- Email: [email protected]
Microvascular Function in Ischemic Heart Disease
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 9, NO. 4, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
Letters TO THE EDITOR
index myocardial infarction, time from qualifying myocardial infarction to randomization, history of percutaneous coronary intervention, presence or
Microvascular Function in Ischemic Heart Disease There May Be Room for Improvement
absence of diabetes, presence or absence of multivessel coronary disease, presence or absence of chronic kidney disease, aspirin dose, and geographic region. However, the heterogeneity in the efficacy of ticagrelor in relation to the presence of high microvascular resistance has never been explored. The
We have read with great interest the papers written by
annual risk for stable patients after the first 12 months
Sara et al. (1) and Patel et al. (2), as well as the editorial
when treated with aspirin as the only antithrombotic
by Yoo and Samady (3), related to physiological testing
drug in addition to an optimal secondary prevention is
in ischemic heart disease. Knowledge of the physio-
only on average 1.0% to 2.0% for nonfatal myocardial
logical basis of ischemic heart disease is extensive, and
infarction, 1.0% for cardiovascular mortality, 0.5% for
few gaps can be found with regard to traditional coro-
ischemic stroke, and 0.5% for stent thrombosis (5), and
nary risk factors, the development and progression of
it may be difficult to demonstrate benefit when we
coronary plaques, and the processes of athero-
compare different antiplatelet strategies in these pa-
thrombosis that can affect the coronary tree. Mean-
tients as could have occurred in PEGASUS. The double
ingful improvements in noninvasive tests provide us
property of ticagrelor with platelet inhibition and also
with invaluable screening information, and coronary
its adenosine-like effect could be more effective in
angiography reinforced with fractional flow reserve
the subgroup of patients with high microvascular
and instantaneous wave-free ratio allow us to decide
resistance. Although it would be difficult to stratify
the most appropriate approach. Finally, the excep-
patients according to the microvascular resistance in
tional progress in the pharmacological armamen-
real practice, we might find that ticagrelor is more
tarium combined with great advances in percutaneous
beneficial in this subgroup compared with other mo-
and surgical techniques have achieved very successful
dalities of double antiplatelet therapy or even as single
results. There is, however, a lack of information related
therapy instead of aspirin in the mid- and long term.
to the phenomena that occur in the microvasculature, and there is also some pessimism because the studies carried out to date that explored potential effective therapies have not brought positive results. In our opinion, there may be room for improvement in those patients with obstructive coronary disease who require long-term antiplatelet therapy, and the benefits of ticagrelor in comparison with other antiplatelet agents should be investigated. Its molecular similarity to adenosine increases the plasma levels of the latter by inhibiting its uptake by erythrocytes (4), and this action could have a beneficial effect in decreasing the microvascular resistance. The strong relationship between microvascular resistance and prognosis has been previously demonstrated. In the PEGASUS (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) trial, as is pointed out in the main paper. There was no apparent heterogeneity in the efficacy of ticagrelor at either dose with respect to the risk of the primary composite endpoint across all of the major subgroups: age, sex, race, weight, type of
*Iñigo Lozano, MD, PhD Juan Rondan, MD, PhD Jose M. Vegas, MD Eduardo Segovia, MD *Departamento de Cardiología Hospital de Cabueñes Avenida Los Prados, 395 Gijón, 33203 Spain E-mail: [email protected] http://dx.doi.org/10.1016/j.jcin.2015.10.041 Please note: Dr. Lozano has presented lectures on ticagrelor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. J Am Coll Cardiol Intv 2015;8:1445–53. 2. Patel N, Petraco R, Dall’Armellina E, Kassimis G, et al. Zero-flow pressure measured immediately after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction provides the best invasive index for predicting the extent of myocardial infarction at 6 months: an OxAMI study (Oxford Acute Myocardial Infarction). J Am Coll Cardiol Intv 2015;8:1410–21.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 4, 2016
Letters to the Editor
FEBRUARY 22, 2016:392–6
3. Yoo SY, Samady H. Can advanced physiological testing bridge the gap between chest pain and nonobstructive coronary atherosclerosis? J Am Coll Cardiol Intv 2015;8:1454–6. 4. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7.
CMD,
exacerbating
perfusion
imbalance
and
explaining why xanthines may have a role in managing microvascular angina. The precise clinical role of ticagrelor and xanthines and the underlying molecular pathways involved require greater clarifica-
5. Wallentin L. Commentary on the OPTIDUAL trial results: how to optimise
tion with larger clinical trials, and may ultimately
prolonged dual antiplatelet treatment and independent randomised clinical trials. Eur Heart J 2016;37:375–7.
trigger a new direction in the search for therapies directed at CMD. Xanthines may also exhibit their analgesic effect through inhibition of cardiac nerve
REPLY: Microvascular Function in Ischemic Heart Disease
fibers, and if found to be more efficacious, may lead the way for the development of therapies directed at
There May Be Room for Improvement
modulating neuropathic pain/pain perception, which is thought to be deregulated in patients with micro-
We recently showed that coronary microvascular
vascular angina. Alternatively, if ticagrelor is more
dysfunction (CMD) is present in up to two-thirds of
efficacious, it may open the door to evaluating drugs
patients presenting with signs and symptoms of sta-
that
ble myocardial ischemia and nonobstructive coronary
creating novel uses for commonly prescribed drugs,
artery disease at coronary angiography (1). Although
including cyclo-oxygenase inhibitors.
modulate
microvascular
tone,
potentially
it is known that CMD is associated with adverse carporting therapies that improve CMD is lacking, as
Jaskanwal D. Sara, MB, ChB *Amir Lerman, MD
highlighted by Dr. Lozano and colleagues in their
*Division of Cardiovascular Diseases
letter to the editor. Therapy may be directed at
Department of Internal Medicine
improving
Mayo College of Medicine
diovascular events, we agree that the evidence sup-
symptoms
and/or
reducing
the
risk
of cardiovascular events, and although the majority
200 First Street SW
of evidence focuses on the former, there certainly
Rochester, Minnesota 55905
remains “room for improvement” in this area. Indeed,
E-mail: [email protected]
reports have shown that beta-blockers may improve
http://dx.doi.org/10.1016/j.jcin.2015.11.029
chest pain in patients with CMD, but do not support the role of calcium channel blockers (2). Further, ev-
Please note: All authors have reported that they do not have any relationships relevant to the contents of this paper to disclose.
idence is either inconsistent or lacking with regard to the efficacy of short- and long-acting nitrates in pa-
REFERENCES
tients with microvascular angina, and among novel
1. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. J Am Coll Cardiol Intv 2015; 8:1445–53.
antianginals, ranolazine may be superior to ivabradine, but recently presented data by Bairey Merz et al. (3) suggest that ranolazine may still be inefficacious in managing chest pain associated with CMD. Dr. Lozano and colleagues highlight a potential novel use for ticagrelor in the management of microvascular angina, which putatively enhances the bioavailability of adenosine (4), leading to microvascular vasodilation and improved myocardial perfusion. Thus, ticagrelor could create a therapeutic opportunity from the concepts that underlie diagnostic testing for CMD in which intracoronary injections of adenosine are used to induce hyperemia.
2. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X. Am J Cardiol 1999;84:854–6. 3. Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebocontrolled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J 2015 Nov 27 [E-pub ahead of print]. 4. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7. 5. Elliott PM, Krzyzowska-Dickinson K, Calvino R, Hann C, Kaski JC. Effect of oral aminophylline in patients with angina and normal coronary arteriograms (syndrome X). Heart 1997;77:523–6.
However, although no study has evaluated the role of ticagrelor in managing microvascular angina, xanthines, which inhibit microvascular vasodilation by
REPLY: Microvascular Function in
antagonizing adenosine receptors, have paradoxically
Ischemic Heart Disease
been shown to improve chest pain in patients with
There May Be Room for Improvement
CMD (5). It may be that adenosine-mediated smooth muscle vasodilation of functionally intact microcir-
The subject of our editorial regarding the paper by
culation distributes blood flow away from regions of
Sara et al. (1) was the use of intravascular imaging
393
VOL. 9, NO. 4, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
Letters TO THE EDITOR
index myocardial infarction, time from qualifying myocardial infarction to randomization, history of percutaneous coronary intervention, presence or
Microvascular Function in Ischemic Heart Disease There May Be Room for Improvement
absence of diabetes, presence or absence of multivessel coronary disease, presence or absence of chronic kidney disease, aspirin dose, and geographic region. However, the heterogeneity in the efficacy of ticagrelor in relation to the presence of high microvascular resistance has never been explored. The
We have read with great interest the papers written by
annual risk for stable patients after the first 12 months
Sara et al. (1) and Patel et al. (2), as well as the editorial
when treated with aspirin as the only antithrombotic
by Yoo and Samady (3), related to physiological testing
drug in addition to an optimal secondary prevention is
in ischemic heart disease. Knowledge of the physio-
only on average 1.0% to 2.0% for nonfatal myocardial
logical basis of ischemic heart disease is extensive, and
infarction, 1.0% for cardiovascular mortality, 0.5% for
few gaps can be found with regard to traditional coro-
ischemic stroke, and 0.5% for stent thrombosis (5), and
nary risk factors, the development and progression of
it may be difficult to demonstrate benefit when we
coronary plaques, and the processes of athero-
compare different antiplatelet strategies in these pa-
thrombosis that can affect the coronary tree. Mean-
tients as could have occurred in PEGASUS. The double
ingful improvements in noninvasive tests provide us
property of ticagrelor with platelet inhibition and also
with invaluable screening information, and coronary
its adenosine-like effect could be more effective in
angiography reinforced with fractional flow reserve
the subgroup of patients with high microvascular
and instantaneous wave-free ratio allow us to decide
resistance. Although it would be difficult to stratify
the most appropriate approach. Finally, the excep-
patients according to the microvascular resistance in
tional progress in the pharmacological armamen-
real practice, we might find that ticagrelor is more
tarium combined with great advances in percutaneous
beneficial in this subgroup compared with other mo-
and surgical techniques have achieved very successful
dalities of double antiplatelet therapy or even as single
results. There is, however, a lack of information related
therapy instead of aspirin in the mid- and long term.
to the phenomena that occur in the microvasculature, and there is also some pessimism because the studies carried out to date that explored potential effective therapies have not brought positive results. In our opinion, there may be room for improvement in those patients with obstructive coronary disease who require long-term antiplatelet therapy, and the benefits of ticagrelor in comparison with other antiplatelet agents should be investigated. Its molecular similarity to adenosine increases the plasma levels of the latter by inhibiting its uptake by erythrocytes (4), and this action could have a beneficial effect in decreasing the microvascular resistance. The strong relationship between microvascular resistance and prognosis has been previously demonstrated. In the PEGASUS (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) trial, as is pointed out in the main paper. There was no apparent heterogeneity in the efficacy of ticagrelor at either dose with respect to the risk of the primary composite endpoint across all of the major subgroups: age, sex, race, weight, type of
*Iñigo Lozano, MD, PhD Juan Rondan, MD, PhD Jose M. Vegas, MD Eduardo Segovia, MD *Departamento de Cardiología Hospital de Cabueñes Avenida Los Prados, 395 Gijón, 33203 Spain E-mail: [email protected] http://dx.doi.org/10.1016/j.jcin.2015.10.041 Please note: Dr. Lozano has presented lectures on ticagrelor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. J Am Coll Cardiol Intv 2015;8:1445–53. 2. Patel N, Petraco R, Dall’Armellina E, Kassimis G, et al. Zero-flow pressure measured immediately after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction provides the best invasive index for predicting the extent of myocardial infarction at 6 months: an OxAMI study (Oxford Acute Myocardial Infarction). J Am Coll Cardiol Intv 2015;8:1410–21.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 4, 2016
Letters to the Editor
FEBRUARY 22, 2016:392–6
3. Yoo SY, Samady H. Can advanced physiological testing bridge the gap between chest pain and nonobstructive coronary atherosclerosis? J Am Coll Cardiol Intv 2015;8:1454–6. 4. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7.
CMD,
exacerbating
perfusion
imbalance
and
explaining why xanthines may have a role in managing microvascular angina. The precise clinical role of ticagrelor and xanthines and the underlying molecular pathways involved require greater clarifica-
5. Wallentin L. Commentary on the OPTIDUAL trial results: how to optimise
tion with larger clinical trials, and may ultimately
prolonged dual antiplatelet treatment and independent randomised clinical trials. Eur Heart J 2016;37:375–7.
trigger a new direction in the search for therapies directed at CMD. Xanthines may also exhibit their analgesic effect through inhibition of cardiac nerve
REPLY: Microvascular Function in Ischemic Heart Disease
fibers, and if found to be more efficacious, may lead the way for the development of therapies directed at
There May Be Room for Improvement
modulating neuropathic pain/pain perception, which is thought to be deregulated in patients with micro-
We recently showed that coronary microvascular
vascular angina. Alternatively, if ticagrelor is more
dysfunction (CMD) is present in up to two-thirds of
efficacious, it may open the door to evaluating drugs
patients presenting with signs and symptoms of sta-
that
ble myocardial ischemia and nonobstructive coronary
creating novel uses for commonly prescribed drugs,
artery disease at coronary angiography (1). Although
including cyclo-oxygenase inhibitors.
modulate
microvascular
tone,
potentially
it is known that CMD is associated with adverse carporting therapies that improve CMD is lacking, as
Jaskanwal D. Sara, MB, ChB *Amir Lerman, MD
highlighted by Dr. Lozano and colleagues in their
*Division of Cardiovascular Diseases
letter to the editor. Therapy may be directed at
Department of Internal Medicine
improving
Mayo College of Medicine
diovascular events, we agree that the evidence sup-
symptoms
and/or
reducing
the
risk
of cardiovascular events, and although the majority
200 First Street SW
of evidence focuses on the former, there certainly
Rochester, Minnesota 55905
remains “room for improvement” in this area. Indeed,
E-mail: [email protected]
reports have shown that beta-blockers may improve
http://dx.doi.org/10.1016/j.jcin.2015.11.029
chest pain in patients with CMD, but do not support the role of calcium channel blockers (2). Further, ev-
Please note: All authors have reported that they do not have any relationships relevant to the contents of this paper to disclose.
idence is either inconsistent or lacking with regard to the efficacy of short- and long-acting nitrates in pa-
REFERENCES
tients with microvascular angina, and among novel
1. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. J Am Coll Cardiol Intv 2015; 8:1445–53.
antianginals, ranolazine may be superior to ivabradine, but recently presented data by Bairey Merz et al. (3) suggest that ranolazine may still be inefficacious in managing chest pain associated with CMD. Dr. Lozano and colleagues highlight a potential novel use for ticagrelor in the management of microvascular angina, which putatively enhances the bioavailability of adenosine (4), leading to microvascular vasodilation and improved myocardial perfusion. Thus, ticagrelor could create a therapeutic opportunity from the concepts that underlie diagnostic testing for CMD in which intracoronary injections of adenosine are used to induce hyperemia.
2. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X. Am J Cardiol 1999;84:854–6. 3. Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebocontrolled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J 2015 Nov 27 [E-pub ahead of print]. 4. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7. 5. Elliott PM, Krzyzowska-Dickinson K, Calvino R, Hann C, Kaski JC. Effect of oral aminophylline in patients with angina and normal coronary arteriograms (syndrome X). Heart 1997;77:523–6.
However, although no study has evaluated the role of ticagrelor in managing microvascular angina, xanthines, which inhibit microvascular vasodilation by
REPLY: Microvascular Function in
antagonizing adenosine receptors, have paradoxically
Ischemic Heart Disease
been shown to improve chest pain in patients with
There May Be Room for Improvement
CMD (5). It may be that adenosine-mediated smooth muscle vasodilation of functionally intact microcir-
The subject of our editorial regarding the paper by
culation distributes blood flow away from regions of
Sara et al. (1) was the use of intravascular imaging
393