understanding the pathophysiology of ischemic chronic ... · pathophysiological processes following...
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Understanding the Pathophysiology of Ischemic Chronic Heart Disease: Stable Angina the Tip of the Iceberg
Filippos Triposkiadis, MD, FESC, FACCProfessor of Cardiology
Director, Department of CardiologyLarissa University Hospital
Larissa, Greece
1st EUROPEAN MEETING OF CARDIOLOGY PRACTICE
Naples, April 16th-18th, 2010
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Ischemic Chronic HeartDisease
Myocardial O2
demand
Myocardial O2
supply
Myocardial Ischemia
Angina
Flow-Limiting Lesion
Relief
•Nitroglycerin•Interruption of
activity
Physical /emotional stress
•Blood pressure•Heart Rate•Contractility
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Angina Prevalence
Murphy, et al. Heart 2006 92: 1047-1054
Age (years)
0
20
40
60
80
100
120
140
160
< 45 45-54 55-64 65-74 75-84 ≥ 85 ≥ 65 ≥ 75 Αll ages
1
18,3
56,6
106,6
127,3
96,1
112,5
119,7
26,3
Series1
Per 1
00
0 P
op
ula
tion
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Per 1
00
0 P
op
ula
tion
Angina Incidence
Murphy, et al. Heart 2006 92: 1047-1054
Age (years)
0
1
2
3
4
5
6
7
8
< 45 45-54 55-64 65-74 75-84 ≥ 85 ≥ 65 ≥ 75 Αll ages
0,1
2
3,9
5,4
5,9
3,2
5,3 5,2
1,6
Series1
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Τhe Euro Heart Survey of Stable Angina
The Euro Heart Survey of Stable Angina set out to prospectively study thepresentation and management of pts with stable angina as first seen by a cardiologist
in Europe. 3779 patients were included in the analysis.
Daly, et al. European Heart Journal 2005; 26: 996–1010
Clinical details of patients presenting with stable angina
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Obstructivelesion
Decreasedcoronary flow
reserve
Depletionof myocardial energy
stores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time Course of Events During Myocardial Ischemia
Modified from. Sigwart U, et al. Ischemic events during coronary artery balloon occlusion. In: Rutishauser W, Roskamm H, editors. Silent myocardial ischemia. Berlin: Springer-Verlag; 1984; 29 – 36.
Time
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Obstructivelesion
DecreasedCFR
Depletionof myocardial energy
stores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time
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Experimental vs. ClinicalStenosis Severity
Gould, et al. Am J Cardiol 1974;33:87-94 White, et al. N Engl J Med 1984 ; 310: 819-24
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Meijboom, et al. JACC 2008; 52:636-43
Diagnostic Performance ofQCA, QCT, CCA, CTCA vs. FFR
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Coronary Function vs. Anatomy With Diffuse CAD and Remodeling
Gould KL. JACC Imaging 2009; 2: 1009-23
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Coronary Artery and Dependent Myocardial Vascular Bed
Pijls and De Bruyne. Heart 1998;80:539–542
FFR=(Pd − P v )/(Pa − Pv )= Pd /P a
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Coronary Function Versus Stenosis and Outcome
Tonino, et al. N Engl J Med 2009;360:213–24
Boden, et al. N Engl J Med 2007;356:1503–16
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Obstructivelesion
DecreasedCFR
Depletion of myocardial
energystores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time
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Glucose and Fatty Acid Metabolism in the Aerobic Heart
Wang and Lopaschuk. Expert Rev Cardiovasc Ther 2007; 5:1123-34
Glucose
Lactate
Glycolysis
Pyruvate
PDH
TCA
Cytosol
Mitochondria
Acetyl-CoA
ETC ATP
O2
Acyl-CoA
Acyl-CoA
Β-oxidation
Fatty acid
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Glucose and Fatty Acid Metabolism During Myocardial
Ischemia/Reperfusion
Wang and Lopaschuk. Expert Rev Cardiovasc Ther 2007; 5:1123-34
Glucose
Lactate
Glycolysis
Pyruvate
PDH
TCA
Cytosol
Mitochondria
Acetyl-CoA
ETC ATP
O2
Acyl-CoA
Acyl-CoA
Β-oxidation
Η+
Η+
Να+
Να+
Ca++
Ca++
X
X
Fatty acid
X
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Obstructivelesion
DecreasedCFR
Depletion of myocardial energy
stores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time
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Na+ and Ca++ Homeostasis in Myocardial Ischemia
Normal Ischemia
Maier LS. J Cardiovasc Pharmacol 2009; 54:279-86
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O2 and ATP
Na+
Ca++
Myofilamentactivation
LVEDP
LV Wall Tension
Extravascularcompression
LV SystolicDysfunction
Late INa
NCX
Maier LS. J Cardiovasc Pharmacol 2009; 54:279-86
Na+ Handling and LV Dysfunction in Myocardial Ischemia
•Electrical instability•Mitochondrial dysfunction
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Obstructivelesion
DecreasedCFR
Depletion of myocardial energy
stores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time
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An ischemic episode is defined as ≥ 1 mm horizontal or down-sloping ST segment depression lasting at least one minute and separated from other episodes by at least one minute (1X1X1 rule)
Before Episode
During Episode
After Episode
ECG during Ischemic Episode
Deedwania and Stone. Curr Probl Cardiol 2001;26:680-727
Three quarters of ischemicepisodes are asymptomatic !
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Multicenter Study of Myocardial Ischemia (MSMI) (n=936)No increase in cardiac events associated with ambulatory ischemia (silent or symptomatic) in stable patients 1 to 6 months after MI or UA.
JAMA 1993;269:2379-85
The Total Ischemic Burden Bisoprolol Study (TIBBS) (n=520) Atenolol and Silent Ischemia Study (ASIST) (n=306) Asymptomatic Cardiac Ischemia Pilot Study (ACIP) (n=496)Ambulatory ischemia is associated with adverse outcome (subjective end points such as revascularization and aggravation of angina were included).
JACC 1996;28:20–4/Circulation 1994;90:762–8/AJC 1997;80:1395–1401
Angina Pectoris Study In Stockholm (APSIS)(n=686)Treatment reduces ambulatory ischemia but does not influence prognosis.
Am J Cardiol 1999;84:1151–7
Total Ischemic Burden European Trial (TIBET)(n=682)Recording of ischemic events in Holter monitoring fails to predict cardiac events (hard or soft).
Eur Heart J 1996;17:104–12
Prognostic Significance of Ambulatory Ischemia in Stable CAD
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Patterson, et al. J Am Coll Cardiol 1989;13:1653-60
Calculation of CAD Probability
45 year-old asymptomatic man with no risk factors
Clinical pretestprobability of CAD present
Po
stt
est
pro
bab
ilit
y o
f C
AD
presen
t
55 year-old man with typical angina
45 year-old asymptomatic man with hypercholesterolemia,hypertension, and diabetes
45 year-old man with atypical chestpain
+ST
-ST
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Duke Exercise Score
Marwick, et al. Circulation 2001;103:2566-71
ST-segmentdeviation during
exercise
Ischemia-reading
line
Angina duringexercise
Prognosis Duration ofexercise
Mark, et al. Ann Intern Med 1987;106:793-800
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Obstructivelesion
DecreasedCFR
Depletion of myocardial energy
stores
LV dysfunction
ECGchanges
Anginapectoris
0 10 20 30
Time (s)
Time
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Angina Pectoris
Sangareddi, et al. Coron Artery Dis 2004;15:111-4
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Classification and Severity of Angina
Sangareddi , et al. Coron Artery Dis 2004;15:111-4
Class I
Class II
Class III
Class IV
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Anginal Stability: a measure of whether a patient’s symptoms are changing over time
Anginal Frequency: a measure of how often a patient is having symptoms now
Physical Limitation: a measure of how much a patient’s condition is hampering his ability to do what he wants to do
Treatment Satisfaction: a measure of how well a patient understands her care and what she thinks of it
Quality of Life: a measure of the overall impact of a patient’s condition on a patient’s interpersonal relationships and state of mind
Spertus, et al. J Am Coll Cardiol 1995;25:333-41
Seattle Angina Questionnaire
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Prognostic utility of the Seattle Angina Questionnaire (SAQ) for patients with CAD. Pts were enrolled in a prospective cohort study from 6 VA General Internal Medicine Clinics. All pts reporting CAD who completed a SAQ and had 1 year of follow-up were analyzed (n=5558). The primary outcome was 1-year all-cause mortality.
Survival Curves by Range of SAQ Physical Limitation Score
Spertus, et al. Circulation. 2002;106:43-49
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Angina Pectoris: Nervous andNeurohumoral (?) Pathways
Autonomicnervoussystem
Limbicsystem
Mechanical andchemicalstimuli
?
Angina pectoris
Somato sensible cortex
Thalamus(coordination and integration)
Spinothalamic tract
Dorsal horn neurons
Dorsal root ganglion
Cardiac sensory fibers(extrinsic cardiac ganglia)
Intrinsic cardiac neurons(intrinsic cardiac ganglia)
Myocardial ischemia
DeJongste, et al. Heart 2004; 90:225-30
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Glucocorticoid-Activated Descending Pathways from the Amygdala
Foreman and Qin. Cleve Clin J Med 2009;76 Suppl 2:S75-9
•Anxiety•Depression
Circulatingglucocorticoids
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myocardial injury in ischemic areas,
which may involve the whole
myocardium.
Neurogenic Hypothesis of Cardiac Ischemic Pain
Ischemia
Ischemia stimulates sensory nerve endings of the heart to release neuropeptides and neurotrans-mitters.
Initiation and aggravation of myocardial injury in ischemic areas, which may involve the whole myocardium.
The nerve endings in the injury tissue are sensitized and more and stronger nociceptive stimuli are produced , and ascend to CNS.
Nociception of CNS might also be sensitized and increased, resulting in more efferent impulses and more secretion of nerve endings.
Wang, et al. Medical Hypotheses 2009; 72:402-4
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SCS and Refractory Angina:Review and Meta-Analysis of RCTs
7 RCTs were identified in a total of 270 refractory angina patients
Exercise capacity
Taylor, et al. BMC Cardiovascular Disorders 2009; 9:13
Ischemic burden
SCS
Pain perception
Sympathetic tone
Myocardial O2
Supply/DemandRatio
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Conclusions
Angina pectoris is considered to be the symptomatic result of chromic ischemic heart disease, which is characterized by the presence of obstructive lesions in the coronaries leading to a decrease in coronary flow reserve.
In outpatients with ischemic chronic heart disease, the patients’ health status (symptoms, physical function, and quality of life) is a strong predictor of subsequent mortality and admission for acute coronary syndrome.
Neurogenic inflammation and neurogenic activity might participate in the pathophysiological processes following myocardial ischemia and contribute to themyocardial ischemic injury.
Antiaginal interventions could not only relieve the pain symptoms, but also block nociception of body and neurogenic reaction induced by ischemia, thereby extenuating ischemic myocardial injury and offering myocardial protection.