS (%) Global Septal Lateral

Peak DCSR (%∙s-1) Global Septal Lateral

MVO2 per beat (mL∙beat-1∙g-1)∙10-3 Global Septal Lateral

Efficiency (SCS / MVO2 per beat) Global Septal Lateral

Myocardial external efficiency (%)

-19.3 ± 1.7 -18.7 ± 1.8 -20.9 ± 2.8

142 ± 28 131 ± 30 158 ± 32

1.43 ± 0.27 1.44 ± 0.30 1.44 ± 0.27

-13864 ± 2330 -13189 ± 2293 -14879 ± 2997

42 ± 6

-20.3 ± 1.7 -19.3 ± 2.3 -22.1 ± 1.8

153 ± 23 135 ± 29 181 ± 32

1.80 ± 0.32* 1.85 ± 0.33* 1.81 ± 0.32*

-11520 ± 1834* -10602 ± 1637* -12521 ± 2036*

28 ± 6*

-15.4 ± 2.1*† -13.5 ± 3.5*† -17.5 ± 2.4*†

90 ± 17*† 79 ± 27*†

102 ± 22*†

1.29 ± 0.23† 1.27 ± 0.23† 1.33 ± 0.24†

-12093 ± 1735

-10749 ± 2615* -13441 ± 2385

22 ± 5*†

Data are presented as mean ± SD or median [range]. G+/Ph-, genotype-positive/phenotype-negative; HOCM, hypertrophic obstructive cardiomyopathy; SCS, systolic circumferential strain; DCSR, diastolic circumferential strain rate; MVO2, myocardial oxygen consumption; * P < 0.05 versus controls; † P < 0.05 HOCM versus G+/Ph-

Figure 3. Scatter plots depicting regional efficiency for controls, G+/Ph- and HOCM (A-B). Regional efficiency for patients with HOCM and AVS at baseline and follow-up (C-D). The dotted lines in panel C and D represent the corresponding mean values for controls. Symbols of the G+/Ph- and HOCM group: Δ represents individuals with a MYBPC3 mutation; □ represents individuals with a MYH7 mutation; ○ represents mutation unknown.

Effects of septal myectomy The effects of septal myectomy on LV and LA dimensions, functional parameters, and metabolic parameters are presented in Table 3. Follow-up could be performed in 8 patients with HOCM (1 patient declined to undergo follow-up measurements and 1 patient had total AV block during septal myectomy necessitating a pacemaker). After septal myectomy, the resting LVOT gradient was significantly reduced (P < 0.05). However, septal myectomy resulted in less reversed cardiac remodeling in patients with HOCM compared with patients with AVS undergoing AVR, evident from a smaller decrease in LVEDV, LVESV and LVM. LVM index significantly decreased in patients with both HOCM and AVS, although values

remained significantly higher than in controls. Global e´ and DCSR did not change after septal myectomy, whereas a significant increase was observed after AVR, indicating a persistent impaired diastolic function in patients with HOCM 4 months after surgery. No significant changes were observed for the amount of myocardial fibrosis and fasting metabolic parameters such as glucose, FFA, lactate, hemoglobin and NT-proBNP in patients with either HOCM or AVS during follow-up. After septal myectomy, no significant change in global SCS, MVO2(beat) and MEE were observed in HOCM (Table 3, Figure 4), whereas all parameters significantly improved in the post-AVR group. At a regional level, septal myectomy resulted in a deterioration of septal SCS (P = 0.02), whereas septal MVO2(beat) did not change. This resulted in a significantly lower septal efficiency after septal myectomy (P = 0.02; Table 3, Figure 3C). In contrast, lateral SCS significantly improved (P = 0.02), whereas lateral MVO2(beat) did not change. As a consequence, lateral efficiency significantly improved after septal myectomy (P = 0.03; Table 3, Figure 3D). The improvement in global efficiency in the post-AVR group was because of improvements in both the septal and lateral LV wall of patients with AVS (Table 3, Figure 3C and 3D).

Figure 4. Reversed remodeling after septal myectomy and AVR. CMR-derived cardiac 4-chamber view and parametric images of [11C]-acetate PET derived average [11C]-acetate clearance rate constant (k2) with corresponding polar maps in patients with HOCM and AVS at baseline and follow-up (FU).

Table 3: Effect of septal myectomy and aortic valve replacement pre-myectomy

(n=8)

post-myectomy

(n=8)

pre-AVR

(n=10)

post-AVR

(n=10)

NYHA class of heart failure

I

II

III

IV

Metabolic parameters

NT-pro-BNP (ng∙L-1)

Hb (mmol∙L-1)

Glucose (mmol∙L-1)

FFA (mmol∙L-1)

Lactate (mmol∙L-1)

Echocardiographic parameters

LVOT gradient (mmHg)

Global e’

Global E/e’

CMR parameters

LVEDV (mL∙m-2)

LVESV (mL∙m-2)

Forward SV (mL∙m-2)

LVEF (%)

LVM (g∙m-2)

LA max volume (mL∙m-2)

LGE mass, % of LV

Peak SCS (%)

Global

Septal

Lateral

Peak DCSR (%∙s-1)

Global

Septal

Lateral

MVO2 per beat (mL∙beat-1∙g-1)∙10-3

Global

Septal

Lateral

Efficiency (SCS / MVO2 per beat)

Global

Septal

Lateral

Myocardial external efficiency (%)

0

4 (50%)

4 (50%)

0

716 [238, 3397]

9.3 ± 0.5

5.5 ± 0.5

0.2 ± 0.1

1.4 ± 0.8

31 ± 20

6.0 ± 2.3

17 ± 6

103 ± 25

36 ± 10

47 ± 10

65 ± 3

102 ± 25

92 ± 28

4.0 [0.7, 13.4]

-15.6 ± 2.3

-13.3 ± 3.9

-17.7 ± 2.2

90 ± 17

79 ± 27

102 ± 22

1.31 ± 0.25

1.28 ± 0.25

1.35 ± 0.26

-12082 ± 1942

-10379 ± 2496

-13481 ± 2639

22 ± 4

6 (75%)

1 (12.5%)

1 (12.5%)

0

513 [163, 1572]

9.0 ± 0.3

5.6 ± 0.3

0.2 ± 0.1

1.4 ± 0.5

11 ± 8*

6.5 ± 1.7

16 ± 5

95 ± 25*

35 ± 10

46 ± 12

63 ± 3

85 ± 27*

69 ± 18*

2.0 [0.9, 15.5]

-16.0 ± 1.6

-10.0 ± 2.5*

-20.3 ± 2.2*

93 ± 27

69 ± 27

119 ± 39

1.26 ± 0.20

1.19 ± 0.17

1.34 ± 0.22

-12779 ± 1125

-8535 ± 2148*

-15325 ± 1082*

26 ± 4

0

6 (60 )

4 (40%)

0

295 [61, 1898]

8.9 ± 0.7

6.2 ± 0.7

0.7 ± 0.3

1.3 ± 0.5

88 ± 20

6.2 ± 1.2

13 ± 3

101 ± 19

43 ± 14

42 ± 9

58 ± 7

104 ± 21

59 ± 7

0 [0, 8.5]

-15.5 ± 2.8

-15.8 ± 3.2

-17.6 ± 1.7

102 ± 19

102 ± 24

108 ± 28

1.65 ± 0.34

1.64 ± 0.36

1.68 ± 0.34

-9592 ± 1520

10123 ± 3024

-10792 ± 1902

24 ± 8

4 (40%)

6 (60%)

0

0

217 [71, 595]

8.8 ± 1.0

5.9 ± 0.6

0.6 ± 0.2

1.8 ± 1.0

24 ± 12†

8.9 ± 1.6†

10 ± 2†

88 ± 16†

35 ± 9†

46 ± 5

61 ± 5

74 ± 15†

49 ± 9†

0 [0, 2.6]

-19.0 ± 1.5†

-17.5 ± 2.8

-21.1 ± 1.5†

118 ± 14

107 ± 17

126 ± 23

1.33 ± 0.27†

1.33 ± 0.28†

1.35 ± 0.29†

-14668 ± 2048†

-13367 ± 2000†

-16185 ± 2711†

32 ± 6†

Data are presented as mean ± SD or median [range]. AVR, aortic valve replacement; NT-pro-BNP, NH2-terminal pro-brain natriuretic peptide; Hb, hemoglobin; FFA, free fatty acid; E, mitral peak velocity of early filling; e, early diastolic mitral annular velocity; LV, left ventricle; LVOT, LV outflow tract; LVEDV, LV end-diastolic volume; LVESV, LV end-systolic volume; SV, stroke volume; LVEF, LV ejection fraction; LVM, LV mass; LA, left atrial; DCSR, diastolic circumferential strain rate ; SCS, systolic circumferential strain; MVO2, myocardial oxygen consumption; * P < 0.05 pre-myectomy versus post-myectomy; † P < 0.05 pre-AVR versus post-AVR.

Discussion The present study demonstrates the results of a comprehensive investigation on (regional) changes in myocardial contractile function and energetics in different stages of HCM. The comparison between healthy mutation carriers without LV hypertrophy (G+/Ph-) and patients with HOCM showed reduced MEE compared with controls evident from a reduced ratio between cardiac work and oxygen consumption. Compared with the asymptomatic early stage, MEE was further decreased at the advanced stage of HCM. The study indicates that different mechanisms underlie the reduction in MEE at the early and advanced stage of HCM. In G+/Ph- reduced MEE is caused by a decrease in cardiac work, which coincides with an increase in MVO2. In contrast, cardiac work did not differ in patients with HOCM, whereas the oxygen consumption per gram tissue is reduced significantly. Because of significant hypertrophy of the heart, the ratio between cardiac work and total oxygen consumption of the heart is reduced in patients with HOCM. The initial increase and subsequent reduction in MVO2 of the heart during disease progression implies that the initial mutation-related increase in ATP (oxygen) utilization is compensated in the hypertrophied heart by secondary mechanisms. This indicates that energy deficiency is a primary event rather than a secondary consequence of cardiac remodeling.

Regional contractile function and efficiency In the present study, global and regional peak SCS were similar in G+/Ph- and controls in accordance with previous reports.26, 31 In contrast, septal and lateral SCS were significantly reduced in patients with HOCM despite normal LV ejection fraction, which has also been described in previous studies. 30, 32 An interesting finding is the significantly higher septal and lateral MVO2(beat) in G+/Ph- individuals compared with that of both controls and patients with HOCM. Moreover, in G+/Ph-, septal MVO2(beat) was significantly higher than in the lateral wall, whereas the opposite was true for the HOCM group. This increase and subsequent reduction of septal MVO2(beat) during disease progression implies that the secondary (mal)adaptive mechanisms are most prominent in the septal wall. Consequently, efficiency was significantly reduced in all regions in the early stage of HCM, whereas in the

advanced stage, a significantly reduced efficiency was observed only in the septum and not in the lateral wall. The latter indicates that changes in cardiac efficiency in the HOCM group are the combined result of the mutation defect and the secondary (mal)adaptive remodeling process of the hypertrophied muscle.

Effects of septal myectomy on LV geometry and diastolic function At present, septal myectomy is the preferred treatment for patients with symptomatic HOCM despite medical therapy. Previous studies performed in large HCM cohorts have shown that LVOT obstruction is an important predictor of disease progression and cardiovascular death.33, 34 LVOT obstruction is also strongly correlated with LV diastolic dysfunction and LA enlargement.35, 36 Increased LA dimension is a risk factor for developing atrial fibrillation and its complications of thromboembolism and heart failure in HOCM.37, 38 Septal myectomy can substantially reduce LVOT obstruction and secondary mitral regurgitation leading to significant improvement in symptoms and survival. 39, 40 In the present study, at 4 months of follow-up, septal myectomy in HOCM resulted in incomplete and less reversed cardiac remodeling41 compared with patients with AVS undergoing AVR. There may be several explanations for incomplete reversed LV remodeling after septal myectomy. At 4 months of follow-up, the process of reversed remodeling may still be ongoing. Moreover, septal myectomy does not completely reduce resting LVOT gradients to normal values and patients could have dynamic LVOT obstruction during exercise, which might limit the reversed remodeling process. Third, no significant improvement in diastolic function

in HOCM patients was observed, illustrated by the lack of improvement in global e′ and DCSR. Ho et al. reported a higher amount of diffuse myocardial fibrosis in HOCM, which correlated with the severity of diastolic dysfunction. They also found that interstitial fibrosis was already present in G+/Ph-.42 These findings suggest that myocardial fibrosis is an early consequence of sarcomere mutations which may lead to irreversible changes within the myocardial extracellular matrix. This could hinder the process of reversed remodeling after septal myectomy. Furthermore, in the present study, no abnormalities in diastolic function in the G+/Ph- group compared with controls were detected. The development of interstitial fibrosis may be ongoing in the G+/Ph- group, but not lead to diastolic dysfunction yet.

Effects of septal myectomy on regional contractility, MVO2 and efficiency Only limited data are available on the effects of septal reduction therapy on MVO2 and efficiency. Timmer et al. reported favorable effects of alcohol septum ablation on myocardial energetics.43 In the present study, no significant changes in global SCS,

MVO2(beat) and efficiency were observed after septal myectomy. At a regional level, septal myectomy resulted in a deterioration of septal SCS, whereas lateral SCS significantly improved in accordance with a previous study.44 Septal and lateral MVO2(beat) did not change after septal myectomy. This resulted in a significantly lower septal efficiency, whereas lateral efficiency significantly improved after septal myectomy.

Study limitations Myocardial ischemia has been associated with alterations of myocardial metabolism and it may also affect myocardial efficiency. In the present study, no measurements of myocardial perfusion were performed in both G+/Ph- and healthy controls to rule out myocardial ischemia. On the contrary, patients were considered to be at low risk for coronary artery disease based on clinical history and ECG findings. No regional wall motion abnormalities were seen on echocardiography or CMR. Furthermore, there was no myocardial fibrosis present in both G+/Ph- and controls as demonstrated by late gadolinium enhancement imaging (Table 1). In addition, AVS and HOCM patients with coronary artery disease were excluded. However, most of the included patients displayed areas of myocardial fibrosis. In this study, the clearance rate (washout) of carbon-11 acetate was fitted into the single compartment model to calculate MVO2. Therefore, in theory, only myocardium that displays myocardial uptake (thus viable myocardium) displays clearance, and scar tissue is not included in these measurements. The effect of areas of late gadolinium enhacement should therefore have minimal effect on the MVO2 estimates and thus myocardial efficiency. To avoid effects of other confounding factors on myocardial efficiency, patients with hypertension, diabetes mellitus and poor LV function were excluded. An alternative explanation for the low MVO2 in patients with HOCM may be a lower oxygen delivery because of microvascular dysfunction45 or a decline of the respiratory capacity of mitochondria46, 47 at the advanced stage of HCM. HOCM is characterized by coronary microvascular dysfunction, which is related to adverse remodeling of intramyocardial coronary arterioles including medial hypertrophy, decreased luminal size and reduced capillary density.48, 49 However, previous studies showed that under basal conditions, myocardial blood flow did not significantly differ between patients and control subjects.50 The noninvasive estimation of external work in HOCM is potentially hampered by the presence of mitral regurgitation, because part of the blood volume is ejected into the low-pressured LA during systole. We largely circumvented this issue by using forward SV only, acquired by CMR flow measurements in the ascending aorta.

Conclusions and clinical implications This is the first study that used CMR tissue tagging and [11C]-acetate PET to evaluate regional changes in myocardial contractile function and energetics during disease progression and after septal myectomy in HOCM. The present study revealed a disease stage-dependant increase in MVO2. The initial increase and subsequent reduction in MVO2 during disease progression implies that the initial mutation-related increase in ATP (oxygen) utilization triggers secondary (mal)adaptive mechanisms leading to diastolic dysfunction and remodeling of the heart. The low MVO2 in HOCM may be related to a compensatory switch in substrate metabolism from high oxygen-consuming lipid oxidation to low oxygen-consuming glycolysis. Alternatively, the low MVO2 may be the consequence of maladaptive mitochondrial changes resulting in reduced mitochondrial oxygen consumption, reduced ATP production and increased oxidative stress.9 Reduced myocardial efficiency and increased atrial dimensions precede the development of diastolic dysfunction in G+/Ph-. As myocardial efficiency already was reduced in seemingly healthy human mutation carriers, optimization of the energetic status of the heart may be beneficial for G+/Ph- individuals at a early stage of the disease, that is, before hypertrophy is evident.

Funding We acknowledge support from the 7th Framework Program of the European Union (‘BIG-HEART’, grant agreement 241577), from the Netherlands organization for scientific research (NWO; VIDI grant 917.11.344), and the Netherlands Heart Foundation (‘Dekker Grant’ grant agreement 2011T33).

Disclosures None.

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