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

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

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

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

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

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

Obstructivelesion

DecreasedCFR

Depletionof myocardial energy

stores

LV dysfunction

ECGchanges

Anginapectoris

0 10 20 30

Time (s)

Time

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

Meijboom, et al. JACC 2008; 52:636-43

Diagnostic Performance ofQCA, QCT, CCA, CTCA vs. FFR

Coronary Function vs. Anatomy With Diffuse CAD and Remodeling

Gould KL. JACC Imaging 2009; 2: 1009-23

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

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

Obstructivelesion

DecreasedCFR

Depletion of myocardial

energystores

LV dysfunction

ECGchanges

Anginapectoris

0 10 20 30

Time (s)

Time

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

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

Obstructivelesion

DecreasedCFR

Depletion of myocardial energy

stores

LV dysfunction

ECGchanges

Anginapectoris

0 10 20 30

Time (s)

Time

Na+ and Ca++ Homeostasis in Myocardial Ischemia

Normal Ischemia

Maier LS. J Cardiovasc Pharmacol 2009; 54:279-86

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

Obstructivelesion

DecreasedCFR

Depletion of myocardial energy

stores

LV dysfunction

ECGchanges

Anginapectoris

0 10 20 30

Time (s)

Time

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 !

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

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

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

Obstructivelesion

DecreasedCFR

Depletion of myocardial energy

stores

LV dysfunction

ECGchanges

Anginapectoris

0 10 20 30

Time (s)

Time

Angina Pectoris

Sangareddi, et al. Coron Artery Dis 2004;15:111-4

Classification and Severity of Angina

Sangareddi , et al. Coron Artery Dis 2004;15:111-4

Class I

Class II

Class III

Class IV

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

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

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

Glucocorticoid-Activated Descending Pathways from the Amygdala

Foreman and Qin. Cleve Clin J Med 2009;76 Suppl 2:S75-9

•Anxiety•Depression

Circulatingglucocorticoids

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

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

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.