Transcript Role of Nitrates in ACS & Heart Failure DONI FIRMAN Acute Coronary Syndrome Definition: a constellation of symptoms related to obstruction of coronary arteries with.

Role of Nitrates in ACS
&
Heart Failure
DONI FIRMAN
Acute Coronary Syndrome
Definition: a constellation of symptoms related to obstruction of
coronary arteries with chest pain being the most common
symptom in addition to nausea, vomiting, diaphoresis etc.
Chest pain concerned for ACS is often radiating to the left arm or
angle of the jaw, pressure-like in character, and associated with
nausea and sweating. Chest pain is often categorized into typical
and atypical angina.
Definition
 Generally
described as retrosternal
heavy or gripping sensation with
radiation to left arm or neck,
provoked by exertion and eased with
rest or nitrates
Acute coronary syndrome
 Based on ECG and cardiac enzymes, ACS is classified
into:



STEMI: ST elevation, elevated cardiac enzymes
NSTEMI: ST depression, T-wave inversion, elevated cardiac
enzymes
Unstable Angina: Non specific EKG changes, normal cardiac
enzymes
Angina can be:
 Stable
 Unstable
caused
by
unstable plaque, occurs at rest,
unpredictable,
pain
can
increase for no obvious reason
 Prinzmetal’s
occurs
without provocation, usually at
rest, as a result of coronary
artery spasm
EKG
 NSTEMI:
 ST depressions (0.5 mm at least) or T wave inversions ( 1.0 mm at
least) without Q waves in 2 contiguous leads with prominent R
wave or R/S ratio >1.
 Isolated T wave inversions:
can correlate with increased risk for MI
 may represent Wellen’s syndrome:
 critical LAD stenosis
 >2mm inversions in anterior precordial leads

 Unstable Angina:
 May present with nonspecific or transient ST segment depressions or
elevations
Etiology and pathogenesis
 Symptoms are results of myocardial ischemia
due to insufficient blood flow through
atherosclerotically changed coronary vessels
IDENTIFYING THOSE AT RISK OF
ATHEROTHROMBOSIS
8
Local factors
• Elevated prothrombotic factors: fibrinogen, CRP, PAI-1
• Blood flow patterns, vessel diameter, arterial wall structure
Generalized
disorders
• Obesity
• Diabetes
Atherothrombosis
manifestations
(myocardial infarction,
stroke, vascular death)
Genetic
• Genetic traits
• Gender
• Age
Systemic
conditions
• History of vascular
events
• Hypertension
• Hyperlipidemia
• Hypercoagulable
states
• Homocystinemia
Lifestyle
• Smoking
• Diet
• Lack of exercise
Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.
IMBALANCE BETWEEN MYOCARDIAL OXYGEN
DEMAND AND SUPPLY
Myocardial
Myocardial
Oxygen demand
Oxygen supply
9
WHAT IS MYOCARDIAL DELIVERY /
SUPPLY ?
* Patency of coronary arteries/severerity of stenosis.
* Coronary perfusion ie : diastolic blood pressure.
* Hemoglobin : anemia, pathological Hb.
* Oxygen saturation.
* Heart rate : diastolic filling periode
WHAT IS MYOCARDIAL
DEMAND/REQUIREMENT ?
*
pre load
: increase end diastolic volume, increase
left ventricular wall stress.
*
after load
: systolic blood pressure.
*
contractility : Left ventricular mass, heart rate.
Diagnosis
Clinical Evaluation of Patients
With Chest Pain
Diagnosis
Resting Electrocardiography to
Assess Risk
Investigations
 Laboratory tests (leukocytes, hemoglobin, thyroid





hormones, troponin I and T, MB-CPK)
Resting ECG
Excercise ECG
Cardiac scintigraphy
Echocardiography
Coronary angiography
Guideline
Diagnosis of Patients with Suspected Ischemic
Heart Disease
Treatment
 Prognostic therapy: DAPT, lipid-lowering therapy
 Symptomatic treatment: GTN, beta-blockers,
long-acting nitrates, calcium-channel blockers, ACEI
 Percutaneous coronary intervention, coronary artery bypass
grafting
Comparation of organic nitrate
GLYCERIL TRINITRATE
Oral, sub lingual , IV
Pro drugs
Require hepatic convertion
metabolism to mononitrate
Rapid onset, rapid effect
onset : 1 – 4 min.
effect : 10 – 30 min.
For angina acut and prophylactis
ISOSORBID DINITRATE
Oral, sublingual , IV
Pro drugs
Require hepatic conversion
metabolism to mononitrate
Rapid onset, slow effect
onset : 5- 10 min
effect : up to 60 min.
For angina acut and prophylactis
ISOSORBID MONONITRATE
Oral
active metabolisme
isn”t subyect to hepatic
metabolism
Slow onset, slow effect
onset : 30 – 45 min.
effect 12 – 14 hours
For angina prophylactis
ACTION OF NTG in ANGINA PECTORIS
SYSTEMIC CIRCULATION
2.REDUCED AFTER LOAD
3. DILATED CORONARY ARTERY
REDUCED RESISTANCE VESSELS
1. REDUCED PRELOAD
ISCHEMIC ZONE
DILATED
INCREASE CAPACITANCE VESSELS
REDUCED VENOUS RETURN
Adverse effects:
1.
2.
3.
4.
5.
The most common side effect of nitrates is headache due to venodilation, patients whom intermittently used nitrate preparation should
be asked about headaches after nitrate use; lack of headache often
indicates degradation of agent with a loss of therapeutic effect.
Postural hypotension & syncope particularly with sublingual use.
Tachycardia induced by decreased PVR may itself induce anginal
symptoms especially with unstable symptoms.
Methemaglobinemia can occur with chronic use of long term agents,
this may occur when sublingual use is combined with long acting
agents.
Withdrawal symptoms may occur (an indication of tolerance) when
nitrate agents are tapered or discontinued, this may precipitate
anginal attacks.
* The function of the heart is to pump an adequate
volume of blood ( which it receives from the veins)
to various tissues of the body as required by metabolic need.
* Heart failure impaires the heart ability to pump
effectively to maintain sufficient circulation to meet
the body needs.
PATHOPHYSIOLOGY OF HEART FAILURE
CONTRACTILITY
FILLING PRESSURE(PRE LOAD)
INCREASE
ARTERIAL IMPEDANCE
( AFTER LOAD ) INCREASE
CARDIAC OUTPUT DECREASE
INCREASE SYSTEMIC
VASCULAR RESISTANCE
COMPENSATORY RESPONSES
1. Activation of sympathoadrenal system
2. Activation of RAA system
3. Renal mechanisms for consevation of sodium and water ec. anti diuretic hormon
NITRATES
 Venodilation
  decreased diastolic heart size and fiber tension
 Arteriolar dilation
  reduced peripheral resistance and BP
 Overall reduction in myocardial fiber tension, O2
consumption and double product
 No direct effects on the cardiac muscle
 Can cause reflex tachycardia and increased force of
contraction when reducing BP
THE ROLE OF NITRATE IN HEART FAILURE
CONTRACTILITY
FILLING PRESSURE ( PRE LOAD )
DECREASE
ARTERIAL IMPEDANCE
( AFTER LOAD ) DECREASE
CARDIAC OUTPUT DECREASE
NITRATE
COMPENSATORY RESPONSES
DECREASE SYSTEMIC
VASCULAR RESISTANCE
NITRATE
1. Activation of sympathoadrenal system
2. Activation of RAA system
3. Renal mechanisms for consevation of sodium and water ec. Anti diuretic hormon
JACC: Heart Failure Vol. 1, No. 3, 2013
Summary
 The organic nitrates are a safe and effective choice
for the management of ischemic syndromes related
to coronary heart disease
 In the absence of arterial hypotension, organic
nitrates are effective in management of acute and
chronic heart failure
JACC: Heart Failure Vol. 1, No. 3, 2013
Stable angina pectoris
 Provoked by physical exertion,
especially in cold weather, after
meals and commonly aggravated
by anger or excitement
 The pain fades quickly with rest
 In some patients pain occurs
predictably at a certain level of
exertion
Unstable Angina
 Occurs at rest and prolonged, usually lasting >20 minutes
 New onset angina that limits activity
 Increasing angina: Pain that occurs more frequently, lasts longer
periods or is increasingly limiting the patients activity
Case 1
 A 54 year old man with DM, HTN, and high cholesterol presents
to the ER complaining of substernal chest pain. The pain feels
like his chest is being squeezed. He first noted it two months ago
when carrying packages up a flight of stairs. Last week he
noticed it when walking to work. The past two days, the pain
has occurred whenever he climbs the stairs in his house. This
morning it occurred while driving to work.
 His initial EKG shows sinus tachycardia with anterior ST
depressions.
 His initial cardiac biomarkers are negative.
 He becomes pain free during his first few minutes in the ER and
his EKG changes resolve.
Case 1
 Is this an ACS?
 YES!!!
 How should this patient be managed?
 Morphine and NTG to make him pain free
 Aspirin, Beta blocker, Heparin, Integrillin
 Plan for catheterization with 24-48 hours
Case 2
 A 75 yom with HTN presents to the ER complaining of
squeezing, substernal chest pain. The pain began this
morning while taking a shower and has waxed and
waned all day (~10 hours time).
 Initial EKG shows sinus tachycardia without ST changes
 Initial biomarkers:

CK 300, MB 20, Trop T 0.5
Case 2
 Is this an ACS?
 YES!!!
 How should this patient be managed?
 Morphine and NTG to make him pain free
 Aspirin, Beta blocker, Heparin, Integrillin
 Plan for catheterization within 24-48 hours
References

2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care. Circulation 2005;112:IV-89-IV-110

2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction : A Report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Circulation 2013, epublished April 29th 2013 and print published june 4th 2013.

Herman LK, et al. Comparison of frequency of inducible myocardial ischemia in patients presenting to
emergency department with typical versus atypical or nonanginal chest pain. Am J Cardiol. 2010 105:1561-4.
Stable angina pectoris
 Provoked by physical exertion,
especially in cold weather, after
meals and commonly aggravated
by anger or excitement
 The pain fades quickly with rest
 In some patients pain occurs
predictably at a certain level of
exertion
Unstable Angina
 Occurs at rest and prolonged, usually lasting >20 minutes
 New onset angina that limits activity
 Increasing angina: Pain that occurs more frequently, lasts longer
periods or is increasingly limiting the patients activity
MAJOR CLINICAL MANIFESTATIONS
OF ATHEROTHROMBOSIS
43
Ischemic
stroke
Myocardial
infarction
Transient ischemic
attack
Angina:
• Stable
• Unstable
Peripheral arterial
disease:
• Intermittent claudication
• Rest Pain
• Gangrene
• Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.
Clinical symptoms
 Patient history is a˝golden standard˝
 Retrosternal pain
 Dyspnea
 Nausea
 Arrhythmia
 Restlessness
 Levine sign
 Pain eased after taking nitrates
71-year-old female
 Cardiovascular risk
factors

Hypertension diagnosed
more than 15 years before.
CORONARY ANGIOGRAPHY : THREE VESSELS DISEASE
Comparing Pretest Likelihood of CAD in Low-Risk Symptomatic
Patients With High-Risk Symptomatic Patients (Duke Database)
Each value represents the percentage with significant CAD. The first is the percentage for a low-risk, mid-decade
patient without diabetes mellitus, smoking, or hyperlipidemia. The second is that of a patient of the same age
with diabetes mellitus, smoking, and hyperlipidemia. Both high- and low-risk patients have normal resting ECGs.
If ST-T-wave changes or Q waves had been present, the likelihood of CAD would be higher in each entry of the
table.
Noninvasive Risk Stratification
*Although the published data are limited; patients with these findings will probably not be at low risk in the presence of either
a high-risk treadmill score or severe resting LV dysfunction (LVEF <35%).
Algorithm for Risk Assessment of Patients
With SIHD*
*Colors correspond to the ACCF/AHA Classification of Recommendations and Levels
of Evidence Table.
Algorithm for Risk Assessment of Patients With
SIHD (cont.)*
*Colors correspond to the ACCF/AHA Classification of Recommendations and Levels
of Evidence Table.
CAD Prognostic Index
*Assuming medical treatment only.
Algorithm for Guideline-Directed Medical
Therapy for Patients With SIHD*
*Colors correspond to the ACCF/AHA Classification of Recommendations and Levels of
Evidence Table.
Algorithm for Guideline-Directed Medical
Therapy for Patients With SIHD* (cont.)
*Colors correspond to the
ACCF/AHA Classification
of Recommendations and
Levels of Evidence Table.
ORGAN SYSTEM EFFECTS OF NITRATES
1. Cardiovascular System
 Smooth muscle relaxation
- peripheral venodilation
-reduced cardiac size and CO through reduced
preload
 Reduced after load because of arteriolar dilation
 increase in ejection and further decrease in cardiac
size
 Sensitivity veins >> arteries > arterioles
ORGAN SYSTEM EFFECT OF NITRATE
Other smooth muscle effect
 Relaxation of the smooth muscle of the bronchi, GIT, GUT
 Effects are too small to be clinically significant
3. Action on platelets

Decrease platelet aggregation
4 . Nitrite ion + hemoglobin  methemoglobin
 Methemoglobin has low affinity for oxygen
 Pseudocyanosis, tissue hypoxia, death
2.
Algorithm for Guideline-Directed Medical
Therapy for Patients With SIHD* (cont.)
*Colors correspond to the
ACCF/AHA Classification of
Recommendations and Levels
of Evidence Table. †The use of
bile acid sequestrant is
relatively contraindicated when
triglycerides are ≥200 mg/dL
and is contraindicated when
triglycerides are ≥500 mg/dL.
‡Dietary supplement niacin
must not be used as a
substitute for prescription
niacin.
JACC: Heart Failure Vol. 1, No. 3, 2013
THE BASIC CAUSE OF HEART FAILURE
1. Myocardial damage :
- Ischemic heart disease, myocarditis, cardiomyopathy
2. Ventricular overload :
- pressure overload : hypertension, coarc. aorta,
aortic stenosis, pulmonary stenosis.
- volume overload : mitral regurgitation, aortic
regurgitation, VSD, ASD, PDA.
3. Restriction and obstruction to ventricular filling :
- mitral stenosis, cardiac tamponade, constrictive
pericarditis, restrictive cardiomyopathy, atrial myxoma.
4. Cor pulmonale.
5. Others : thyrotoxicosis, myxedema, A V fistula
Management
 @ Improved LV function :
* decrease preload
: diretics (furosemid, aldosteron
antagonist), NITRATE.
: vasodilators, ACE inhibitors,
* decrease afterlod
NITRATE
* increase contractility : digitalis, dopamin, dobutamin.
@ Cure the potentially causes of heart failure : valvular heart
diseses, congenital heart lesion, endocarditis, pericarditis,
reccurent arrhythmia, thyrotoxicosis, AV fistula beri-beri.
@ Treat and eliminate the precipitating factor : infection
especially respiratory), pulmonary infarction, over exertion,
high sodium intake, anemia.
Clinical Classification of Chest Pain
Coronary artery disease Imbalance between oxygen
demand and oxygen consumption
ECG :
ST-T changes
QS wave
normal
LABORATORY :
increase cardiac
enzymes
( CK, CKMB,
Troponin I /T )
METABOLISM :
ichemia ,
actic acidosis ,
pain
CLINICAL :
Asymptomatic
Angina pectoris
Myocardial infarction
Aritmia
Heart failure
Sudden death
Treatment
 NITRATES
 CALCIUM CHANNEL BLOCKERS
 BETA BLOCKERS
 ANTIPLATELET AGREGATION
 EFFISIENCY OF OXYGEN UTILIZATION
 RISK FACTORS MODIFICATION
 PTCA, CABG