Very low calorie diets are associated with transient ventricular impairment before reversal of diastolic dysfunction in obesity

Rayner, Jennifer; Abdesselam, Inès; Peterzan, Mark; Akoumianakis, Ioannis; Akawi, Nadia; Antoniades, Charalambos; Tomlinson, Jeremy W.; Neubauer, Stefan; Rider, Oliver J

doi:10.1038/s41366-018-0263-2

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…Some diets are accompanied by large losses of lean components and severe functional deficits, even sudden death. 33 Uniquely, ActRII blockade with bimagrumab not only limited the loss of lean mass but also increased the mass of this compartment by nearly 4% after 4 monthly doses. Additional studies are needed to gain insights into the functional implications of lean mass expansion during the course of weight loss and weight maintenance programs.…”

Section: Discussionmentioning

confidence: 95%

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Heymsfield

Coleman²,

Miller³

et al. 2021

JAMA Netw Open

118

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IMPORTANCE Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.OBJECTIVE To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity. DESIGN, SETTING, AND PARTICIPANTSThis double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA 1c ) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis. INTERVENTIONSPatients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. MAIN OUTCOMES AND MEASURESThe primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA 1c level, and body weight (BW) changes from baseline to week 48. RESULTS A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA 1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, −20.5% (−7.5 kg [80% CI, −8.3 to −6.6 kg]) vs −0.5% (−0.18 kg [80% CI, −0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs −0.8% (−0.4 kg [80% CI, −1.0 to 0.1 kg]) (P < .001); WC, −9.0 cm (80% CI, −10.3 to −7.7 cm) vs 0.5 cm (80% CI, −0.8 to 1.7 cm) (P < .001); HbA 1c level, −0.76 percentage points (80% CI, −1.05 to −0.48 percentage points) vs −0.04 percentage points (80% CI, −0.23 to 0.31 percentage points) (P = .005); and BW, −6.5% (−5.9 kg [80% CI, −7.1 to −4.7 kg]) vs −0.8% (−0.8 kg [80% CI, −1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies. CONCLUSIONS AND RELEVANCEIn this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks (continued) Key Points Question What are the effects of bimagrumab, an antibody that blocks activin type II receptors and stimulates skeletal muscle growth, on total body fat mass and glycemic control in patients with type 2 diabetes and excess adiposity? Findings In this phase 2 randomized clinical trial of 75 patients with type 2 diabetes and body mass index between 28 and 40 who received bimagrumab or placebo du...

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Section: Discussionmentioning

confidence: 95%

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Heymsfield

Coleman²,

Miller³

et al. 2021

JAMA Netw Open

118

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“…The changes induced by weight loss on the wider cardiovascular system are well documented, with improvements in blood pressure, cardiac chamber size, cardiac hypertrophy, and both resting and exertional diastolic function all being reported. [31][32][33] In addition, weight loss…”

Section: Effects Of Weight Loss On the Ck Systemmentioning

confidence: 99%

Myocardial Energetics in Obesity

et al. 2020

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Background: Obesity is strongly associated with exercise intolerance and the development of heart failure. Whereas myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesized that ATP transfer rate through creatine kinase (CK) ( k f CKrest ) would be increased, compensating for depleted energy stores (phosphocreatine/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesized that these changes would normalize with weight loss. Methods: We recruited 80 volunteers (35 controls [body mass index 24±3 kg/m 2 ], 45 obese [body mass index 35±5 kg/m 2 ]) without coexisting cardiovascular disease. Participants underwent body composition analysis, magnetic resonance imaging of abdominal, liver, and myocardial fat content, left ventricular function, and 31 P magnetic resonance spectroscopy to assess phosphocreatine/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before reexamination. Results: At rest, although myocardial phosphocreatine/ATP was 14% lower in obesity (1.9±0.3 versus 2.2±0.2, P <0.001), k f Ckrest was 33% higher (0.23±0.07 s –1 versus 0.16±0.08 s –1 , P =0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9 µmol·g –1 ·s –1 versus control 2.2±1.1 µmol·g –1 ·s –1 , P =0.232). In controls, increasing cardiac workload led to an increase in both k f CK (+86%, P <0.001) and ATP delivery (+80%, P <0.001). However, in obesity, similar stress led to no significant increase in either k f CK ( P =0.117) or ATP delivery ( P =0.608). This was accompanied by reduced systolic augmentation (absolute increase in left ventricular ejection fraction, obese +16±7% versus control +21±4%, P =0.031). Successful weight loss (–11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference in comparison with controls. Conclusions: In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced phosphocreatine/ATP. During increased workload, although the nonobese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery through CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, and a fascinating modifiable pathway involved in the progression to heart failure, as well.

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“…If this were the case, obesity cardiomyopathy could not only be distinct in terms of energy delivery from dilated cardiomyopathy (where ATP delivery is low) but also would be amenable to therapies that improve cardiac efficiency. As weight loss has been shown to reduce left ventricular (LV) hypertrophy, 6 haemodynamic load, improved insulin sensitivity, 7 and cardiac lipid content, 8 this should result in improved cardiac function.…”

Section: Introductionmentioning

confidence: 99%

Obesity modifies the energetic phenotype of dilated cardiomyopathy

Rayner

Peterzan

Clarke

et al. 2021

European Heart Journal

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Aims We sought to determine if myocardial energetics could distinguish obesity cardiomyopathy as a distinct entity from dilated cardiomyopathy. Methods and results Sixteen normal weight participants with dilated cardiomyopathy (DCMNW), and 27 with DCM and obesity (DCMOB), were compared to 26 normal weight controls (CTLNW). All underwent cardiac magnetic resonance imaging and 31P spectroscopy to assess function and energetics. Nineteen DCMOB underwent repeat assessment after a dietary weight loss intervention. Adenosine triphosphate (ATP) delivery through creatine kinase (CK flux) was 55% lower in DCMNW than in CTLNW (P = 0.004), correlating with left ventricular ejection fraction (LVEF, r = 0.4, P = 0.015). In contrast, despite similar LVEF (DCMOB 41 ± 7%, DCMNW 38 ± 6%, P = 0.14), CK flux was two-fold higher in DCMOB (P < 0.001), due to higher rate through CK [median kf 0.21 (0.14) vs. 0.11 (0.12) s−1, P = 0.002]. During increased workload, the CTLNW heart increased CK flux by 97% (P < 0.001). In contrast, CK flux was unchanged in DCMNW and fell in DCMOB (by >50%, P < 0.001). Intentional weight loss was associated with positive left ventricular remodelling, with reduced left ventricular end-diastolic volume (by 8%, P < 0.001) and a change in LVEF (40 ± 9% vs. 45 ± 10%, P = 0.002). This occurred alongside a fall in ATP delivery rate with weight loss (by 7%, P = 0.049). Conclusions In normal weight, DCM is associated with reduced resting ATP delivery. In obese DCM, ATP demand through CK is greater, suggesting reduced efficiency of energy utilization. Dietary weight loss is associated with significant improvement in myocardial contractility, and a fall in ATP delivery, suggesting improved metabolic efficiency. This highlights distinct energetic pathways in obesity cardiomyopathy, which are both different from dilated cardiomyopathy, and may be reversible with weight loss.

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Very low calorie diets are associated with transient ventricular impairment before reversal of diastolic dysfunction in obesity

Cited by 13 publications

References 29 publications

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Myocardial Energetics in Obesity

Obesity modifies the energetic phenotype of dilated cardiomyopathy

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