Ischaemic heart disease

Coronary supply

• LAD: apex, anterior wall of left ventricle, anterior 2/3rd of ventricular septum

• RCA or LCX giving rise to posterior descending branch .

• Right dominant circulation: Circumflex branch of left coronary artery perfuse only the lateral wall of left ventricle. The RCA supplies entire right ventricular free wall and the posterobasal wall of left ventricle and posterior 3rd of septum.

Ischemic heart disease (IHD)

• Definition

• Epidemiology

• Pathogenesis (Acute plaque change, Inflammation, thrombus, vasoconstriction)

• Angina pectoris

• Myocardial infarction

• Chronic IHD

• SCD

Ischemic heart disease (IHD)

• Is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium.

• It typically occurs when there is an imbalance between myocardial oxygen supply and demand.

• The most common cause of myocardial ischemia is

atherosclerotic disease (>90% cases) of coronary artery sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery.

Determinants of myocardial oxygen demand

• The major determinants of myocardial oxygen demand are heart rate, myocardial contractility, and myocardial wall tension.

• An adequate supply of oxygen to the myocardium requires a satisfactory level of oxygen-carrying capacity of the blood and an adequate level of coronary blood flow.

Reduction in Coronary Flow

Decreased aortic diastolic pressure

Increased intraventricular pressure

Coronary artery stenosis

Aortic valve stenosis- left ventricular hypertrophy

Increased right atrial pressure

Epidemiology

25% of all deaths in the United States by ischemic heart disease

½ million die of IHD yearly in USA

Given the projection of large increases in IHD throughout the world, IHD is likely to become the most common cause of death worldwide b

y 2020

Pathogenesis

• Diminished coronary perfusion relative to myocardial demand.

• Dynamic interaction among fixed or disrupted atherosclerotic plaque, intraluminal thrombosis, platelet aggregation and vasospasm.

• More than 90% patient with IHD have atherosclerotic plaques. Plaques can be located anywhere but tend to predominate within the first several centimeters of the LAD and LCX, and along the entire length of the RCA.

• A lesion obstructing 70% to 75% or more of a vessel lumen generally causes symptomatic ischemia in in the setting of increased demand.

• 90% stenosis can lead to inadequate coronary blood flow even at rest.

ACUTE CORONARY SYNDROME FACTORS

• ACUTE PLAQUE CHANGE *******

• Inflammation

• Thrombus

• Vasoconstriction

Acute plaque changes

In most patients, unstable angina, infarction, and many cases of SCD occur because of abrupt plaque change followed by thrombosis, hence the term acute coronary syndrome. The initiating event is typically disruption of a plaque due to:

• Rupture, fissuring, or ulceration of plaques

• Hemorrhage into the core of plaques with expansion of plaque volume and worsening of the luminal occlusion

Vulnerable plaques

• Plaques containing large a areas of foam cells and extracellular lipid

• Thin fibrous cap, contain few smooth muscle cells

• (Drugs such as statin stabilizes the plaque)

Atherosclerotic plaque rupture

Role of Inflammation

• Inflammation plays an essential role at all stages of atherosclerosis.

• Atherosclerosis begins with the interaction of endothelial cells and circulating leukocytes, resulting in T-cell and macrophage recruitment and activation.

• These cells subsequently drive smooth muscle cel

l proliferation, with variable amounts of extracellular matrix (ECM) accumulating over an atheromatous core of lipid, cholesterol, calcification, and necrotic debris.

Role of Inflammation

• Endothelial cells release CAMs, selectins

• T-cells release TNF, IL-6, IFN-gamma to stimulate and activate endothelial cells and macrophages

• CRP predicts the risk of damage in coronary heart disease

Role of Thrombus

• Total or partial vascular occlusion by a newly formed thrombus on a disrupted atherosclerotic plaque lead to unstable angina or sudden death.

• Mural thrombus in a coronary artery can embolize in the distal intramyocardial circulation. Finally, organizing thrombi produce potent activators of smooth muscle proliferation, which can contribute to the growth of atherosclerotic lesions.

Role of Vasoconstriction

• Vasoconstriction directly compromises lumen diameter and potentiate plaque disruption.

• Vasoconstriction in atherosclerotic plaques can be stimulated by (1) circulating adrenergic agonists, (2) locally released platelet contents, (3) an imbalance between endothelial cell relaxing factors versus contracting factors, and (4) mediators released from perivascular inflammatory cells.

Summary

• Acute coronary syndrome (unstable angina, MI and SCD) share a common pathophysiologic basis in coronary atherosclerotic plaque disruption and associated intraluminal thrombus formation.

• Stable angina results from fixed coronary obstruction (chronic plaque).

Often small platelet aggregates or thrombi and/or thromboemboli

FrequentUsually severe

Sudden death

Widely variable, may be absent, partial/complete, or lysed

VariableVariableSubendocardial myocardial infarction

OcclusiveFrequentVariableTransmural myocardial infarction

Nonocclusive, often with thromboemboliFrequentVariableUnstable angina

NoNo>75%Stable angina

Plaque-Associated ThrombusPlaque DisruptionStenosesSyndrome

Coronary Artery Pathology in Ischemic Heart Disease

Clinical syndromes of IHD

• Angina pectoris: stable, variant angina or Prinzmetal and unstable

• Acute myocardial infarction (MI): wherein the severity or duration of ischemia is enough to cause cardiac muscle death

• Chronic IHD: progressive cardiac decompensation (heart failure) following MI.

• Sudden cardiac death (SCD)

• The term acute coronary syndrome is applied to three catastrophic manifestations of IHD: unstable angina, acute MI, and SCD.

Angina pectoris

• Symptom complex of IHD characterized by paroxysmal and usually recurrent attack of substernal chest pain caused by transient (15 sec. to 15 minutes) and reversible myocardial ischemia.

• Type:– Typical or stable angina– Prinzmetal angina – Unstable angina

Stable angina

• Stable angina is usually associated with a fixed atherosclerotic narrowing (≥75%) of one or more coronary arteries.

• The chest pain is usually relieved by rest (reducing demand) or by administering agents such as nitroglycerin; such drugs cause peripheral vasodilatation and thus reduce venous blood delivered to the heart (hence reducing cardiac work).

• In larger doses, nitroglycerin also increases blood supply to the myocardium by direct coronary vasodilatation

Prinzmetal, or variant angina

• Prinzmetal, or variant angina: occurs at rest due to coronary artery spasm. Although such spasms typically occur on or near an existing atherosclerotic plaque, completely normal vessels can be affected.

• The Prinzmetal angina typically responds promptly to the administration of vasodilators such as nitroglycerin or calcium channel blockers

Unstable angina

• Unstable angina : Characterized by increasing frequency of pain, the episodes also tend to be more intense and longer lasting than stable angina.

• Unstable angina is associated with plaque disruption and superimposed partial thrombosis, distal embolization of the thrombus, and/or vasospasm.

• Unstable angina is sometimes called pre-infarction angina.

ANGINA PECTORIS

• Paroxysmal (sudden)• Recurrent• 15 sec.15 min.• Reduced perfusion, but NO infarction• THREE TYPES

– STABLE: relieved by rest or nitro– PRINZMETAL: SPASM is main feature, responds to

nitro, S-T elevation– UNSTABLE (crescendo, PRE-infarction, Q-wave

angina): perhaps some thrombosis, perhaps some non transmural necrosis, perhaps some embolization, but DISRUPTION of PLAQUE is universally agreed upon

Myocardial infarction (MI)

• Definition• Transmural versus subendocardial• Incidence and risk factors• Pathogenesis • Morphology• Infarct modification by reperfusion• Clinical features• Complication

Definition

• is necrosis of heart muscle resulting from ischemia.

• Leading cause of death in US and indudstrilized nation

• 1.5 million people in the US suffer from an acute MI every year; of these, one-third die annually.

• The major underlying cause of IHD is atherosclerosis.

Incidence and risk factors

• EXACT SAME risk factors as atherosclerosis

• The frequency of MIs rises progressively with increasing age and presence of other risk factors such as hypertension, smoking, and diabetes

• Approximately 10% of MIs occur in people younger than 40 years, and 45% occur in people younger than age 65. Blacks and whites are equally affected.

• M>F. Women are protected against MI during their reproductive years.

Myocardial infarction

• Transmural: ischemic necrosis involves full or nearly full thickness of the ventricular wall

• Subendocardial: limited to inner 1/3- ½ of ventricular wall

• Most are TRANSMURAL, and MOST are caused by coronary atherosclerosis.

• In the 10% of transmural MIs NOT associated with atherosclerosis:

– Vasospasm– Emboli– Unexplained

Pathogenesis

• Coronary artery occlusion

• Myocardial response

Coronary Artery Occlusion

• In a typical MI, the following sequence of events transpires:

• Sudden disruption of an atheromatous plaque-expose subendothelial collagen and necrotic plaque contents.

• Platelets adhere, aggregate, become activated, and release potent secondary aggregators including TxA2, ADP, and serotonin. Vasospasm is stimulated by platelet aggregation and mediator release.

• Activation of the extrinsic pathway of coagulation, adding to the bulk of the thrombus.

PROGRESSION OF NECROSIS

MYOCARDIAL RESPONSE

>1 hrMicrovascular injury

20–40 minIrreversible cell injury

40 minto 10% of normal  

10 minto 50% of normal  

 ATP reduced

<2 minLoss of contractility

SecondsOnset of ATP depletion

TimeFeature

Gross appearance

• < 12 hours old MI: not grossly apparent. Infarcts > 3 hours old can be visualized by exposing heart slices to vital stains (e.g., triphenyl tetrazolium chloride). Dehydrogenases are depleted in the area of ischemic necrosis. An infarcted area is revealed as an unstained pale zone (old scars appear white and glistening).

• 12 to 24 hours: reddish blue discoloration caused by stagnant, trapped blood. Progressively, an infarct becomes more sharply delineated as a yellow-tan, softened area.

• 10 to 14 days: infarcts become rimmed by hyperemic granulation tissue.

• Over the weeks (> 7 weeks): white fibrosis

Pale area in recent infarct

Old infarct. It is a firm scar

Microscopic

• Typical features of coagulative necrosis become detectable within 4 to 12 hours of infarction.

• "Wavy fibers" can also be present at the edges of an infarct; these reflect the stretching and buckling of noncontractile dead fibers.

• Sublethal ischemia can also induce myocyte vacuolization. These are large cleared intracellular spaces, probably containing water; such myocytes are still alive but are poorly contractile

Microscopic

• Acute inflammation (1-3 days after MI), followed by a wave of macrophages to remove necrotic myocytes and neutrophil fragments (most pronounced 5-10 days after MI).

• The infarcted zone is replaced by granulation tissue (most prominent 2-3 weeks after MI. In most instances scarring is well advanced by the end of the sixth week.

• MI heals from its borders toward the center. Once an MI is completely healed, it is impossible to distinguish its age (i.e., the dense fibrous scars of 8-week-old and 10-year-old lesions look similar).

TIMING of Gross and Microscopic Findings

Dense collagenous scarScarring complete>2 mo

 Increased collagen deposition, with decreased cellularity

Gray-white scar, progressive from border toward core of infarct

2–8 wk

 Well-established granulation tissue with new blood vessels and collagen deposition

Red-gray depressed infarct borders

10–14 days

 Well-developed phagocytosis of dead cells; early formation of fibrovascular granulation tissue at margins

Maximally yellow-tan and soft, with depressed red-tan margins

7–10 days

 Beginning disintegration of dead myofibers, with dying neutrophils; early phagocytosis of dead cells by macrophages at infarct border

Hyperemic border; central yellow-tan softening

3–7 days

 Coagulation necrosis, with loss of nuclei and striations; interstitial infiltrate of neutrophils

Mottling with yellow-tan infarct center

1–3 days

 Ongoing coagulation necrosis; pyknosis of nuclei; myocyte hypereosinophilia; marginal contraction band necrosis; beginning neutrophilic infiltrate

Dark mottling12–24 hr

 Beginning coagulation necrosis; edema; hemorrhageOccasionally dark mottling4–12 hr

Usually none; variable waviness of fibers at borderNone½–4 hr

MI - Microscopic Appearance

1-3 hrs - Wavy fibers

2-3 hrs - Tetrazolium dye staining defect

4-12 hrs - Coagulation necrosis

18-24 hrs - Pyknosis, contraction bands

24-72 hrs - Neutrophils, loss of striations

3-7 days - Macrophages and fibrosis

7 weeks and beyond - Fibrosis

1 day, 3-4 days, 7 days, weeks, months

Contraction bands in an early infarct. They are dark pink, and consist of greatlycontracted, ineffective actin and myosin fibrils.

Wavy fibers are another sign of an early infarct

Loss of nuclear basophilia in early infarct. Some contraction bands also present.

Coagulative necrosis and a few inflammatory cells

Infarct with numerous macrophages (slightly older, ~7 days).

Macrophages and granulation tissue (~ 10-day-old infarct)

Infarct modification by reperfusion

• Thrombolysis (streptokinase or t-PA)• PTCA (percutaneous transluminal coronary

angioplasty)• CABG (coronary arterial bypass graft)Reperfusion CANNOT restore necrotic or dead

fibers, only reversibly injured onesREPERFUSION “INJURY”

– Free radicals, apoptosis, microvascular injury

– Interleukins

AMI DIAGNOSIS

• Typical symptoms• EKG• DIAPHORESIS (sweating profusely)• (10% of MIs are “SILENT” with Q-waves,

common in DM and elderely)• Lab. Evaluation: CK-MB gold standard

enzyme• Troponin-I, Troponin-T better• CRP predicts risk of AMI in angina patients

Investigations

• EKG: Q waves infarction (transmural) and non-Q wave infarction (subendocardial)

• Peaked T wave (first several minute)

• ST-segment elevation (minute to hours)

• Q-wave and T-wave inversion (hours to days)

Investigations

• TnI and TnT: after 2 to 4 hrs and peak at 48 hrs; remain elevated for 7 to 10 days.

• CK-MB: begins to rise within 2 to 4 hrs of MI, peaks at 24 hrs, and returns to normal within approximately 72 hrs.

• Troponin and CK-MB: With reperfusion, both troponin and CK-MB peaks occur earlier as a result of washout of the enzyme from the necrotic tissue.

• AST: Appear- 6-12hrs, peak at 1-2 days, return to normal-7days

• Absence of change in the level of CK-MB during first 2 days of chest pain and the troponin in the days following exclude the diagnosis of MI.

MI - Therapeutic Modalities

• Thrombolysis (streptokinase or t-PA)

• PTCA (percutaneous transluminal coronary angioplasty)

• CABG (coronary arterial bypass graft

Coronary artery bypass graft (Dacron).

COMPLICATIONS

• Contractile dysfunction• Arrhythmias• Myocardfial rupture • Pericarditis• RV infarction• Infarct extension• Mural thrombus• Ventricular aneurysm• Papillary muscle dysfunction (regurgitation)• Heart failue

Chronic IHD

• Chronic IHD is progressive heart failure as a consequence of ischemic myocardial damage. Chronic IHD usually results from postinfarction cardiac decompensation that follows exhaustion of the hypertrophy of the viable myocardium.

• Hearts from patients with chronic IHD are usually enlarged and heavy from left ventricular dilation and hypertrophy. Invariably there is moderate to severe atherosclerosis of the coronary arteries.

• Gross: Discrete, gray-white scars of healed infarcts are usually present. The endocardium generally shows patchy, fibrous thickening, and mural thrombi may be present.

• Microscopic findings: myocardial hypertrophy, diffuse subendocardial myocyte vacuolization, and fibrosis from previous infarcts.

• Clinical Features: severe, progressive heart failure. Arrhythmias are common and, along with CHF and intercurrent MI, account for many deaths.

CIHD( ischemic “cardiomyopathy”)

• Progress to CHF often with no pathologic or clinical evidence of localized infarction– Extensive atherosclerosis

– No infarct

Diffuse fibrosis in chronic ischemic heart disease. There is also myocytehypertrophy and a decrease in small vessels.

Sudden Cardiac Death

Unexpected death within one hour of cardiac event

300,000-400,000 persons per year

Usually high grade coronary stenosis

Ventricular electrical instability

SUDDEN CARDIAC DEATH

• 350,000 in USA yearly from atherosclerosis• NON-atherosclerotic sudden cardiac death includes:

– Congenital coronary artery disease– Aortic stenosis– MVP– Myocarditis– Cardiomyopathy (sudden death in young athletes)

– Pulmonary hypertension– Conduction defects– HTN, hypertrophy of UNKNOWN etiology

AUTOPSY findings in SCD

• >75% narrowing of 1-3 vessels

• Healed infarcts 40%

• “ARRHYTHMIA” is often a very convenient conclusion when no anatomic findings are present