scholarly journals Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction

2019 ◽  
Vol 127 (4) ◽  
pp. 1012-1033 ◽  
Author(s):  
David C. Poole
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Tolerance ◽  
Contractile Function ◽  
Past Century ◽  
Capillary Recruitment ◽  
Improve Exercise Tolerance ◽  
Exercise Muscle ◽  
And Function ◽  
Exchange Surface

This review strikes at the very heart of how the microcirculation functions to facilitate blood-tissue oxygen, substrate, and metabolite fluxes in skeletal muscle. Contemporary evidence, marshalled from animals and humans using the latest techniques, challenges iconic perspectives that have changed little over the past century. Those perspectives include the following: the presence of contractile or collapsible capillaries in muscle, unitary control by precapillary sphincters, capillary recruitment at the onset of contractions, and the notion of capillary-to-mitochondrial diffusion distances as limiting O2 delivery. Today a wealth of physiological, morphological, and intravital microscopy evidence presents a completely different picture of microcirculatory control. Specifically, capillary red blood cell (RBC) and plasma flux is controlled primarily at the arteriolar level with most capillaries, in healthy muscle, supporting at least some flow at rest. In healthy skeletal muscle, this permits substrate access (whether carried in RBCs or plasma) to a prodigious total capillary surface area. Pathologies such as heart failure or diabetes decrease access to that exchange surface by reducing the proportion of flowing capillaries at rest and during exercise. Capillary morphology and function vary disparately among tissues. The contemporary model of capillary function explains how, following the onset of exercise, muscle O2 uptake kinetics can be extremely fast in health but slowed in heart failure and diabetes impairing contractile function and exercise tolerance. It is argued that adoption of this model is fundamental for understanding microvascular function and dysfunction and, as such, to the design and evaluation of effective therapeutic strategies to improve exercise tolerance and decrease morbidity and mortality in disease.

Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure

2021 ◽  
Author(s):  
Scott K. Ferguson ◽  
Mary Nina Woessner ◽  
Michael J. Holmes ◽  
Michael D. Belbis ◽  
Mattias Carlström ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Tolerance ◽  
Vascular Dysfunction ◽  
Vital Role ◽  
Inorganic Nitrate ◽  
Clinical Investigations ◽  
Improve Exercise Tolerance ◽  
Complementary Role ◽  
No Bioavailability

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Central to these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2 delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. While many pre-clinical investigations have suggested that enhanced reduction of nitrite to NO in low PO2 and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in HFrEF and HFpEF patients. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.

scholarly journals Impaired Exercise Tolerance in Heart Failure: Role of Skeletal Muscle Morphology and Function

2018 ◽  
Vol 15 (6) ◽  
pp. 323-331 ◽  
Author(s):  
Wesley J. Tucker ◽  
Mark J. Haykowsky ◽  
Yaewon Seo ◽  
Elisa Stehling ◽  
Daniel E. Forman
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Tolerance ◽  
Muscle Morphology ◽  
And Function

Abstract 1102: Cardiac-Specific Myosin Light Chain Kinase (MLCK), a Third Member of MLCK Family, Potentiates Sarcomere Formation and Cardiac Contraction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jason Y Chan ◽  
Morihiko Takeda ◽  
Laura E Briggs ◽  
Jonathan T Lu ◽  
Nobuo Horikoshi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Cardiac Hypertrophy ◽  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Contractile Function ◽  
Severe Heart Failure ◽  
Cardiac Contraction

Background: Two myosin light chain kinase (MLCK) proteins, skeletal (encoded by mylk2 gene) and smooth muscle MLCK (encoded by mylk1 gene) have been shown to be expressed in mammals. Human mylk2 has been mapped as a disease locus for familial cardiac hypertrophy (OMIM 606566 ), suggesting that abnormal function of skeletal MLCK stimulates cardiac hypertrophy. While phosphorylation of the putative substrate of skeletal MLCK, myosin light chain 2 (MLC2), is recognized as a key regulator of cardiac contraction, the abundance of skeletal MLCK in the heart is controversial, suggesting the existence of an additional MLCK that is preferentially expressed in cardiac muscle. Methods and Results: We characterized a new kinase named cardiac MLCK that is encoded by a gene homologous to mylk1 and 2 and is specifically expressed in the heart in both atrium and ventricle. Expression of cardiac MLCK was highly regulated by the cardiac homeobox transcription factor, Nkx2.5, in neonatal cardiomyocytes. The overall structure of cardiac MLCK protein is conserved with skeletal and smooth muscle MLCK including putative catalytic and adjacent Ca2+/calmodulin binding domains at the carboxyl-terminus. The amino-terminus is unique without significant homology to other known proteins. Cardiac MLCK phosphorylated MLC2v with a catalytic value of Km=4.3 micro M (Lineweaver-Burk analysis) indicating high affinity of cardiac MLCK to MLC2v, similar to the affinity of skeletal muscle MLCK to skeletal muscle MLC2 and smooth muscle MLCK to smooth muscle MLC2. Adenoviral-mediated overexpression of cardiac MLCK and knockdown of cardiac MLCK using RNAi in cultured cardiomyocytes revealed that cardiac MLCK regulates MLC2v phosphorylation, sarcomere organization and cardiac myocyte contraction. Expression of cardiac MLCK protein was significantly decreased in severe heart failure in vivo (post-myocardial infarction heart failure mouse model). Conclusion: Cardiac MLCK is a new key regulator of cardiac contraction and sarcomere organization. Reduction of cardiac MLCK function leading to decreased phosphorylation of MLC2v may contribute to compromised contractile function in the failing heart.

Protein catabolism and impairment of skeletal muscle insulin signalling in heart failure

2010 ◽  
Vol 119 (11) ◽  
pp. 465-466 ◽  
Author(s):  
P. Christian Schulze
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Protein ◽  
Insulin Signalling ◽  
Muscle Metabolism ◽  
Exercise Intolerance ◽  
Skeletal Muscle Protein ◽  
Glucose And Lipid Metabolism ◽  
Muscle Protein Metabolism ◽  
And Function

Derangements in systemic and local metabolism develop in patients with CHF [chronic HF (heart failure)] and contribute to the progression of the disease. Impaired skeletal muscle metabolism, morphology and function leading to exercise intolerance are hallmarks of the syndrome of CHF. These changes result in abnormal glucose and lipid metabolism, and the associated insulin resistance, which contribute to progression of skeletal muscle catabolism and development of muscle atrophy in patients with advanced HF. In the present issue of Clinical Science, Toth and co-workers demonstrate the impairment of skeletal muscle protein metabolism in patients with HF, and specifically show an impaired anabolic response in the skeletal muscle of these patients following a period of nutritional deficiency.

scholarly journals Skeletal Muscle Microvascular Dysfunction Manifests Early in Diabetic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Sadi Loai ◽  
Yu-Qing Zhou ◽  
Kyle D. W. Vollett ◽  
Hai-Ling Margaret Cheng
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Myocardial Perfusion ◽  
Cardiac Dysfunction ◽  
Exercise Tolerance ◽  
Time Course ◽  
Microvascular Dysfunction ◽  
Diabetic Rats ◽  
Exercise Intolerance ◽  
Muscle Perfusion

Aim: To perform a deep cardiac phenotyping of type II diabetes in a rat model, with the goal of gaining new insight into the temporality of microvascular dysfunction, cardiac dysfunction, and exercise intolerance at different stages of diabetes.Methods and Results: Diabetes was reproduced using a non-obese, diet-based, low-dose streptozotocin model in male rats (29 diabetic, 11 control). Time-course monitoring over 10 months was performed using echocardiography, treadmill exercise, photoacoustic perfusion imaging in myocardial and leg skeletal muscle, flow-mediated dilation, blood panel, and histology. Diabetic rats maintained a normal weight throughout. At early times (4 months), a non-significant reduction (30%) emerged in skeletal muscle perfusion and in exercise tolerance. At the same time, diabetic rats had a normal, slightly lower ejection fraction (63 vs. 71% control, p < 0.01), grade 1 diastolic dysfunction (E/A = 1.1 vs. 1.5, isovolumetric relaxation time = 34 vs. 27 ms; p < 0.01), mild systolic dysfunction (ejection time = 69 vs. 57 ms, isovolumetric contraction time = 21 vs. 17 ms; p < 0.01), and slightly enlarged left ventricle (8.3 vs. 7.6 mm diastole; p < 0.01). Diastolic dysfunction entered grade 3 at Month 8 (E/A = 1.7 vs. 1.3, p < 0.05). Exercise tolerance remained low in diabetic rats, with running distance declining by 60%; in contrast, control rats ran 60% farther by Month 5 (p < 0.05) and always remained above baseline. Leg muscle perfusion remained low in diabetic rats, becoming significantly lower than control by Month 10 (33% SO2 vs. 57% SO2, p < 0.01). Myocardial perfusion remained normal throughout. Femoral arterial reactivity was normal, but baseline velocity was 25% lower than control (p < 0.05). High blood pressure appeared late in diabetes (8 months). Histology confirmed absence of interstitial fibrosis, cardiomyocyte hypertrophy, or microvascular rarefaction in the diabetic heart. Rarefaction was also absent in leg skeletal muscle.Conclusion: Reduced skeletal muscle perfusion from microvascular dysfunction emerged early in diabetic rats, but myocardial perfusion remained normal throughout the study. At the same time, diabetic rats exhibited exercise intolerance and early cardiac dysfunction, in which changes related to heart failure with preserved ejection fraction (HFpEF) were seen. Importantly, skeletal muscle microvascular constrictionadvanced significantly before the late appearance of hypertension. HFpEF phenotypes such as cardiac hypertrophy, fibrosis, and rarefaction, which are typically associated with hypertension, were absent over the 10 month time-course of diabetes-related heart failure.

scholarly journals Targeting the DPP-4-GLP-1 pathway improves exercise tolerance in heart failure patients: a systematic review and meta-analysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chengcong Chen ◽  
Ying Huang ◽  
Yongmei Zeng ◽  
Xiyan Lu ◽  
Guoqing Dong
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Systematic Review ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Exercise Tolerance ◽  
Meta Analysis ◽  
Heart Failure Patients ◽  
Improve Exercise Tolerance

Abstract Background The most significant manifestation of heart failure is exercise intolerance. This systematic review and meta-analysis was performed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RAs), widely used anti-diabetic drugs, could improve exercise tolerance in heart failure patients with or without type 2 diabetes mellitus. Methods An electronic search of PubMed, EMBASE and the Cochrane Library was carried out through March 8th, 2019, for eligible trials. Only randomized controlled studies were included. The primary outcome was exercise tolerance [6-min walk test (6MWT) and peak O2 consumption], and the secondary outcomes included quality of life (QoL), adverse events (AEs) and all-cause death. Result After the literature was screened by two reviewers independently, four trials (659 patients) conducted with heart failure patients with or without type 2 diabetes met the eligibility criteria. The results suggested that targeting the DPP-4-GLP-1 pathway can improve exercise tolerance in heart failure patients [MD 24.88 (95% CI 5.45, 44.31), P = 0.01] without decreasing QoL [SMD -0.51 (95% CI -1.13, 0.10), P = 0.10]; additionally, targeting the DPP-4-GLP-1 pathway did not show signs of increasing the incidence of serious AEs or mortality. Conclusion Our results suggest that DPP-4 inhibitors or GLP-1 RAs improve exercise tolerance in heart failure patients. Although the use of these drugs for heart failure has not been approved by any organization, they may be a better choice for type 2 diabetes mellitus patients with heart failure. Furthermore, as this pathway contributes to the improvement of exercise tolerance, it may be worth further investigation in exercise-intolerant patients with other diseases.

Abstract 15025: Visceral Adiposity and Muscle Composition in Heart Failure With Preserved Ejection Fraction and Association With Exercise Tolerance

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Wendy Ying ◽  
Kavita Sharma ◽  
Lisa R Yanek ◽  
Dhananjay Vaidya ◽  
Michael Schar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Ejection Fraction ◽  
Exercise Tolerance ◽  
Nyha Class ◽  
Well Being ◽  
Liver Fat ◽  
Exercise Intolerance ◽  
Preserved Ejection Fraction ◽  
Intermuscular Fat

Introduction: Visceral adipose tissue (AT) promotes inflammation and adverse metabolic changes that mediate disease progression in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but little is known about its relation to the extent and distribution of AT. We characterized regional AT distribution in HFpEF patients and controls and analyzed associations with comorbidities and exercise tolerance. Methods: MRI was performed to quantify epicardial, liver, abdominal and thigh skeletal muscle AT. We assessed NYHA class, 6-minute walk distance (6MWD), and global well-being score (GWBS). Multivariable linear and logistic regression models were used, adjusted for age, sex, and body surface area. Results: We studied 55 HFpEF patients (41 women, mean age 67) and 33 controls (21 women, mean age 57). Epicardial AT (4.6 vs 3.2mm, p = 0.03), thigh intermuscular fat (11.0 vs 5.0cm 2 , p < 0.01) and liver fat fraction (FF) (6.4% vs 4.1%, p = 0.04) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal (443.9 vs 297.3 cm 2 , p = 0.03) and thigh (228.6 vs 112.3 cm 2 , p < 0.001) subcutaneous AT than men. Higher thigh intermuscular fat was associated with higher blood pressure (β [SE] 14.1 [3.3], p < 0.001) and diabetes (β [SE] 2.6 [1.1], p = 0.02), and liver FF was associated with chronic kidney disease (β [SE] 1.6 [0.6], p = 0.01). Higher thigh intramuscular fat was associated with both higher NYHA class and shorter 6MWD, and higher thigh intermuscular AT FF was associated with higher NYHA class ( Table ). Higher epicardial AT and liver FF were associated with lower GWBS. Conclusions: HFpEF patients have increased epicardial, liver, and skeletal muscle fat compared to controls out of proportion to their body size, and adiposity was associated with worse exercise intolerance in HFpEF. These results provide the basis for further investigation into regional AT distribution in relation to HFpEF symptoms and pathophysiology.

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