Rhematic heart disease

23 May 2020
Keep distance ; stay safe Harischandra
HOD paediatrics
1

Fever // heart
• Rheumatic involvement of the
valves and endocardium is the
most important manifestation of
rheumatic fever.
• The valvular lesions begin as small
verrucae composed of fibrin and
blood cells along the borders of one
or more of the heartvalves.
23 May 2020 Keep distance ; stay safe 2

attacker // Victim
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Keep distance ; stay safe
3
• The mitral valve is affected
most often, followed in
frequency by the aortic
valve; right-sided heart
manifestations arerare.
• As the inflammation subsides, the
verrucae tend to disappear and
leave scar tissue.With repeated
attacks of rheumatic fever, new
verrucae form near the previous
ones, and the mural endocardium
and chordae tendineae become
involved.

• There is lossof valvular substanceand shortening and
thickening of the chordae tendineae.
• During acute rheumatic fever with severe cardiac
involvement, heart failure is caused by acombination of
mitral insufficiency coupled with inflammatory disease of
the pericardium, myocardium, endocardium, and
epicardium.
• Becauseof the high volume load and inflammatory
process, the left ventricle becomes enlarged. The left
atrium dilates asblood regurgitates into this chamber.
Increased left atrial pressure results in pulmonary
congestion and symptoms of left-sided heart failure.
1. Mitral Insufficiency

• With mild disease, signs of heart failure are
not present, the precordium is quiet,
• auscultation reveals a high- pitched
holosystolic murmur at the apex that radiates
to the axilla.
C F

With mild disease,
signs of heart failure
are not present,
high- pitched holosystolic
murmur atthe apex
The heart is enlarged heaving apical left
ventricular impulse and
often an apical systolic
severe mitral insufficiency, signs
of chronic heart failure
short mid-diastolic
rumbling murmur
Mitral Insufficiency
3 rd HS prominent
holosystolicmurmur at
apex

C F
1. With severe mitral insufficiency, signs of chronic heart failure
may be noted.
2. The heart is enlarged, with a heaving apical left ventricular
impulse and often an apical systolic thrill.
3. The 2nd heart sound may be accentuated if pulmonary
hypertension is present.
4. A 3rd heart sound is generally prominent.Aholosystolic
murmur is heard at the apex with radiation to the axilla.
5. A short mid-diastolic rumbling murmur is caused by increased
blood flow across the mitral valve asaresult of the insufficiency

23 May 2020
Role & Responsibilities of Investigator MUR Naidu
M U R Naidu
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Treatment
• Mild mitral insufficiency, prophylaxis against recurrences of
rheumatic fever is all that is required.
• Afterload-reducing agents (captopril,hydralazine) may
reduce the regurgitant volume and preserve left
ventricular function.
• Surgical treatment is indicated for patients who despite
adequate medical therapy have recurrent episodes of
heart failure, dyspnea with moderate activity, and
progressive cardiomegaly, often with pulmonary
hypertension.

Mitral stenosis
Mitral stenosis of rheumatic origin results from
fibrosis of the mitral ring, commissural
adhesions, and contracture of the valve
leaflets, chordae, and papillary muscles over
time.
• It takes 10yr or more for the lesion to
become fully established, although the
process may occasionally be
accelerated.
•

• Significant mitral stenosis results in
increased pressure and enlargement and
hypertrophy of the left atrium, pulmonary
venous hypertension, increased pulmonary
vascular resistance, and pulmonary
hypertension.
• Right ventricular and atrial dilatation
and hypertrophy ensue and are
followed by right-sided heart failure.

• the correlation between symptoms and the severity of obstruction is good.
Patients with mild lesions are asymptomatic.
• More severe degrees of obstruction are associated with
exercise intolerance anddyspnea.
• Critical lesions can result in orthopnea, paroxysmal nocturnal dyspnea, and
overt pulmonary edema, aswell asatrial arrhythmias.
• When pulmonary hypertension has developed, right ventricular
dilatation may result in functional tricuspid insufficiency,
hepatomegaly, ascites, andedema.
• Hemoptysis causedby rupture of bronchial or pleurohilar veins
and, occasionally, by pulmonary infarction may occur.
Clinical Manifestations

severe degrees of
obstruction
exercise intolerance and
dyspnea,
orthopnea, paroxysmal
nocturnal dyspnea,
pulmonary edema, atrial
arrhythmias.
functional tricuspid insufficiency, hepatomegaly,
ascites, edema
pulmonary infarction 
Hemoptysis
pulmonary hypertension has
developed, R V dilatation.
low-pitched,
rumbling mitral
diastolic murmur
with presystolic
accentuation
Mitral stenosis
loud 1st heart sound,
an opening snap

•The principal auscultatory findings are a loud 1st heart sound,
an opening snap of the mitral valve, and a long, low-pitched,
rumbling mitral diastolic murmur with presystolic
accentuation at the apex.
•The mitral diastolic murmur may be virtually absent in patients
who are in heart failure. A holosystolic murmur secondary to
tricuspid insufficiency may be audible. In the presence of
pulmonary hypertension, the pulmonic component of the 2nd
heart sound is accentuated.
•An early diastolic murmur may be caused by associated aortic
insufficiency or secondary pulmonary valvular insufficiency.

Treatment.
• Intervention is indicated in patients with clinical signs and hemodynamic
evidence of severe obstruction but before the severe manifestations outlined
earlier.
• Surgical valvotomy or balloon catheter mitral valvuloplasty generally yields
good results; valve replacement is avoided unless absolutely necessary.
• Balloon valvuloplasty is indicated for symptomatic, stenotic, pliable,
noncalcified valves of patients without atrial arrhythmias orthrombi.

3.AorticInsufficiency
• In chronic rheumatic aortic insufficiency, sclerosis of the aortic valve
results in distortion and retraction of the cusps.
• Regurgitation of blood leadsto volume overload with dilatation and
hypertrophy of the left ventricle.
• Combined mitral and aortic insufficiency is more common than
aortic involvement alone.

Clinical Manifestations.
• Symptoms are unusual except in severe aortic insufficiency. The large stroke volume
and forceful left ventricular contractions may result inpalpitations.
• Excessivesweating and heat intolerance are related to vasodilation.
• Dyspneaon exertion canprogress to orthopnea andpulmonary
edema; angina may be precipitated by heavy exercise.
• Nocturnal attacks with sweating, tachycardia, chest pain, and hypertension may
occur.
• The pulse pressure is wide with bounding peripheral pulses.
• Systolic blood pressure is elevated, and diastolic pressure is lowered.

unusual except in severe
aortic insufficiency. large
stroke volume and
forceful left ventricular
contractions may result
inpalpitations.
Excessive sweating and
heat intolerance
Nocturnal attacks
pulse pressure is wide
with bounding
peripheral pulses.
• Systolic
BPelevated, and
diatolic BP is low
DOE canprogress to orthopnea
and pulmonary edema;
angina may be precipitated by
heavy exercise
typical murmur
begins immediately
with the 2nd heart
sound and
continues until late
in diastole
diastolic thrill
aortic insufficiency

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Keep distance ; stay safe 23

• In severe aortic insufficiency, the heart is enlarged, with aleft
ventricular apical heave.Adiastolic thrill may be present.
• The typical murmur begins immediately with the 2nd heart sound and continues until
late in diastole.The murmur is heard over the upper and midleft sternal border with
radiation to the apex and the aorticarea.
• Characteristically, it has ahigh-pitched blowing quality and is easily audible in full
expiration with the diaphragm of the stethoscope placedfirmly on the chest and
the patient leaning forward.
• Asystolic ejection murmur is frequent becauseof the increased
stroke volume.
• An apical presystolic murmur (Austin Flint murmur) resembling that of mitral stenosis
is sometimes heard and is a result of the large regurgitant aortic flow in diastole that
prevents the mitral valve from openingfully.

Prognosis andTreatment.
• Mild and moderate lesions are well tolerated.
• Unlike mitral insufficiency, aortic insufficiency does not regress. Patients
with combined lesions during the episode of acute rheumatic fever may
have only aortic involvement 1-2 yrlater.
• Treatment consists of afterload reducers(e.g., captopril, hydralazine) and
prophylaxis against recurrenceof acute rheumatic fever and the
development of infective endocarditis.

Tricuspid ValveDisease
• Primary tricuspid involvement is rare after rheumatic fever.
• Tricuspid insufficiency is more common secondary to right ventricular
dilatation resulting from unrepaired left-sided lesions.
• The signs produced by tricuspid insufficiency include prominent pulsations of
the jugular veins, systolic pulsations of the liver, and ablowing holosystolic
murmur at the lower left sternal border that increases in intensity during
inspiration.

Pulmonary ValveDisease
• Pulmonary insufficiency usually occurson afunctional basis secondary to
pulmonary hypertension and is alate finding with severe mitralstenosis.
• The murmur (Graham Steell murmur) is similar to that of aortic insufficiency,
but peripheral arterial signs (bounding pulses) areabsent.
• Thecorrect diagnosis is confirmed by two-dimensional echocardiography
and Dopplerstudies

23 May 2020
M U R Naidu
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Thank you

Investigator – Communication with IRB
• Before Initiating a trial the investigator must have in his/her
possession:
• Written date approval letter for the trial period
• Written and approved informed consent form
• Consent form updates (if any)
• Subject recruitment procedures (e.g., advertisements)
• Any other information to be provided to the subjects
• Provide a current copy of the Investigator’s brochure
• If the Investigator’s Brochure is updated, the investigator must supply a
copy of the updated brochure to the IRB
• Any other documents that are subject to review by the IRB
MUR NAIDU 30

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Discuss study,
risk/benefits, etc.
Update participants
Allow time for understanding
Assess understanding
and willingness
Ensure comprehensionEncourage questions
Provide informed consent form
The Consenting Process
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Investigator Responsibilities
Subject Informed Consent
• Comply with regulatory requirements
• Update consent documents as necessary
• Inform subject that study involves “investigational”
product
• May not coerce subject to participate
• May not waive subject’s legal rights
• Keep subject informed of new information regarding
study
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Investigator Responsibilities
Subject Informed Consent
• Provide informed consent in understandable
language
• Give subject the chance to ask questions
• If subject can’t read, need impartial witness
• If subject is “disadvantaged”, need legally
authorized witness
• Get subject consent in writing prior to initiation of
study procedures
• Give subject a copy of signed consent document
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5 Medical care of the trial participant

Investigator – Medical Care of Trial Subjects
• A qualified physician, who is an investigator or
sub-investigator for the trial must be responsible
for all trial-related medical decisions.
• The investigator should ensure that adequate
medical care is provided to a subject for any
adverse events (including lab values).
• The investigator must inform the subject when
medical care is needed for inter-current
illness(es)..
MUR NAIDU 36

Investigator – Medical Care of Trial Subjects
• The investigator inform subject’s primary physician
about subject’s participation (subject ‘s agreement
to this requirement is required)
• If subject wishes to withdraw from the study, the
investigator should make reasonable effort to
ascertain the reasons – while fully respecting the
subject’s rights.
MUR NAIDU 37

6 Investigator – Compliance with Protocol
• The investigator should conduct the trial in compliance with:
• The protocol agreed to by the sponsor , regulatory authority(ies)
and approval by the IRB
• The investigator/institution should sign the protocol, to confirm the agreement
• The investigator should not implement any deviation from, or changes of the protocol
without:
• Agreement by the sponsor , by the IRB except where necessary to eliminate an immediate
hazard (s) to trial subjects or when the changes involve only logistical or administrative aspects
of the trial
(e.g, change in the monitor(s), change of telephone number However, as soon as possible, the
proposed protocol amendment(s) should be submitted to:
• The IRB for review and approval
• To the sponsor for agreement
• If required, to the regulatory authorities
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7 Investigational Product(s)

Investigational Study Product
• Responsibility for investigational product
accountability lies with the
Investigator/institution.
• Some or all of these duties can be delegated
to the pharmacist or other individual who is
under the supervision of the Investigator.
• The product should be stored as specified by
the sponsor and in accordance with regulatory
requirements.
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Investigational Study Product
• Investigator or designee should ensure products
are only used in accordance with the approved
protocol.
• The Investigator or designee should explain the
correct use of the product and should check
throughout the trial that each participant is
following instructions properly.
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Product Accountability Records
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• These records should include the following
information:
• Product delivery to the trial site.
• Inventory at the site.
• Use by each subject.
• Return to the sponsor or alternative disposition of
unused product.
• Dates, quantities, batch/serial numbers, expiration
dates (if applicable), unique code assigned to the
product and trial participant.

8 Investigator – Randomization Procedures and
Un blinding
• The investigator should follow trial’s randomization
procedure
• Ensure that the code is broken only in accordance with
protocol
• If trial is blinded, the investigator should promptly
document and explain to the sponsor any:
• Premature unblinding
• Accidental unbliniding
• Unblinding due to serious adverse events
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9 Investigator Responsibilities –
Records and Reports
- Records and Reports
• Data is ALCOA (accurate, legible, contemporaneous,
original and attributable) and complete
• Data on the CRF’s is consistent with (exactly the same
as) that of the source documents (raw data)
• All changes to a CRF are dated and signed such that the
original data is not obscured
• Essential documents are retained at least 2/ years after
the last approval of the test agent for market
44

Documentation
Document what happened,
as well as what did NOT happen.
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10 Investigator Responsibilities
Safety Reporting -
Safety Reporting
• All SAE’s are immediately reported to the sponsor and
followed up by a written report forthwith
• Study Participants are not to be identified to anyone
• All AE’s critical to the safety evaluation are reported to
the sponsor per protocol
• The sponsor and the IRB are given all details in the
event of a death of a SP while on study
46
SAE Dilemma ?

Premature stopping or suspending the study-
- Premature stopping or suspending a study
• All trial participants are informed if a study is terminated or even
suspended
• The institution, the sponsor, and the IRB are informed in writing if
the PI terminates the study
• The institution and the IRB are informed in writing
if the sponsor terminates the study
• The institution and the sponsor are informed in writing
if the IRB terminates the study
47

Progress reports
- Progress Reports
• A written report is submitted to the IRB / IEC at least annually is
required but….
• Low Risk – yearly is OK
• Moderate Risk – twice a year
• High Risk – monthly to quarterly as needed
48

13 Investigator –Final Reports
• Upon the completion of the trial, the
investigator should inform and provide the
IRB and the sponsor:
•All required reports
•Summary of the trial’s outcome
•Reports to regulatory authorities if
applicable
MUR NAIDU 49

Investigator’s Noncompliance
• Insufficient investigator involvement in study conduct.
• Poor supervision and training of study staff.
• Inappropriate delegation of study tasks to unqualified
persons.
• Overworked investigator and study staff (e.g., too many
subjects, complex study with large data collection, too
many concurrent studies).
• Failure to adequate protect study subjects.
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Potential Impact of Noncompliance
• Impact on risk to the participant
• Impact on data quality
• Impact on scientific integrity and credibility
• Rejection of data by regulatory bodies
• Selection of the site for regulatory Inspection
• Disqualification of the Investigator
• Suspension of site activities
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Advice to Investigators
Before the Study:
• Understand what you are responsible for…and get training
• Document the delegation of duties
• Develop forms or checklists to make sure all appropriate
activities are performed
• Develop a plan for organizing records
• Train study staff before the study starts, and train
replacements before they conduct work on the study
• Do not overextend to many concurrent projects
• Do not take on satellite sites you cannot directly supervise
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During the Study:
• Track the dates when reports are due to the IRB and the sponsor
• Promptly report protocol violations to the IRB and sponsor
• Obtain WRITTEN APPROVAL from the sponsor BEFORE you do
something prohibited by the protocol
• Verify delegated duties are performed by appropriate study staff
• Work with the monitors
• Correct small problems before they grow
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After the Study
• Organize the study records
• So non-study staff can find them
• To show what a good job you did
• To fulfill record retention requirements
• For possible FDA inspection (years later…)
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Finally Investigator Responsibilities

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