- Email: [email protected]
Detecting Skeletal Microvascular Flow Abnormalities in Diabetes
JACC: CARDIOVASCULAR IMAGING
VOL. 8, NO. 8, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jcmg.2014.12.034
EDITORIAL COMMENT
Detecting Skeletal Microvascular Flow Abnormalities in Diabetes Could Microvascular Recruitment Be a Fundamental Problem?* Thomas R. Porter, MD
P
atients with diabetes are at increased risk for
CIPU has provided new insights into skeletal
microvascular and macrovascular complica-
muscle flow abnormalities in diabetes (Table 1).
tions (1). When microvascular complications
Although different muscle groups and different forms
or poor blood glucose control occur in diabetic pa-
of exercise have been studied, CIPU has consistently
tients, the risk for cardiac complications increases
shown that diabetes is associated with abnormal
significantly, including sudden cardiac death (2).
skeletal blood flow reserve. The original work from
How might the development of microvascular compli-
Lindner’s group (4,5) using either plantar flexion or
cations in diabetes be related to skeletal blood flow ab-
handgrip exercise pointed to a potential defect in
normalities? In this issue of iJACC, Sacre et al. (3)
capillary
SEE PAGE 913
recruitment
(capillary
blood
volume
reserve) in patients with overt peripheral vascular disease or microvascular complications. Moreover,
examined skeletal microvascular blood flow abnor-
they demonstrated that abnormal capillary blood flow
malities with continuous infusion perfusion ultra-
reserve was not seen in diabetic patients who did not
sound (CIPU) in 117 diabetic patients who had no
have microvascular complications.
known microvascular or macrovascular complica-
Sacre et.al. (3), however, demonstrated that re-
tions. These were the typical overweight diabetic pa-
ductions in maximal oxygen uptake were not related
tients we see in clinic (mean age 59 years, mean body
to capillary blood volume reserve. Because they did
2
mass index 30.9 kg/m , duration of diabetes 3 to 10
not perform their exercise measurements of skeletal
years). Furthermore, these patients did not complain
blood flow until more than 2 min after exercise, it
of claudication and most likely did not have any sig-
may have prevented the detection of blood volume
nificant peripheral vascular disease. Nonetheless,
abnormalities. However, they did note that approxi-
reduced capillary blood flow in the quadriceps muscle
mately 25% of the patients had paradoxical re-
of diabetic patients during exercise was directly corre-
ductions in capillary blood volume in this time period
lated with impaired maximal oxygen uptake. Because
following exercise. Although this could have been
Sacre et al. (3) used contrast echocardiography during
explained by high resting values for plateau intensity
a continuous infusion of microbubbles, they were able
that may have led to erroneously blunted values at
to delineate that the main abnormality appeared to be
peak stress due to system saturation, we cannot rule
microvascular blood cell velocity reserve (red blood
out that this subgroup may represent a unique group
cell flux rates) and not capillary blood volume reserve.
that may be at higher risk for microvascular compli-
Muscle capillary blood velocity reserve was an inde-
cations. In addition, the investigators did have 32
pendent predictor of maximal oxygen uptake, as was
patients in their group that had microalbuminuria,
systolic (but not diastolic) functional reserve.
but their results were not analyzed separately from those without this early microvascular abnormality. Nonetheless, this interesting correlation between skeletal blood flow reserve and maximal oxygen up-
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Department of Cardiovascular Medicine, University of Nebraska
take, combined with the findings of others (4,5), indicates a potential link between skeletal blood flow reserve and the cardiovascular and microvascular
Medical Center, Omaha, Nebraska. Dr. Porter has received grant support
complications that complicate diabetes. Part of
from Astellas Pharma, Lantheus, GE Healthcare, and Philips Healthcare.
this may be defective nitric oxide availability or
Porter
JACC: CARDIOVASCULAR IMAGING, VOL. 8, NO. 8, 2015 AUGUST 2015:922–3
Editorial Comment
T A B L E 1 Methods Used With Continuous Infusion Perfusion Echocardiography to Explore Skeletal Muscle Blood Flow Abnormalities in
Different Type 2 Diabetic Populations
Muscle Group Studied
Defective Skeletal Blood Flow Abnormality
Form of Exercise
Limitations
Asymptomatic diabetics (3)
Quadriceps
Post-treadmill exercise
Reduced velocity reserve
No control subjects, no viscosity measurements
Microvascular disease (4)
Forearm flexor muscles
Handgrip exercise at 25% and 80%
Blunted capillary blood volume reserve
Small number of patients
Overt peripheral vascular disease (5)
Gastrocnemius soleus
Calibrated pedal ergometer
Blunted capillary blood volume and velocity reserve
No reference standard for disease severity
responsiveness, but independent problems in the
blood flow reserve was an independent predictor of
redistribution of flow to muscle capillary beds must
peak oxygen consumption.
also be explored. The effect of skeletal muscle blood
Further work is needed now to explore the role of
flow responses to exercise on blood glucose control
microvascular recruitment and capillary blood veloc-
and microvascular complications must be studied
ity reserve in the pathophysiology of diabetic micro-
further. If a link should be identified, it would be
vascular and macrovascular complications. Because
significant, because CIPU could be used to not only
skeletal microvascular assessments in all published
identify patients with defects in skeletal blood flow,
studies to date have only been examined at 1 point in
but it could be a method to assess the effects of
time, the large database that Sacre et al. (3) have
lifestyle and pharmacologic interventions that may
developed could now potentially be used to prospec-
prevent this serious complications.
tively examine what role defective blood velocity or
One important limitation with the study group of
blood volume reserve has on the development of
Sacre et al. (3) is that there were no control subjects.
microvascular and macrovascular complications. The
Previous studies have demonstrated that skeletal
link between plasma glucose levels, triglyceride
muscle flow reserve is not different in diabetics
levels, and viscosity with skeletal blood flow reserve
without overt microvascular reserve when compared
can now be explored longitudinally, to examine
with age-matched nondiabetic patients (4). The lack
whether aggressive exercise and pharmacologic mea-
of a control group is also important when looking at
sures that reduce these levels can improve skeletal
the composition of the patient group (overweight,
perfusion during exercise. With CIPU, these in-
increased abdominal girth, wide range of ages, 42%
vestigators and others (3–5) have the imaging tools
smokers, beta-blocker use), which may have affected
that could potentially help us explore the role of
maximal oxygen uptake. Also, as stated previously,
skeletal blood flow reserve in contributing to the
imaging was not performed during stress, but over
ravaging complications of diabetes.
2 min after stress, which may have limited the impact that capillary blood volume or velocity reserve played
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
in predicting peak oxygen consumption. Despite
Thomas R. Porter, Department of Cardiovascular Med-
these limitations, the series of multiple linear re-
icine, University of Nebraska Medical Center, Omaha,
gression models performed still indicated capillary
Nebraska 68198-1165. E-mail: [email protected].
REFERENCES 1. Fowler MJ. Microvascular and macrovascular com-
skeletal muscle blood flow reserve. J Am Coll
5. Lindner JR, Womack L, Barrett EJ, et al. Limb
plications of diabetes. Clin Diabetes 2008;26:77–82.
Cardiol Img 2015;8:913–21.
stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral artery disease severity. J Am Coll Cardiol Img 2008;1:343–50.
2. Jouven X, Lemaitre RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS. Diabetes, glucose level, and risk of sudden cardiac death. Eur Heart J 2005;26:2142–7. 3. Sacre JW, Jellis CL, Haluska BA, et al. Associa-
4. Womack L, Peters D, Barrett EJ, Kaul S, Price W, Lindner JR. Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications. J Am Coll Cardiol 2009;53:
tion of exercise intolerance in type 2 diabetes with
2175–83.
KEY WORDS contrast agents, diabetic cardiomyopathy, echocardiography, exercise test, perfusion
923
VOL. 8, NO. 8, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jcmg.2014.12.034
EDITORIAL COMMENT
Detecting Skeletal Microvascular Flow Abnormalities in Diabetes Could Microvascular Recruitment Be a Fundamental Problem?* Thomas R. Porter, MD
P
atients with diabetes are at increased risk for
CIPU has provided new insights into skeletal
microvascular and macrovascular complica-
muscle flow abnormalities in diabetes (Table 1).
tions (1). When microvascular complications
Although different muscle groups and different forms
or poor blood glucose control occur in diabetic pa-
of exercise have been studied, CIPU has consistently
tients, the risk for cardiac complications increases
shown that diabetes is associated with abnormal
significantly, including sudden cardiac death (2).
skeletal blood flow reserve. The original work from
How might the development of microvascular compli-
Lindner’s group (4,5) using either plantar flexion or
cations in diabetes be related to skeletal blood flow ab-
handgrip exercise pointed to a potential defect in
normalities? In this issue of iJACC, Sacre et al. (3)
capillary
SEE PAGE 913
recruitment
(capillary
blood
volume
reserve) in patients with overt peripheral vascular disease or microvascular complications. Moreover,
examined skeletal microvascular blood flow abnor-
they demonstrated that abnormal capillary blood flow
malities with continuous infusion perfusion ultra-
reserve was not seen in diabetic patients who did not
sound (CIPU) in 117 diabetic patients who had no
have microvascular complications.
known microvascular or macrovascular complica-
Sacre et.al. (3), however, demonstrated that re-
tions. These were the typical overweight diabetic pa-
ductions in maximal oxygen uptake were not related
tients we see in clinic (mean age 59 years, mean body
to capillary blood volume reserve. Because they did
2
mass index 30.9 kg/m , duration of diabetes 3 to 10
not perform their exercise measurements of skeletal
years). Furthermore, these patients did not complain
blood flow until more than 2 min after exercise, it
of claudication and most likely did not have any sig-
may have prevented the detection of blood volume
nificant peripheral vascular disease. Nonetheless,
abnormalities. However, they did note that approxi-
reduced capillary blood flow in the quadriceps muscle
mately 25% of the patients had paradoxical re-
of diabetic patients during exercise was directly corre-
ductions in capillary blood volume in this time period
lated with impaired maximal oxygen uptake. Because
following exercise. Although this could have been
Sacre et al. (3) used contrast echocardiography during
explained by high resting values for plateau intensity
a continuous infusion of microbubbles, they were able
that may have led to erroneously blunted values at
to delineate that the main abnormality appeared to be
peak stress due to system saturation, we cannot rule
microvascular blood cell velocity reserve (red blood
out that this subgroup may represent a unique group
cell flux rates) and not capillary blood volume reserve.
that may be at higher risk for microvascular compli-
Muscle capillary blood velocity reserve was an inde-
cations. In addition, the investigators did have 32
pendent predictor of maximal oxygen uptake, as was
patients in their group that had microalbuminuria,
systolic (but not diastolic) functional reserve.
but their results were not analyzed separately from those without this early microvascular abnormality. Nonetheless, this interesting correlation between skeletal blood flow reserve and maximal oxygen up-
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Department of Cardiovascular Medicine, University of Nebraska
take, combined with the findings of others (4,5), indicates a potential link between skeletal blood flow reserve and the cardiovascular and microvascular
Medical Center, Omaha, Nebraska. Dr. Porter has received grant support
complications that complicate diabetes. Part of
from Astellas Pharma, Lantheus, GE Healthcare, and Philips Healthcare.
this may be defective nitric oxide availability or
Porter
JACC: CARDIOVASCULAR IMAGING, VOL. 8, NO. 8, 2015 AUGUST 2015:922–3
Editorial Comment
T A B L E 1 Methods Used With Continuous Infusion Perfusion Echocardiography to Explore Skeletal Muscle Blood Flow Abnormalities in
Different Type 2 Diabetic Populations
Muscle Group Studied
Defective Skeletal Blood Flow Abnormality
Form of Exercise
Limitations
Asymptomatic diabetics (3)
Quadriceps
Post-treadmill exercise
Reduced velocity reserve
No control subjects, no viscosity measurements
Microvascular disease (4)
Forearm flexor muscles
Handgrip exercise at 25% and 80%
Blunted capillary blood volume reserve
Small number of patients
Overt peripheral vascular disease (5)
Gastrocnemius soleus
Calibrated pedal ergometer
Blunted capillary blood volume and velocity reserve
No reference standard for disease severity
responsiveness, but independent problems in the
blood flow reserve was an independent predictor of
redistribution of flow to muscle capillary beds must
peak oxygen consumption.
also be explored. The effect of skeletal muscle blood
Further work is needed now to explore the role of
flow responses to exercise on blood glucose control
microvascular recruitment and capillary blood veloc-
and microvascular complications must be studied
ity reserve in the pathophysiology of diabetic micro-
further. If a link should be identified, it would be
vascular and macrovascular complications. Because
significant, because CIPU could be used to not only
skeletal microvascular assessments in all published
identify patients with defects in skeletal blood flow,
studies to date have only been examined at 1 point in
but it could be a method to assess the effects of
time, the large database that Sacre et al. (3) have
lifestyle and pharmacologic interventions that may
developed could now potentially be used to prospec-
prevent this serious complications.
tively examine what role defective blood velocity or
One important limitation with the study group of
blood volume reserve has on the development of
Sacre et al. (3) is that there were no control subjects.
microvascular and macrovascular complications. The
Previous studies have demonstrated that skeletal
link between plasma glucose levels, triglyceride
muscle flow reserve is not different in diabetics
levels, and viscosity with skeletal blood flow reserve
without overt microvascular reserve when compared
can now be explored longitudinally, to examine
with age-matched nondiabetic patients (4). The lack
whether aggressive exercise and pharmacologic mea-
of a control group is also important when looking at
sures that reduce these levels can improve skeletal
the composition of the patient group (overweight,
perfusion during exercise. With CIPU, these in-
increased abdominal girth, wide range of ages, 42%
vestigators and others (3–5) have the imaging tools
smokers, beta-blocker use), which may have affected
that could potentially help us explore the role of
maximal oxygen uptake. Also, as stated previously,
skeletal blood flow reserve in contributing to the
imaging was not performed during stress, but over
ravaging complications of diabetes.
2 min after stress, which may have limited the impact that capillary blood volume or velocity reserve played
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
in predicting peak oxygen consumption. Despite
Thomas R. Porter, Department of Cardiovascular Med-
these limitations, the series of multiple linear re-
icine, University of Nebraska Medical Center, Omaha,
gression models performed still indicated capillary
Nebraska 68198-1165. E-mail: [email protected].
REFERENCES 1. Fowler MJ. Microvascular and macrovascular com-
skeletal muscle blood flow reserve. J Am Coll
5. Lindner JR, Womack L, Barrett EJ, et al. Limb
plications of diabetes. Clin Diabetes 2008;26:77–82.
Cardiol Img 2015;8:913–21.
stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral artery disease severity. J Am Coll Cardiol Img 2008;1:343–50.
2. Jouven X, Lemaitre RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS. Diabetes, glucose level, and risk of sudden cardiac death. Eur Heart J 2005;26:2142–7. 3. Sacre JW, Jellis CL, Haluska BA, et al. Associa-
4. Womack L, Peters D, Barrett EJ, Kaul S, Price W, Lindner JR. Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications. J Am Coll Cardiol 2009;53:
tion of exercise intolerance in type 2 diabetes with
2175–83.
KEY WORDS contrast agents, diabetic cardiomyopathy, echocardiography, exercise test, perfusion
923