Takotsubo cardiomyopathy

Vignette says a 64 year old female with a history of well controlled hypertension presents to the emergency department with chief complaints of sudden onset chest pain and shortness of breath for 1 hour; She reports that she has been under a lot of stress recently as her husband is diagnosed with terminal stage lung cancer; Vital signs show blood pressure of 100/60 mm of Hg, pulse rate of 106 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 98.9 F; Laboratory studies show slight elevation of cardiac troponins; ECG shows ST segment elevations; Echocardiography shows apical ballooning with hypercontractile basal segments; Coronary angiography shows no evidence of obstructive coronary artery disease; Diagnosis?

Diagnosis is Takotsubo cardiomyopathy. 

Takotsubo cardiomyopathy is characterized by transient wall motion abnormalities of the left ventricular apex and mid ventricle in the absence of any angiographically significant CAD that leads to transient left ventricular systolic and diastolic dysfunction (i.e. Takotsubo cardiomyopathy is a transient left ventricular systolic and diastolic dysfunction that results in apical akinesis, hypokinesis or dyskinesis with basal segments hypercontractility giving the classic “takotsubo” (octopus trap) appearance on the echocardiography); It is often precipitated by an intense physical or emotional stress and is commonly present in postmenopausal women.

Pathophysiology:- Intense physical or emotional stress leads to catecholamine surge that leads to excessive coronary vasoconstriction and transient ischemia which ultimately results in myocardial stunning (i.e. contractile dysfunction).

Presents with acute onset substernal chest pain, SOB, syncope, arrhythmias, cardiogenic shock and sudden cardiac death.

Mayo Clinic diagnostic criteria for takotsubo includes:- 
1. Absence of coronary artery disease on angiography.
2. Transient akinesis, hypokinesis or dyskinesis of the left apical and mid-ventricular segments extending beyond a single epicardial vascular distribution.
3. New electrocardiographic abnormalities (either ST-segment elevation and/or T wave inversion).
4. Modest elevation of troponin levels.
5. Absence of all of the following (i.e. recent significant head trauma, intracranial bleeding, pheochromocytoma, obstructive epicardial CAD, myocarditis, hypertrophic cardiomyopathy).

Diagnosis:- 
1. Lab shows slight elevation of cardiac biomarkers (i.e. CK-MB, troponins). 
2. ECG shows ST elevations/T wave inversions. 
3. Echocardiography shows apical ballooning (due to akinesis, hypokinesis or dyskinesis of the  mid to apical segments), basal hypercontractility, decreased LVEF and LVOT obstruction. 
4. Coronary angiography shows no evidence of coronary obstruction.
5. Cardiac MRI.

Treatment:- 
1. Hemodynamically stable patients are treated with diuretics, ACE inhibitors, Beta blockers and anticoagulants (if LV thrombus present). 
This transient left ventricular apical ballooning syndrome often resolves within a few weeks.

Pheochromocytoma

Vignette says 30 years old male with a history of uncontrolled hypertension presents to the emergency department with chief complaints of  palpitations, headache and profuse sweating over the past few months; He has a history of hypertension for which he takes amlodipine and losartan since 18 months; He doesn’t smoke but drinks alcohol occasionally; Vital signs show blood pressure of 160/100 mm of Hg, pulse rate of  140 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 96% in RA and temperature of 98.7 F; Laboratory studies show increased 24 hours urinary catecholamines and its metabolites metanephrines (i.e. vanillyl mandelic acid, homovanillic acid); ECG shows sinus tachycardia with no other abnormalities; CECT of the abdomen and pelvis shows a well-defined mass arising from the right adrenal gland; Diagnosis?

Diagnosis is pheochromocytoma.

Pheochromocytoma is a rare catecholamine secreting tumor, which are derived from chromaffin cells (arise from neural crest) situated within adrenal medulla or extra adrenal paraganglioma; Pheochromocytoma is associated with multiple endocrine neoplasia type 2a (MEN 2a), multiple endocrine neoplasia type 2b (MEN 2b), von Hippel Lindau syndrome (VHL), neurofibromatosis type I (NF 1), hereditary paraganglioma syndrome; Approximately 0. 1 to 1 % of total cases of hypertension is due to pheochromocytoma. 

Types:- 
1. Adrenal pheochromocytomas:- The MC site in adrenal medulla; NE: E ratio is high as 20:1 
2. Extra adrenal pheochromocytomas (Paragangliomas):- The common sites are along the paraaortic sympathetic chain, within organs of zuckerkandl, along the sympathetic chain in the neck and mediastinum, in the wall of the urinary bladder; The extra adrenal pheochromocytomas secrete NE exclusively.

Pheochromocytoma is clinical manifested with signs and symptoms like paroxysmal hypertension, headache, diaphoresis, palpitations, pallor, dyspnea and anxiety attacks from excessive catecholamines (i.e. mainly norepinephrine and epinephrine) secreted either intermittently or continuously by chromaffin cells of the tumor; The paroxysmal attacks are generally precipitated by exertion, trauma, stress, induction of anesthesia, drugs (metoclopramide, steroids, TCA’s), contrast dye.
Presents with the triad of headache, diaphoresis, and palpitations with sustained or paroxysmal hypertension. 

Diagnosis:- 
1. Increased catecholamines and its metabolites metanephrines (e.g. vanillyl mandelic acid, homovanillic acid) in urine and plasma; 24 hour urinary catecholamines and urinary metanephrines is used for the screening of pheochromocytoma. 
2. Increased plasma fractionated metanephrines level is the gold standard method for the diagnosis of pheochromocytoma.
3. CT scan / MRI shows a well-defined mass arising from the adrenal gland.
4. Somatostatin receptor scintigraphy, to rule out paragangliomas.

Management:- 
1.Medical therapy includes selective alpha-1 blockers (prazosin, terazosin) or nonselective alpha blockers (phenoxybenzamine) and non-selective beta blockers (Propranolol) or selective beta blockers (Atenolol, Metoprolol); Beta blockers should be given only after the complete alpha blockade to prevent hypertensive crisis.
2. Surgical resection of tumor is the mainstay of treatment.

Polycythemia vera

Vignette says a 55 year old male presents to his primary care physician with chief complaints of persistent headaches and dizziness over the past few months; He also reports of episodic blurring of vision and burning sensation in hands and feet over the past few months; Interestingly, he also suggests of having generalized pruritus, especially after a hot shower; Vital signs show blood pressure of 140/90 mm of Hg, pulse rate of  80 bpm, respiratory rate of 16 breaths/min, oxygen saturation of 96% in RA and temperature of 98.7 F; Examination shows splenomegaly; Laboratory studies show hemoglobin of 20 mg/dl, hematocrit of 56%, WBC count of 18,000 cells/mm3 and platelet count of 5 lakhs/mm3; Serum erythropoietin level is low; Bone marrow biopsy shows hypercellular marrow with increased erythroid, granulocytic and megakaryocytic proliferation (i.e. panmyelosis); F.I.S.H  demonstrates JAK-2 mutation; Diagnosis?

Diagnosis is polycythemia vera.

Clinical features:-
1. Hyperviscosity symptoms (due to erythrocytosis) include headache, dizziness, tinnitus, and blurred vision.
2. Thrombosis (due to thrombocytosis) includes Budd Chairi syndrome, erythromelalgia (intense burning, pain and erythema of extremities due to microvascular ischemia), DVT, MI and stroke.
3. Bleeding (due to abnormal platelet function) manifests as easy bruising, epistaxis, GI bleeding.
4. Pruritus after hot water exposure (i.e. aquagenic pruritus) is due to histamine release from the basophils.
5. Hyperuricemia (due to increased cell turnover i.e. tumor lysis syndrome).
6. Splenomegaly 

Diagnosis:-
1.  Hb >18.5 g/dL or HCT >49% in men and Hb >16.5 g/dL or HCT >48% in women, or ↑ red cell mass.
2. Bone marrow biopsy shows  hypercellularity marrow (i.e. erythroid, granulocytic and megakaryocytic proliferation).
3. Serum erythropoietin level is below the reference range for normal.
4. F.I.S.H demonstrates JAK-2 mutation and is the investigation of choice.

WHO criteria for polycythemia vera 
Major Criteria 
1. Elevated red blood cell mass or hematocrit (high hemoglobin levels)
Hemoglobin (Hb): >18.5 g/dL in men and  >16.5 g/dL in women. 
Hematocrit (Hct):  >49% in men and  >48% in women. 
2. JAK2 V617F mutation or JAK2 exon 12 mutation.
3. Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
Minor Criteria
1. Low serum erythropoietin (EPO) levels.
2. Endogenous erythroid colony formation in vitro.
Diagnosis of polycythemia vera includes all 3 major criteria, or 2 major criteria and at least 1 minor criterion.

Treatment:-
1. Phlebotomy till hematocrit is <45% in men and <42% in women.
2. Low dose aspirin (reduces thrombosis), allopurinol (for hyperuricemia) and antihistamines (for pruritus).
3. Hydroxyurea (inhibits the production of RBCs and platelets).
4. JAK-2 inhibitors (e.g. ruxolitinib) if refractory to or intolerant of hydroxyurea.

Complications:-
1. DVT, MI and stroke (due to increased risk of thrombosis).
2. Progression to myelofibrosis, acute leukemia (i.e. AML).