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

Prinzmetals 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 Wellens 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
Systemic
conditions
Generalized Atherothrombosis History of
disorders manifestations vascular events
Obesity Hypertension
(myocardial Hyperlipidemia
Diabetes infarction, Hypercoagulable
stroke, vascular states
death) Homocystinemia

Genetic Lifestyle
Genetic Smoking
traits Diet
Gender Lack of
Age exercise
Yusuf S et al. Circulation 2001; 104: 274653. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl
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.

 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 ISOSORBID DINITRATE
ISOSORBID MONONITRATE

Oral, sub lingual , IV Oral, sublingual , IV Oral

Pro drugs Pro drugs
active metabolisme
Require hepatic convertion Require hepatic conversion isnt
subyect to hepatic
metabolism to mononitrate metabolism to mononitrate
metabolism
Rapid onset, rapid effect Rapid onset, slow effect Slow
onset, slow effect
onset : 1 4 min. onset : 5- 10 min
onset : 30 45 min.
effect : 10 30 min. effect : up to 60 min.
effect 12 14 hours
For angina acut and prophylactis For angina acut and prophylactis 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. The most common side effect of nitrates is headache due to veno-

dilation, 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.
2. Postural hypotension & syncope particularly with sublingual use.
3. Tachycardia induced by decreased PVR may itself induce anginal
symptoms especially with unstable symptoms.
4. Methemaglobinemia can occur with chronic use of long term agents,
this may occur when sublingual use is combined with long acting
agents.
5. 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) ARTERIAL IMPEDANCE

INCREASE ( 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

DECREASE SYSTEMIC
NITRATE VASCULAR RESISTANCE
COMPENSATORY RESPONSES

NITRAT
1. Activation of sympathoadrenal system E
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 Transient
stroke ischemic
attack
Myocardial Angina:
infarction Stable
Unstable

Peripheral
arterial
disease:
Intermittent claudication
Rest Pain
Gangrene
Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16.
 Clinical symptoms
Patient history is agolden 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

2. 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

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
 Management

@ Improved LV function :
* decrease preload : diretics (furosemid, aldosteron
antagonist), NITRATE.
* decrease afterlod : vasodilators, ACE inhibitors, 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 : LABORATORY : METABOLISM :

CLINICAL :
ST-T changes increase cardiac ichemia ,
Asymptomatic
QS wave enzymes actic acidosis ,
Angina pectoris
normal ( CK, CKMB, pain Myocardial
infarction Troponin I /T )
 Treatment

NITRATES
CALCIUM CHANNEL BLOCKERS
BETA BLOCKERS
ANTIPLATELET AGREGATION
EFFISIENCY OF OXYGEN UTILIZATION
RISK FACTORS MODIFICATION
PTCA, CABG