Problem-based Questions in Pathology Sanjay Sengupta
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Cardiovascular SystemChapter One

Problems related to different organ systems are discussed separately starting with cardiovascular system. Definitely, there will be some degree of overlapping. Salient clinical features of the ailments, included in the differential diagnosis of the problems, will be discussed in a nutshell. Students should not incorporate these discussions in their answer, but it will help them in their understanding.
***CQ1: A 9-year-old girl from an urban slum seeks medical attention for fever with pain and swelling of both knee and right wrist joints, affected one after another for last 7 days.
What is your provisional diagnosis? What are the other possibilities? How do you investigate the case?
Ans.: According to the history, provisional diagnosis is:
  • Acute rheumatic fever (ARF)
  • Other possible causes are:
  1. Juvenile idiopathic arthritis (JIA)
  2. Septic arthritis.
Steps for diagnosis:
History
3
Symptoms
ARF
JIA
Septic arthritis
Age
5-15 years
Younger
Any age
Duration
Acute
Chronic
Acute
Outcome
Spontaneous resolution
Chronic progressive
Resolution or chronicity
Socio-economic status
Low
No significance
No significance
Preceding history of sore throat
Important
Not relevant
May not relevant
Cardiological
Palpitation and respiratory
Not associated
Not associated
symptoms
distress may occur
Examination
Symptoms
ARF
JIA
Septic arthritis
Temperature
↑ or, N
↑↑
Pulse rate
↑↑
↑ or, N
Lymphadenopathy
+ or −
Hepatosplenomegaly
+ or −
Subcutaneous nodules
+ /− (uncommon in ARF)
− (Rheumatoid nodule may develop)
Erythema marginatum
− / +
− (Skin rash may occur)
Heart sounds
Tachycardia, S-3 gallop, systolic murmur
No such
No such
Features of heart failure
May be present
Absent
Absent
Neurological features
Chorea ±
Absent
Absent
Lab Investigations
Routine blood Examination:
ARF
JIA
Septic arthritis
Hb%
Variable
Variable
Variable
TLC
↑ or, N
↑↑
DC of leucocytes
Variable
Variable
Neutrophilic leucocytosis
ESR
↑↑
↑↑
Platelet count
Normal
Normal
Normal
(N-normal; ↑ increased; ↑↑ − highly increased; = positive; − = negative; +/− = may be positive) Stool, urine or, sputum examination not significant, but may help in identifying the source of infection in case of septic arthritis
Tests for Streptococcal infection:
  1. Isolation of organism from throat culture – possible in few cases
  2. ASO titre: Elevated in 80% cases of ARF. Progressive rise of titre is more significant. Normally a titre of more than equal to 1/200 is usually taken as positive. But different areas should have individual reference ranges.
  3. Anti-DNAase-B activity and antihyaluronidase activity: May be helpful in cases where ASO titre is less than 1/200.
These tests are significant for diagnosis of ARF.
Tests for acute phase reactants:
ESR and C-reactive protein estimation are the two popular tests. Raised in all three conditions.4
ECG and echocardiography: Abnormal patterns can be seen in ARF. Rest two conditions will not usually show any changes.
Cerebrospinal fluid study, EEG and CT scan: Done in cases of Sydenham chorea in order to exclude other neurological diseases.
Joint fluid aspiration: In case of septic arthritis pus will be aspirated. Staining and culture of aspirated materials will help in identifying the organism (commonly Streptococcus or, Staphylococcus).
Not helpful in other conditions.
Rheumatoid factor assay:
May be positive in few cases of JIA (sero-positive cases). Not significant in ARF or, septic arthritis;
Acute rheumatic fever is diagnosed essentially on clinical manifestations.
Laboratory investigations only supply supportive evidences.
***CQ2: A boy aged 15 years complaining of palpitation and breathlessness for 1 week. O/E, fever with tender swelling of left elbow joint. Right ankle joint was similarly affected 4 days back. H/O sore throat 3 weeks back.
What is your provisional diagnosis?
How will you confirm your diagnosis?
Ans.: Provisional diagnosis:
  • Acute rheumatic fever with carditis
  • Steps for diagnosis:
  • Also similar to CQ1 excluding differentiation from JIA or, septic arthritis.
***CQ3: A 5-year-old girl is admitted into hospital with jerky, irregular, uncontrolled movement of both hands for 7 days. There was an attack of febrile polyarthritis involving both elbow and ankle joints about 1 month back. or
What is the most likely diagnosis? How will you proceed for confirmation of diagnosis?
Ans.: Most likely diagnosis:
  • Rheumatic fever with Sydenham chorea
  • Steps for diagnosis:
  • Similar to CQ1
***CQ4: A boy, aged 16, comes with fever and migratory polyarthritis for 1 wk. He is also complaining of palpitation, respiratory distress and chest pain.
What are the possible causes?
How will you proceed for diagnosis?
Ans.: Possible causes:
  • Acute rheumatic fever with features of myocarditis
  • Lyme disease
Steps for diagnosis:
ARF can be diagnosed on Jone's criteria as stated in CQ1.
5Lyme disease on the other hand requires following points for diagnosis:
 
History
  • Geographical distribution: Rare in India
  • Outdoor activities
  • H/O tick bite
  • No H/O preceding throat infection -Can occur in older age also
  • Appearance of skin lesion will be before arthritis
 
Examination
  • Typical maculopapular skin lesion at the site of bite
  • Neurological features like meningitis or, facial palsy, etc.
  • Arthritis: One or multiple joints are involved
  • Both large and small joints can be involved.
 
Investigations
  • Specific tests: Anti B. burgdorferi antibody (IgG or IgM) – Rises slowly and takes weeks to appear. Elevated IgG after few weeks of disease, almost diagnostic
    Isolation of organism: Most specific test; but by direct examination or, culture of joint fluid or, skin lesions only in 25% cases organisms can be isolated.
  • Other non-specific tests: Routine blood: Neutrophilic leucocytosis with high ESR
    Serum IgM level: Elevated
    Serum AST: Elevated Joint fluid study: High cell count – mainly polymorphs
    Synovial biopsy: Villous hypertrophy, vascular proliferation, fibrin deposition and chronic inflammatory cell infiltration
  • Important negative tests:
    ASO titre – Not elevated
    Rheumatoid factor - Negative
***CQ5: 28-year female comes to outdoor with gradually increasing respiratory distress, palpitation and cough for 1 year. On enquiry, past H/O multiple attacks of febrile polyarthritis.
What are the probable causes?
How will you investigate the case?
Ans.: Most probable cause:
  • Chronic rheumatic heart disease (CRHD) Other causes:
    • Cardiomyopathy
    • Tuberculosis of lung with pleural effusion
    • Constrictive pericarditis
    • Primary pulmonary hypertension
    • Rheumatoid heart disease.
7
Steps of diagnosis:
History
Symptoms
CRHD
Cardiomyopathy
TB with effusion
Constrictive pericarditis
PPH
Rheumatoid heart disease
•Past H/O ARF
Significant (S)
Not significant (NS)
NS
NS
NS
NS
•H/O contact with TB
NS
NS
S
NS
NS
NS
•Past H/O pericardial effusion
NS
NS
NS
S
NS
NS
•H/O ingestion of offending drugs, toxins or, exposure to radiation
NS
S
NS
NS
NS
NS
•Prolonged H/O small and large joint arthritis
NS
NS
NS
NS
NS
S
Examination
CRHD
Cardio-myopathy
TB with effusion
Constrictive pericarditis
PPH
Rheumatoid heart disease
Fever
±
+
±
Joint swelling
±
+
Murmur
+
±
+
±
Cardiac enlargement
±
±
+
±
Dullness on percussion
+
 
Investigations
Routine blood examination: Important in case of pulmonary tuberculosis with anaemia, lymphocytosis and raised ESR
Sputum examination: +ve for AFB in open cases of TB; trans-bronchial aspiration of sputum may be used for culture of AFB. Not significant in other cases
Chest X-ray: Often confirmatory for TB; most of the other cases show cardiac enlargement and features of heart failure.
Echocardiography with Doppler study: Unique investigation for assessment of valvular deformity and ventricular ejection fraction; also relevant in constrictive pericarditis
Endomyocardial biopsy: Important in diagnosis of HCM or, restrictive cardiomyopathy
CT scan of the thorax (± CT guided FNAC):
Rarely required in some cases of tuberculosis to differentiate from neoplasms
Bronchoscopy with biopsy:
Only indicated where tubercular lesion mimics malignancy.
Immunological tests:
  • Elevated ASO titre may or, may not be present in CRHD
  • Positive Mantoux test in T.B.
  • Positive Kveim test in Cardiomyopathy secondary to sarcoidosis
  • Rheumatoid factor: Positive in most cases of rheumatoid arthritis (Rheumatoid factor – IgG or, IgM against Fc portion of IgG).
  • Positive ELISA test for TB in tuberculosis
Pulmonary wedge pressure (= lt. atrial pressure) measurement:
↑ in both primary and secondary pulmonary hypertension
Synovial biopsy:
Indicated in rheumatoid arthritis and is characterized by pannus formation.8
CRHD can be diagnosed mainly on history and physical findings. Investigations like chest X– ray and echocardiography help in identifying the precise location of valvular defect.
***CQ6: Middle aged man is complaining of gradually increasing respiratory distress, chronic cough, palpitation, and paedal oedema with occasional haemoptysis for last 3 years. He admits multiple attacks of polyarthritis during childhood.
What is your provisional diagnosis? How will you confirm it?
Ans.: Provisional diagnosis:
  • Chronic rheumatic heart disease (CRHD)
  • Diagnosis is based upon (see also CQ5):
 
History
Past H/O ARF is most important
 
Examination
Auscultation of heart for abnormal heart sounds are important in diagnosing underlying valvular defects, such as:
Mitral stenosis (MS) - Mid-diastolic rumbling murmur
Mitral regurgitation (MR) - High pitched systolic murmur
 
Investigations
Echocardiography with Doppler study helps in identifying valvular pathology.
***CQ7: A 25-year-old male patient gets admitted into hospital with low grade, irregular fever for more than 6 weeks. Patient also complains of fatigue, lassitude, palpitation and respiratory distress. Careful history taking unmasks two additional features:
  • – Presence of gradually increasing breathlessness for last 2 years.
  • – Past history of multiple attacks of febrile polyarthritis during childhood.
    What are the possible causes? How will you proceed for diagnosis?
Ans.: Provisional diagnosis:
Sub acute bacterial endocarditis (SBE)
Other causes:
Tuberculosis of lung with pleural effusion
Restrictive pericarditis (Tuberculous etiology)
9Below main differentiating features of major forms of vegetative endocarditis are given in tabulated form:
Infective endocarditis
Rheumatic heart disease
Non-bacterial thrombotic endocarditis
Libman Sack's endocarditis (SLE)
Size
Large
Small
Small
Small or medium
Shape
Irregular mass
Warty
Regular, round to oval
Regular
Distribution
On the valve cusps
Along the line of closure with extension to the cords
At the line of closure of valve leaflets
On either or both sides of leaflets
Bacteria
+
Embolism
+
±
+
Steps for diagnosis:
History
SBE
TB with effusion
Restrictive pericarditis
Past H/o ARF
S
NS
NS
H/o CRHD
S
NS
NS
H/o valvular disease
S
NS
NS
Past H/o tubercular infection
NS
S
S
H/o contact with TB cases
NS
S
S
(S-significant; NS-not significant)
Examinations
SBE
TB with effusion
Restrictive pericarditis
Cardiac murmur
+
Fever
+
+
Weight loss
+
+
±
Splenomegaly
+
±
Jaundice Uncommon
±
Clubbing
+
±
Chronic cough
±
+
±
Haemoptysis
Rare
±
Rare
Dullness on percussion
+
Tracheal shifting
±
Petechial spots and subungual haemorrhage
±
Other thrombo-embolic mani-festations
±
Lymphadeno-pathy
Rare
±
Investigations
Routine blood examination
SBE
TB with effusion
Restrictive pericarditis
Hb%
↓ or N
TLC
↑ or N
↑ or N
N
ESR
↑↑
↑ or N
DC of leucocytes
No significance
Lympho-cytosis
No change
10Sputum examination:
Very important in identifying AFB for diagnosis of open cases of tuberculosis
Restrictive pericarditis is often a squela of fibrinous pericarditis, which can be of tuberculous etiology. So, it can also be associated with AFB positivity in sputum, if lung parenchyma is affected (rare).
Urine examination: Presence of RBC and albumin may indicate renal involvement in SBE.
Chest X-ray:
Immensely helpful in diagnosis of tuberculosis
Significant changes also can be seen in cases of underlying CRHD
Pleural fluid study: May help in establishing tuberculous nature of effusion.
CT Scan/Bronchoscopy with or without FNAC and/or lung biopsy: Rarely needed in cases of tuberculous lesion
Lymph node FNAC / biopsy, if palpable: Helpful in establishing Koch's etiology
Echocardiography: Two-dimensional scanners can diagnose cardiac vegetations of more than 2 mm diameter.
Underlying valvular defect also can be diagnosed.
Helpful in diagnosis of restrictive pericarditis
Blood culture: Most useful in diagnosing SBE; at least 3-5 samples are needed to show the presence of bacteremia. Identification of infecting organisms with sensitivity test for antibiotics is also essential for therapy.
SBE can be diagnosed on clinical history, examination and finding of blood culture along with echocardiographic features.
***CQ8: A 65-year-old male, living in a slum, alone, comes to outdoor with fatigue, weight loss and malaise for 2 months. Patient is also suffering from chronic cough, occasional haemoptysis and slowly progressive breathlessness for years. O/E, muco-cutaneous petechial spots and subungual haemorrhage seen
What is your provisional diagnosis?
What can be other possibilities? Describe the steps for confirmation of diagnosis.
Ans.: Provisional diagnosis:
  • Subacute bacterial endocarditis
    (Possibly over pre-existing valvular disease manifested by gradually developing breathlessness with cough and occasional haemoptysis for years)
Other causes:
  • Tubercular pleural effusion
  • Restrictive pericarditis
  • Approach for diagnosis is similar to previous question
***CQ9: A 48-year male complaining of sudden onset severe retrosternal chest pain, diaphoresis and respiratory distress. O/E, rapid and feeble pulse with cold extremities
What are the possible causes? How will you pinpoint your diagnosis?
Ans.: Most possible diagnosis:
  • Myocardial infarction (MI)
  • Other causes:
  • Massive pulmonary embolism with infarction
  • Aortic dissection
  • Tension pneumothorax
  • Acute bacterial pneumonia with pleuritis (Pleuritis will give rise to sharp pain)
  • Acute pancreatitis
Steps for diagnosis:
History
MI
Acute pneumonia
P. embolism
A. dissection
T. pneumothorax
A. pancreatitis
Age
40+
Young
40+
40+
Any age
40+
Sex
Male
Male
Female
Male
Male
Male
Hypertension
S
NS
S
S
NS
NS
Atherosclerosis (Predisposing factors)
S
NS
S
NS
NS
NS
Smoking
S
S
S
NS
S
NS
Drug history
NS
NS
S
NS
NS
S
Obesity
S
NS
S
NS
NS
NS
Immobility
NS
NS
S
NS
NS
NS
Fever
+
±
+
Nausea, vomiting
±
NS
±
±
S
S
Cough
NS
S
NS
S
±
NS
Examination
MI
P. embolism
Acute pneumonia
A. dissection
T. pneumothorax
A. pancreatitis
Arrhythmias
+
Shifting of mediastinum
+
Breath sound
Basal creps
Creps
Creps
No change
Basal creps
Percussion of lung
Normal
Normal
Dull
Normal
Hyper-resonant
Normal
Cullen's sign
+
Turner's sign
+
Shock
+
+
Rare
+
+
±
18
Investigations
Routine haematology
MI
P. embolism
Acute pneumonia
A. dissection
T. pneumothorax
A. pancreatitis
Hb%
N
N
N
N
N
N
TLC
N/↑
N/↑
DC
↑Neutro
↑Neutro
↑Neutro
N/↑Neutro
N/↑Neutro
↑Neutro
ESR
↑/N
↑/N
Sputum examination: Acute pneumonia: Gram stain can identify organism. Culture can be done. Not very much useful in other cases.
Assay of enzymes and proteins:
MI: ↑level of AST, LDH, CK and CKMB, ↑level of TnI and TnT
Pulmonary embolism: ↑ LDH
Acute pancreatitis: ↑ Serum amylase, pancreatic isoamylase and lipase
Chest X-ray:
Lobar pneumonia: Radiopaque lobe
Pulmonary infarct: Demarcation possible after 12-36 hours
Tension pneumothorax: Visible visceral pleural edge
ECG: ST changes and Q wave in MI are almost diagnostic.
All other diseases may show ECG changes, if there is any secondary cardiac involvement.
Echocardiography:
MI: Abnormal motion of infarcted area with ejection fraction estimation
Aortic dissection: Helpful in diagnosis
CT scan: Useful in diagnosis of aortic dissection.
MRI: Aortic dissection can be diagnosed. Helps in structural characterization of MI cases.
Angiography:
Coronary: Localizes proper location of obstruction in MI.
Pulmonary: Localizes site of block in pulmonary embolism.
Aortic: Helpful in diagnosis of aortic dissection.
A diagnosis of myocardial infarction is made on clinical signs and symptoms along with suggestive ECG changes and serum enzymes or, protein elevation. Angiography may be done. But other tests are not usually required routinely.
***CQ10: A 39-year male smoker with hypertension suddenly develops severe left sided chest pain with extension to left arm, sweating, respiratory distress and syncopal attack.
What are the possibilities?
How will you investigate the case?
Ans.: Possibilities:
  • Myocardial infarction
  • Massive pulmonary embolism with infarction
  • Aortic dissection
Approach for diagnosis: Same as CQ9
***CQ11: A 65-year-old diabetic male gets admitted into hospital with mild retro-sternal discomfort, breathlessness, tachycardia and progressively falling blood pressure for 3 hours.
What is the most likely diagnosis?
How will you establish your diagnosis?
Ans.: Provisional diagnosis:
  • Myocardial infarction
  • (Chest pain of MI may be diminished or, even absent in old age and in diabetics.)
  • Steps for diagnosis: See CQ9
**CQ12: A 56-year-old female, in the postoperative period, suddenly developed severe chest pain, breathlessness, cough with haemoptysis and pyrexia.
19What is your provisional diagnosis?
How will you proceed for diagnosis?
Ans.: Provisional diagnosis:
  • Massive pulmonary embolism with infarction
  • Diagnosis will be confirmed by:
    • History
    • Examination
    • Investigations– Routine blood, serum LDH assay, chest X-ray, pulmonary perfusion scan and angiography (ECG – no significant change) [See also CQ9]
***CQ13: A 33-year male smoker comes to Surgical outdoor with severe pain in both lower limbs, particularly during walking, with bilateral wasting of calf muscles and ulceration over right great toe.
What is your provisional diagnosis?
How will you justify your diagnosis?
Ans.: Provisional diagnosis:
  • Buerger's disease
Steps for diagnosis:
 
History
  • Age: Young adult
  • Sex: Male
  • Duration: Slowly progressive
  • History of smoking: Almost always present
  • Numbness of the extremities:
  • Pain during walking:
  • Pain at rest: Late feature
 
Examination
  • Loss or, absent pulse of peripheral arteries
  • Cold extremities
  • Wasting of muscles of extremities
  • Ulceration
 
Investigations
Already mentioned.
**CQ14: A 56-year-old male, complaining of severe headache over right temporal region for 3 months, suddenly developed dimness of vision of right eye.
O/E.: Painful, tender blood vessel over temporal region.
What is the most likely diagnosis?
How will you investigate the case?
Ans.: Most likely diagnosis:
  • Temporal arteritis
20Steps for diagnosis:
 
History
  • Age: Commonly older age group, more than 50 years
  • Sex: Occur in both sexes almost equally
  • Frequency: Most common type of vasculitis
  • Site: Temporal arteries commonly involved; unilateral involvement is usual
  • Common presentation: Non-specific symptoms like low-grade fever, weight loss, fatigue for a variable period with localizing symptoms depending upon arterial system involved:
    Temporal artery: Severe throbbing headache of the side affected
    Vertebral artery: Dizziness, vertigo, etc. Ophthalmic artery: Diminution of vision, diplopia even unilateral blindness.
 
Examination
Most important sign is palpable nodular temporal artery
Other neurological tests should be done to exclude any other causes of vertigo, headache and dimness of vision (like intracranial tumours, meningitis, etc.)
 
Investigations
Routine investigations usually fail to show any significant abnormality. When there will be clinical suspicion, the only way to prove diagnosis is biopsy of the temporal artery.
  • Gross examination of excised artery: Nodular thickening of affected segment
    Cut section: Reduction of lumen
  • Microscopy: Most of the cases show granulomatous inflammation of the vessel with presence of:
    • Necrosis
    • Macrophages
    • Lymphocytes
    • Fibrosis
    • Acute inflammatory cells
    • Giant cells both foreign body type and Langhan's type
Some cases show only chronic nonspecific inflammation with infiltration of acute and chronic inflammatory cells without any specific changes.
*CQ15: Young female, aged 25, seeks medical attention with coldness and numbness of fingers, vertigo and dimness of vision.
O/E: Radial pulse on both upper limbs very weak.
What is your diagnosis? How will you establish your diagnosis?
Ans.: Provisional diagnosis:
  • Takayasu's arteritis
Steps for diagnosis:
 
History
Age: Commonly less than 40 years
Sex: Females predominantly affected
Duration: Slowly progressive usually takes 1-2 years; but may also be rapid
  • Common presentations:
  • Numbness and coldness of fingers
  • Ocular disturbances
  • Dizziness
21
 
Examination
Weak pulsation in both upper limbs (pulseless disease)
Low blood pressure in upper limbs
Visual defects
Hemiparesis
Claudication of lower limbs (if distal portion of aorta is involved)
Pulmonary hypertension (with involvement of pulmonary artery)
 
Investigations
Routine investigations may not show any abnormality
  • Gross examination: Irregular thickening of branches with intimal kinking
  • Histology:
Early: Mononuclear cell infiltrate in the outermost layer of arteries with perivascular cuffing Intermediate: Mononuclear cells will infiltrate tunica media; granulomatous inflammation occurs in some cases with necrosis and giant cell formation
Late: Fibrosis of all layers of arteries with lymphocytic infiltrate in the intima
Diagnosis mainly depends upon clinical features.
*CQ16: A 30-year female presenting with a small, elevated, firm and tender nodule, reddish in colour, at the subungual region of left second finger.
What is your provisional diagnosis?
How will you confirm your diagnosis?
Ans.: Provisional diagnosis:
  • Glomus tumour (Glomangioma)
Steps for diagnosis:
 
History
  • Age: Young adult
  • Sex: Female preponderance
  • Size: Small, less than 1 cm
  • Colour: Reddish or, red-blue
  • Common locations: Distal portion of digits, commonly under finger nail (Other sites: Any part of skin, soft tissue and GI tract).
 
Examination
Shape—Elevated and rounded
Consistency – Firm
Associated pain–Highly tender
 
Investigation
Biopsy of the elevated lesion is the mainstay of diagnosis.
  • Histopathology: The lesion is composed of glomus cells and blood vessels. Glomus cells are small regular round cells with large round to oval nucleus and scanty cytoplasm. Nests of glomus cells are arranged surrounding blood vessels.
  • Electron microscopy: Will show smooth muscle differentiation of glomus cells.
***CQ17: A 36-year homosexual male, HIV +ve for 7 years, developed rapidly progressive multiple reddish nodules over ankle and calf of right leg with right popliteal and inguinal lymphadenopathy.
What are these lesions?
How can you confirm the diagnosis?
Ans.: Provisional diagnosis:
Kaposi's sarcoma
Steps for diagnosis:
 
History
  • HIV positive.
  • Homosexual male.
  • Young age.
  • Typical skin lesions with rapid progression
 
Examination
  • Multiple nodular lesions
  • Localized or, generalized lymphadenopathy
  • Visceral involvement
 
Investigations
  • FNAC of the nodules and lymph node: Characteristic spindle cells, inflammatory cells, RBC, hyaline droplets and mitotic figures
  • Biopsy of the nodules
  • Biopsy from metastatic sites
 
Exercises
***CQ18: Teen-age girl comes for consultation with excessive pain and swelling of both knee and elbow joints for a week. H/O cold, cough, fever and throatache 2 weeks prior to onset of presenting symptoms is present.
What is your provisional diagnosis? What can be other possibilities? How will you approach for diagnosis?
***CQ19: A 39-year-female, presented with slowly developing breathlessness, chronic cough and occasional haemoptysis for last 3 years. Past H/O repeated attacks of joint swelling with fever during childhood.
What are the possible causes? Discuss lab. investigations for confirmation of your diagnosis.
***CQ20: A 56-year-male, smoker and hypertensive, complaining of severe pain in the left side of chest with sweating, palpitation and respiratory distress for 1 hour. What are the probable causes? Describe the steps for diagnosis.