Skeletal Muscle Microvascular Dysfunction Manifests Early in Diabetic Cardiomyopathy

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.

Impact of Cutaneous Blood Flow on NIR-DCS Measures of Skeletal Muscle Blood Flow Index

Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical technique for estimating relative changes in skeletal muscle perfusion during exercise, but may be affected by changes in cutaneous blood flow, as photons emitted by the laser must first pass through the skin. Accordingly, the purpose of this investigation was to examine how increased cutaneous blood flow affects NIR-DCS blood flow index (BFI) at rest and during exercise using a passive whole-body heating protocol that increases cutaneous, but not skeletal muscle, perfusion in the uncovered limb. BFI and cutaneous perfusion (laser Doppler flowmetry) were assessed in 15 healthy young subjects before (e.g., rest) and during 5-minutes of moderate-intensity hand-grip exercise in normothermic conditions and after cutaneous blood flow was elevated via whole-body heating. Hyperthermia significantly increased both cutaneous perfusion (~7.3-fold; p≤0.001) and NIR-DCS BFI (~4.5-fold; p≤0.001). Although relative BFI (i.e., fold-change above baseline) exhibited a typical exponential increase in muscle perfusion during normothermic exercise (2.81±0.95), there was almost no change in BFI during hyperthermic exercise (1.43±0.44). A subset of 8 subjects were subsequently treated with intradermal injection of botulinum toxin-A (Botox) to block heating-induced elevations in cutaneous blood flow, which 1) nearly abolished the hyperthermia-induced increase in BFI, and 2) restored BFI kinetics during hyperthermic exercise to values that were not different from normothermic exercise (p=0.091). Collectively, our results demonstrate that cutaneous blood flow can have a substantial, detrimental impact on NIR-DCS estimates of skeletal muscle perfusion and highlight the need for technical and/or pharmacological advancements to overcome this issue moving forward.

The effect of muscle contusion on cortical bone and muscle perfusion following reamed, intramedullary nailing: a novel canine tibia fracture model

Background Management of tibial fractures associated with soft tissue injury remains controversial. Previous studies have assessed perfusion of the fractured tibia and surrounding soft tissues in the setting of a normal soft tissue envelope. The purpose of this study was to determine the effects of muscle contusion on blood flow to the tibial cortex and muscle during reamed, intramedullary nailing of a tibial fracture. Methods Eleven adult canines were distributed into two groups, Contusion or No-Contusion. The left tibia of each canine underwent segmental osteotomy followed by limited reaming and locked intramedullary nailing. Six of the 11 canines had the anterior muscle compartment contused in a standardized fashion. Laser doppler flowmetry was used to measure cortical bone and muscle perfusion during the index procedure and at 11 weeks post-operatively. Results Following a standardized contusion, muscle perfusion in the Contusion group was higher compared to the No-Contusion group at post-osteotomy and post-reaming (p < 0.05). Bone perfusion decreased to a larger extent in the Contusion group compared to the No-Contusion group following osteotomy (p < 0.05), and the difference in bone perfusion between the two groups remained significant throughout the entire procedure (p < 0.05). At 11 weeks, muscle perfusion was similar in both groups (p > 0.05). There was a sustained decrease in overall bone perfusion in the Contusion group at 11 weeks, compared to the No-Contusion group (p < 0.05). Conclusions Injury to the soft tissue envelope may have some deleterious effects on intraosseous circulation. This could have some influence on the fixation method for tibia fractures linked with significant soft tissue injury.

The effect of muscle contusion on cortical bone and muscle perfusion following reamed, intramedullary nailing: a novel canine tibia fracture model

Background Management of tibial fractures associated with soft tissue injury remains controversial. Previous studies have assessed perfusion of the fractured tibia and surrounding soft tissues in the setting of a normal soft tissue envelope. The purpose of this study was to determine the effects of muscle contusion on blood flow to the tibial cortex and muscle during reamed, intramedullary nailing of a tibial fracture. Methods Eleven adult canines were distributed into two groups, Contusion or No-Contusion. The left tibia of each canine underwent segmental osteotomy followed by limited reaming and locked intramedullary nailing. Six of the 11 canines had the anterior muscle compartment contused in a standardized fashion. Laser doppler flowmetry was used to measure cortical bone and muscle perfusion during the index procedure and at 11 weeks post-operatively. Results Following a standardized contusion, muscle perfusion in the Contusion group was higher compared to the No-Contusion group at post-osteotomy and post-reaming (p < 0.05). Bone perfusion decreased to a larger extent in the Contusion group compared to the No-Contusion group following osteotomy (p < 0.05), and the difference in bone perfusion between the two groups remained significant throughout the entire procedure (p < 0.05). At 11 weeks, muscle perfusion was similar in both groups (p > 0.05). There was a sustained decrease in overall bone perfusion in the Contusion group at 11 weeks, compared to the No-Contusion group (p < 0.05). Conclusions Injury to the soft tissue envelope may have some deleterious effects on intraosseous circulation. This could have some influence on the fixation method for tibia fractures linked with significant soft tissue injury.

Histamine H1 and H2 receptors are essential transducers of the integrative exercise training response in humans

Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H1/H2 receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H1/H2 receptors were pharmaceutically blocked. Our work suggests that histamine H1/H2 receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.

Pilot study of contrast-free MRI reveals significantly impaired calf skeletal muscle perfusion in diabetes with incompressible peripheral arteries

Patients with diabetes mellitus (DM) are more likely to have densely calcified lesions in the below-the-knee tibial arteries. However, the relationship between peripheral arterial calcification and local skeletal muscle perfusion has not been explored. Thirty subjects were prospectively recruited into three groups in this pilot study: (1) Non-DM: 10 people without DM; (2) DM, ABI < 1.3: 10 people with DM and normal ankle–brachial index (ABI) (0.9–1.3); and (3) DM, ABI ⩾ 1.3: 10 people with DM and ABI ⩾ 1.3. All subjects underwent calf perfusion measurements at rest and during an isometric plantarflexion contraction exercise within the magnetic resonance imaging (MRI) system. The noncontrast MRI techniques were applied to quantitatively assess skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in medial gastrocnemius and soleus muscles. Both SMBF and SMOEF reserves were calculated as the ratio of the exercise value to the resting value. Exercise SMBF and SMOEF values in the medial gastrocnemius muscle were lower in the two DM groups than in the non-DM group ( p < 0.05). The SMBF reserve in medial gastrocnemius was significantly lower in the DM, ABI ⩾ 1.3 group compared to the DM, ABI < 1.3 group ( p < 0.05). This study demonstrates that people with DM and calcified arteries had lower perfusion in gastrocnemius muscle compared to those without DM and those with DM and a normal ABI.