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Editor : Dr. P. K. DebDr. D. RoyPublished by :

BENGALHEART JOURNAL

Volume I No. II december 2015

A PUBLICATION OF THE CSI - WEST BENGAL BRANCH

BENGAL HEART JOURNALVolume I No. II december 2015

Contents

1

1. Editorial Dr. P. K. Deb 2

2. Bentall operation in a 27 year old doctor with Atanu Saha 3Type A Stanford Aortic Dissection– A case report

3. An interesting case of transient left ventricular Debanu GhoshRoy 6dysfunction following urinary fact infection in apost- menopausal woman

4. HIV, Cardiovascular Diseases, and Chronic Arghya Panigrahi, 9Arsenic Exposure co-exist in a Positive Synergy Amit K Chattopadhyay,

Goutam Paul, Soumya Panigrahi

5. Struma Cordis - A Case Report Bhabani Prasad Chattopadhyay, 20Sanhita Chatterjee,Sudakshina Chanda, Kunal Sarkar,Sanjeev Garg

6. Memorable Change in Shape of interventional B. P. Chattopadhyay, Sunip Bannerjee, 24Cardiology by Shape Memory Alloys (SMA) S. Das, A. S. Tripathi

7. Febrile Neonate - An Atypical Presentation Indira Banerjee, 28Amitabha Chattopadhyay, Mahua Roy,Prabhat Kumar,Biswajit Bandopadhyay,Kuntal Bhattacharyya

A STRIVE FOR 'MADE IN INDIA':A STEP FORWARD

Any present day search of scienti�c journals would yield loads of epidemiological and

clinical trials done on Indian soil. But when it comes to innovation, the result is

surprisingly meager. Unfortunately most of our research is predominantly a

reproduction of existing data with an Indian touch on some occasion. Innovative

techniques or innovative ideas originating on Indian soil and from Indian minds is

strikingly rare.

However, absence of such scienti�c articles does not warrant a dearth of basic medical

research done in India by Indians. In fact, a good number of such works have been

already done or are underway at various Indian institutes as a multidisciplinary effort

involving cardiologists, engineers and scholars of basic sciences. In this journal we

endeavour to publish such works and take a step forward from reproduction to

procration.

In this present issue, two important review articles on innovative ideas and techniques

by A. Panigrahi et al (1) and B. P. Chattopadhyay et al (2) were published.

The article by A. Panigrahi et al, explored the suitability of application of a mathametical

model in predicting a positive synergistic action of arsenic exposure with HIV infection in

precipitating cardiovascular disease.

On the other hand, the article by B. P. Chattopadhyay et al, reviewed the development of

various cardiolocal devices made up of a special alloy, including their own ongoing

research in collaboration with IIT, Kharagpur, towards development of a dedicated

bifurcation wire.

The journal, however, is still in its neonatal stage and the present issue failed to publish

any original article which it can �nd worthy of. But it boasts of four excellent case reports

which surely will make interesting reading.

Wishing you all a happy reading experience in the new year !

References:

1. A. Panigrahi , A. K. Chattopadhyay, G. Paul, S. Panigrahi, HIV, Cardiovascular

diseases and chronic arsenic exposure co-exit in a positive synergy. Bengal Heart

J.2015; 1(2) : pg. 9-19.

2. B. P. Chattopadhyay, S. Banerjee, S. Das, A. S. Tripathi. Memorable change in

shape of interventional cardiology by shape memory alloy. Bengal Heart J.2015;

1(2):Pg. 24-27.

3

EDITORIAL

Dr. P. K. Deb

Bentall operation in a 27 year old doctor withType A Stanford Aortic Dissection – A case report

Abstract :Type A Stanford aortic dissection has a worse prognosis and requires emergency surgical repair. The present

case report describes a rare case of Type A Stanford dissection along with anomalous origin of the right coronary

artery from left sinus. The clinical presentation, investigation �ndings and operative procedure were discussed.

5

Key-words :Type A Stanford aortic dissection, anomalous origin of the right coronary artery, Bentalli opration.

Introduction :Acute aortic dissection is an event of sudden onset in which blood leaves the normal aortic lumen through a

usually discrete point of exit (intimal tear) and rapidly dissects the inner from outer layers of the media to produce a

false lumen. There are two classi�cation systems for Acute aortic dissection: DeBakey classi�cation and Stanford1

classi�cation . The 2 classi�cation systems are depicted in the �gure below :2

Without surgical treatment Type A Stanford has a worser prognosis than Type B Stanford. During the acute episode

patient can succumb to the false lumen rupture leading to hemothorax or hemopericardium and exsanguination. If

the patient survives the initial period, death may strike later consequent to organ dysfunction secondary to arterial

occlusions or delayed rupture.

Morris and colleagues in Houston reported the �rst successful repair of acute ascending aortic dissection with

aortic regurgitation in 1963 . Ever since that period technological advancements in CPB and synthetic3

replacements has grown to a great extent contributing to improved outcomes following surgical treatment of acute

aortic dissection. The main principle involved in surgery is to replace the aortic segment containing the intimal tear

with a synthetic conduit without removing the entire false lumen.

Atanu SahaSenior Consultant Cardiac Surgeon, NH-RTIICS

6

In this case report, we are reporting the real time management strategies undertaken in treating a 27 year old

doctor with Type A Stanford Acute aortic dissection.

Case Report :A 27 year old doctor presented with sudden onset retrosternal pain radiating to the neck. Echocardiography done

outside was suggestive of dissecting aortic aneurysm. CT angiography thorax was ordered immediately.

CT Angio Thorax Findings :Fusiform dilatation with intimal dissection was seen extending from the aortic root to the aortic arch involving the

proximal parts of the arch branches(Stanford Type A Dissection). Anomalous origin of the right coronary artery

from the left coronary sinus near the origin of left main coronary artery was also noted.

Plan of management :Bentall operation was planned for the patient. Patient was immediately shifted to the operating Room after high risk

of the procedure was informed to the patient party and consent obtained.

Operation :Bentall Operation with 21mm Aortic Valved Conduit + along with RSVG to RCA grafting was done.

Procedure :Medican sternotomy was done, thymus was dissected, pericardial cradle was made. Right groin was prepared,

femoral artery was exposed and cannulated using a 8 mm Haemashield side graft. Similarly axillary and left

common carotid cannulation was done after systemic heparinization. CPB started after bicaval cannulation. LV

vent placed through right superion Pulmonary vein. Patient was cooled to 26 C. Aorta was cross clamped just0

below the innominate artery. Aorta was opened obliquely .Antegrade direct ostial cardioplegia was given. Left

coronary button was harvested, after keeping about 1 cm of aortic margin around the ostia. Right coronary artery

had an abnormal origin from left coronary sinus and had an intramural course.

Aortic valve was excised. 21 mm St. Jude aortic valve conduit was sutured with interrupted 2/0 Ethibond

plegdetted sutures.Periacardial strip was used as a sandwich between the sutures. A 1 mm hole was made in the

corresponding site over the graft for LCA anastomosis. Anastomosis was done with 6-0 prolene. Right coronary

artery was bypassed using RSVG graft. The origin of the artery was closed using 5-0 prolene sutures. Patient was

cooled to 18 C and cross clamp was removed. Distal arch was inspected. No internal tear was found. Distal part of0

the conduit was �xed to the proximal arch using 4-0 prolene sutures. Proximal end of RSVG was attached to the

conduit using 7-0 prolene sutures. Patient was re warmed. CPB was gradually weaned off. Patient came off bypass

in normal sinus rhythm with mild doses of inotropes. Protamine was started. Hemostasis was achieved. One left

pleural and two mediastinal drains were left. One RV and one RA pacing were put. Chest was closed in layers.

Discussion :It has been proven beyond doubt that emergency surgical repair is the treatment of choice in Type A Stanford aortic

dissection. According to data collected by International Registry on Aortic Dissection(IRAD), during the period

between 1996 and 2003, there is an in-hospital mortality of 54% in people who were managed medically owing to

other contraindications for surgery .4

In addition to the dissection of the ascending aorta, the patient also had anomalous origin of right coronary artery

from the left coronary sinus.

Another interesting observation made is that the patient had some of the marfan traits. However the patient was not

evaluated for Marfan's syndrome or any other connective tissue disorders during the hospital stay. Plan is drawn to

evaluate him for Marfan's syndrome during the follow-up visits and also prophylactic echocardiographic

evaluation of his �rst degree relatives to rule out ascending aorta aneurysm in them.

7

Conclusion :In this case report we try to explore the management strategies of Acute Aortic Dissection. In our institution we

have performed signi�cant number of Bentall operation with good results. We also stress the importance of

evaluating the patient for connective tissue disorders.

References :

1. Daily PO, Trueblood HW, Stinson EB, Wuer�ein RD, Shumway NE. Management of acute aortic dissections. Ann Thorac Surg .

1970;10:237.

2. DeBakey ME, McCollum CH, Crawford ES, Morris GC, Jr., Howell J, Noon GP, et al. Dissection and dissecting aneurysms of the aorta:

twenty- year follow- up of �ve hundred twenty- seven patients treated surgically. Surgery . 1982;92:1118.

3. Morris GC, Jr., Henly WS, DeBakey ME. Correction of acute dissecting aneurysm of aorta with valvular insuf�ciency. JAMA .

1963;184:63

4. Thomas T. Tsai, Arturo Evangelista, Christoph A. Nienber: Long Term Survival in Patients with Type A Acute Aortic Dissection: Insights

from the International Registry of Acute Aortic Dissection(IRAD): Circulation 2006;114[suppl I]:I-350-I-356

8

An interesting case of transient left ventriculardysfunction following urinary fact infection in a post-

menopausal womanDebanu GhoshRoy

Assoc. Prof. of Cardiology , KPC Medical Collage, Kolkata

Abstract :Takotsubo cardiomyopathy is characterized by transient systolic dysfunction of left ventricle in presence of normalcoronary arteries, and occurs especially in post-menopausal women. In the present case report, one such patientis described who developed the syndrome following urinary tract infection.

Key-words :Takotsubo cardiomyopathy, urinary treat infection.

Introduction :Here we report a case of Takotsubo cardiomyopathy following urinary treat infection.

Case Report :A 67 years old female was admitted for evaluation of chronic constipation for 2months. She was receivingamlodipine 5mg for hypertension. Investigations done 15 days before admission showed normal serumelectrolytes, serum creatinine and liver function test. She started taking lactulose and sodium picosulphate 2weeks back.

On admission blood pressure was 130/80 mm of Hg. Examination was normal except for slight abdominaldistension. Investigations on day 1 showed haemoglobin was 10.4 g /dl (hypochromic microcytic). Total anddifferential counts were normal. ESR was 47mm. Blood sugar, prothrombin time and thyroid function test werenormal. Abdominal X ray was normal. ECG showed minor ST – T changes (Fig 1). CT scan of abdomen wasnormal but the colon was loaded with stool. She was posted for colonoscopy next day. She was given lesuride andLibrium.

On day 2 she was given polyethylene glycol for bowel preparation. As she was taking the medicine she hadvomiting followed by syncope. She was shifted to the intensive care unit and IV �uids were given rapidly. BPincreased to 90/60 mm and she felt better. She developed high grade fever. All drugs were stopped and antibioticswere given.Normal saline was continued . Urgent ECG showed minor non -speci�c ST-T changes. Chest Xray wasnormal (Fig 2). Blood reports were as follows : Sodium 135mEq/L, Potassium 2.4mEq/L, g/dl, Magnesium1.8mg/dl, Troponin T 17.99ng/l (normal upto 14ng/l), Creatine Kinase was 64 U/L and MB faction was 13U/L.Echocardiogram showed mild global hypokinesia of left ventricle with ejection fraction of 50%.

She became afebrile and asymptomatic. Potassium supplements and spironolactone were given. Patient wasclosely monitored. CRP was 124.9mg/l. Procalcitonin was 3.39ng/ml. Urine showed plenty of pus cells and grewKlebsiella. Haemoglobin HPCL showed she was heterozygous for HbE. Tests for Dengue and Malaria werenegative.

She remained asymptomatic but serial ECG showed worsening of ST – T changes (Fig 3). She developed leftventricular failure on day 5 and received intravenous diuretics. Repeat chest X ray(Fig 4) showed cardiomegaly.Repeat echocardiogram showed akinesia of anterolateral wall and apex of left ventricle. Ejection fraction now was37%. Creatine Kinase now increased to 813U/L and MB fraction was 32U/L. Troponin T was now 175.4ng/L. Shewas given dual antiplatelet , statin and ramipril.

After control of failure, coronary angiogram was done which showed normal coronary arteries. Final diagnosiswas Takotsubo cardiomyopathy. Beta blockers were given . Patient went home with advice to do echocardiogramand follow up after 1 month.

9

Discussion :Takotsubo cardiomyopathy was reported in Japan in the early 90s. It is characterized by transient systolicdysfunction in the absence of obstructive coronary artery disease. It is also known as stress – inducedcardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy and broken heart syndrome.

Symptoms typically occur in post-menopausal women after an emotionally or physically stressful event. Stressinduced cardiomyopathy may follow other stressful events such as hypoglycaemia, hyperthyroidism, cocaine,opiate or alcohol withdrawal, pneumothorax, non-cardiac surgery, severe pain, neurological injuries, cardiacstress testing, all of which increase catecholamine levels. In one �fth of cases there is no identi�ed trigger.

More than 90% of Takotsubo cardiomyopathy patients are females. The usual age of presentation is the 7th decadeof life. Chest pain is the commonest symptom present in two third of patients. One �fth of patients have dyspnea.Rare presentations include cardiogenic shock and ventricular �brillation. ECG changes are present in almost allpatients. ST segment elevations were observed in four �fth of patients, whereas T wave abnormalities and q waveswere observed in two third and one third of patients respectively(1). Rarely there could be left bundle branch block.Mild elevations in cardiac enzymes were seen in more than 85% patients. Echocardiography showed LV systolicdysfunction with ejection fraction of 20% to 50%. There is hypokinesia or akinesia of the middle and apicalsegments of the left ventricle, which results in ballooning of the apical wall and sparing of the basal systolicfunction. Occasionally there is transient dysfunction localized to basal portion of the left ventricle (reverseTakotsubo) or mid portion of the left ventricle only (Figure5). They do not demonstrate delayed hyperenhancementby magnetic resonance imaging (MRI) with gadolinium. Coronary angiography shows absence of obstructivecoronary artery disease.

Criteria for diagnosis of stress cardiomyopathy was proposed by Mayo clinic in 2004 and later modi�ed in 2008. Itincludes (a) transient hypokinesis, akinesis, or dyskinesis in the LV mid-segments with or without apicalinvolvement; RWMA extending beyond a single epicardial vascular distribution ; the presence (often, but notalways) of a stress trigger ; (b) the absence of obstructive coronary disease or angiographic evidence of acuteplaque rupture; (c) new electrocardiographic abnormalities (ST-segment elevation and/or T-wave inversion ) ormodest elevation of cardiac troponin levels in the serum; (d) the absence of pheochromocytoma or myocarditis.All four criteria must be met for diagnosis(2).

The pathophysiology of this disorder is not entirely clear. Many believe it is high levels of stress inducedcatecholamine and stress related neuropeptides that leads to myocardial stunning. Serum catecholamine levelsare higher in stress induced cardiomyopathy than in acute myocardial infarction. High levels of catecholamine maycause impaired myocardial perfusion, left ventricular out�ow tract obstruction, myocyte injury or a combination ofthese features. Exact mechanism may differ in different patients. Some studies have shown multi vessel coronaryartery spasm, whereas others have not. There may be a genetic bias of this disease. As this disease accurs inpostmenopausal women , it could be due to hormonal disturbances, perhaps de�ciency in oestrogens. Smallersize of left ventricle in women may have a propensity to develop left ventricular out�ow tract obstruction with aninterventricular pressure gradient causing oxygen mismatch at the apex of the ventricle, leading to ballooning.Microvascular dysfunction may also contribute to LV dysfunction.

It is essential to exclude acute coronary syndrome (ACS), especially myocardial infarction due to occlusion of theleft anterior descending artery (See Table 1). Once ACS is excluded, treatment is largely supportive with diureticsand vasodilators. Vasopressors and inotropes should be avoided if possible.

The prognosis is generally good with reversal of LV systolic dysfunction within few weeks. Prognosis does notdepend on age at onset, sex, presenting symptoms, type of stress, degree of LV systolic dysfunction or ECGchanges. The in-hospital mortality is 2%. The recurrence rate is less than 10%. The 4 year survival rate is same asage and gender matched general population.

References :

1. Gianni M, Dentali F, Grandi AM, et al: Apical ballooning syndrome or takatsubo cardiomyopathy: a systematic review. Eur Heart J

27:1523, 2006.

2. A.Prasad, A. Lerman, and C. S. Rihal, “Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial

infarction,” The American Heart Journal, vol.155, no.3, pp. 408-417, 2008.

10

Fig 1 : Ecg on day 1 Fig 2 : Chest Xray on Day 2

Fig 3 : Ecg on day 4 Fig 4 : Chest Xray on Day 5

Fig 5 : Different ventricographic morphogies in takotsubo cardiomyopathy

Table 1

11

Arghya Panigrahi , Amit K Chattopadhyay , Goutam Paul , Soumya Panigrahi1 2 3 4*

1. Department of Physiology, Jhargram Raj College, Govt. of West Bengal. Jhargram, West Midnapore, WB, India. (apandada1@gmail.com);2. Non-linearity and Complexity Research Group - Aston University, Aston Triangle, Birmingham, B4 7ET, UK. (a.k.chattopadhyay@aston.ac.uk);3. Department of Physiology, University of Kalyani, West Bengal, India. (gpaul@klyuniv.ac.in)4. Department of Medicine, Division of Infectious Diseases, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH,

44106 (sxp579@case.edu). *corresponding author)

HIV, Cardiovascular Diseases, andChronic Arsenic Exposure co-exist in a Positive Synergy

Abstract

Recent epidemiological evidences indicate that arsenic exposure increases risk of atherosclerosis, cardio vascular

diseases (CVD) such as hypertension, atherosclerosis, coronary artery disease (CAD) and microangiopathies in

addition to the serious global health concern related to its carcinogenic effects. In experiments on animals, acute

and chronic exposure to arsenic directly correlates with cardiac tachyarrhythmia, and atherogenesis in a

concentration and duration dependent manner. Moreover, the other effects of long-term arsenic exposure include

induction of non-insulin dependent diabetes by mechanisms yet to be understood. On the other hand, there are

controversial issues, gaps in knowledge, and future research priorities in accelerated incidences of CVD and

mortalities in patients with HIV who are under long-term anti-retroviral therapy (ART). Although, both HIV infection

itself and various components of ART initiate signi�cant pathological alterations in the myocardium and the

vasculature, simultaneous environmental exposure to arsenic which is more convincingly being recognized as a

facilitator of HIV viral cycling in the infected immune cells, may contribute an additional layer of adversity in these

patients. A high degree of suspicion and early screening may allow appropriate interventional guidelines to

improve the quality of lives of those affected. In this mini-review which have been forti�ed with our own preliminary

data, we will discuss some of the key current understating of chronic arsenic exposure, and its possible impact on

the accelerated HIV/ART induced CVD. The review will conclude with notes on recent developments in

mathematical modeling in this �eld that probabilistically forecast incidence prevalence as functions of aging and

life style parameters, most of which vary with time themselves; this interdisciplinary approach provides a

complementary kernel to conventional biology.

ABBREVIATIONS : As O , arsenic trioxide; AsV, arsenate; AsIII, arsenite; CAD, coronary artery disease; CVD,2 3cardiovascular disease; EC, endothelial cell; NO, nitric oxide; NOS, nitric oxide synthase; eNOS, endothelial nitric

oxide synthase; ROS, reactive oxygen species; HUVEC, Human Umbilical Vein Endothelial Cell.

Key-words : HIV, arsenic exposure, cardiovascular diseases, positive synergy.

Introduction

The World of Arsenic

The knowledge of medicinal and homicidal use of arsenic can be traced back to the early days of human

civilization. The poisonous and carcinogenic proper ties of arsenic

compounds, or “Arsenicals”, have been known for more than 2000 years

[2,3]. In the west, much of the current awareness can be traced back to the

1 9 4 4 c o m e d y m o v i e a n d O l d L a c eA r s e n i c

(http://www.imdb.com/title/tt0036613/). Emperors, kings, arctic explorers,

heirs and commoners have been treated with arsenicals for both legitimate

and homicidal purposes. A popular myth suggests that in 55 AD, the infamous

1. In the 1800s, , a 1%Fowler's solutionpotassium arsenite solution, was usedas a general tonic for treatingleukemia, psoriasis, and asthma.Fowler's solution was not withdrawnfrom the US market until the 1950s.

2. T h e a r s e n i c - c o n t a i n i n g d r u gmelarsoprol is still the drug of choicefor treating African trypanosomiasis.

12

Roman emperor Nero poisoned his stepbrother Britannicus with

arsenic before his 14th birthday. Conversely, Hippocrates used

arsenicals to treat ulcers.

In the course of t ime,

Arsenicals made their place

in medicine for treating

sleeping sickness, syphilis,

tuberculosis and cer tain

skin diseases. In the early

1800s, Arsenic exposure

was linked to cancer leading

to a progressive diminution

i n i t s m e d i c i n a l u s e .

Arsenical have widespread use in embalming during and after the

American Civil War, and today, Arsenic leaching from old

cemeteries is a known groundwater pollutant in the Unites States.

Arsenic has been used widely in the United States as a wood

preservative until the year 2004 [4]. Eventually, as wood comes

into contact with

soil and water, it

releases Arsenic to

the environment. This is a major source of Arsenic in the

environment, in particular in children playgrounds. In addition,

Arsenic plays an important role in the semiconductor industry in

the form of gallium arsenide, a compound used in a wide range of

electronic devices [5].

Most Arsenic in the terrestrial environment is found in rocks and

soils. Arsenic in surface and ground water is mostly a mixture of

arsenite and arsenate. Arsenic is widely distributed in food;

particularly high levels are found in seafood [6]. The major man-

made sources of

Arsenic include coal

c o m b u s t i o n ,

nonferrous metal

smelting, and the

burning of agricultural wastes. Arsenic compounds have been

widely used as herbicides, fungicides, wood preservatives,

desiccants, cattle and sheep dips, and as coloring agents. Arsenic

continues to be widely used in agriculture, in glass and ceramics, as

a metal alloy, and in semiconductors and other electronic devices.

In the past, Arsenic containing rodenticides and ant poisons were

responsible for many exposures. Suicidal and homicidal poisonings

continue to be reported. Bacteria within soils and sediments can

transform arsenate to arsenite, which can be converted into

methylarsenic acid. Also within the soils and sediments, bacteria

can transform methylarsenic acid into dimethylarsinic acid. All

Air : Arsenic in air range from 0.02 to 4ng/m ) in3

remote and rural areas, to (3 to ~ 200ng/m ) in urban3

areas, higher concentrations (more than 1000 ng/ m )3

can be found near industrial area, in some countries.

Water : Open ocean seawater are typically low(1–2μg/l) whereas surface waters may be 1000 timeshigher (up to 5000 μg/l)in arsenic content. Arseniclevels in groundwater are typically as low as in openocean water (about 1–2 μg/l), except in areas withvolcanic rock and sulphide mineral deposits wherearsenic levels can range up to 3000 μg/l.

In sediment : Arsenic concentrations range from 5 to3000 mg/kg. The higher levels are found in areascontaminated by mining and smelting. In soil,concentrations range from 1 to 40 mg/kg, usuallyaveraging around 5 mg/kg.

Marine biome : Marine organisms normally containarsenic residues ranging from < 1 to more than100mg/kg, predominantly as organic arsenic speciessuch as a rsenosuga rs (mac roa lgae ) andarsenobetaine (invertebrates and �sh).

Terrestrial plants : Plants may accumulate arsenic byroot uptake from the soil or by adsorption of airbornearsenic deposited on the leaves. Arsenic levels arehigher in biota collected near anthropogenic sourcesor in areas with geothermal activity.

An ACUTE FATAL DOSE of Arsenic is in therange of 2-20 mg/kg body weight/day. Thus,a relatively healthy person with a bodyweight of 75 kg may die if he ingests about145 mg to 1.45gm of Arsenic Trioxide (mostcommonly available arsenic compound).Considering the high density of the oxide,less than 1/8 of a tea spoon can be fatal.Smaller amounts may be fatal for exposedunhealthy people, elderly or children. Thesymptoms of poisoning by SMALL amountsof Arsenic are indistinguishable fromsymptoms of other illness.

Sources of Occupational Exposure to Arsenic

1. notably of fast chipsSemi-conductors industry,based on gallium arsenide often involving the toxicgas ARSINE, AsH3.

2. Glass manufacturing.

3. Mining operations and purification of metal oresand metals. Speci�cally, sul�de base oreprocessing (iron pyrite, lead sul�de)

4. Manufacturing of certain drugs, Cattle andpoultry food additives (some anti-cancer drugs,e.g. Roxarsone).

5. andManufacturing and use of pesticidesinsecticides which contain Arsenic.

6. Wood Treatment

7. Rat and animal poisons.

8. Old paintsN.B. Although in most countries the use of Arsenic and its compounds forApplications 5, 6, 7 and 8 has been banned or discontinued, there are stillmany products that contain Arsenic which were manufactured before theban took effect. This includes treated wood in children playgrounds and oldcontainers of rat poison.

Sources of Exposure to Arsenic in Daily Life.

1. Most drinking water contains small amounts ofArsenic. Natural water leaches small amounts ofArsenic from rocks and sand. Some industrialoperations sometimes contaminate water withArsenic.

2. Arsenic was found in items such as wine, juice,syrup, glues and pigments.

3. Arsenic is found in many foods both as organiccompounds such as methyl arsines, and asinorganic arsenates and arsinates. The organiccompounds are less toxic than the inorganiccompounds.

4. Inorganic arsenic compounds were found in applejuice, orange and grapefruit juice, in vinegars andsalad dressings, in milk and dairy products, beef,pork, poultry and in cereal.

5. Arsenic is found in most unshelled rice but also inshelled rice and in its products.

13

these arsenic compounds are then sublimated through rain and

thereby percolate into drinking water. Molds can convert

methylarsenic acid into trimethylarsine, which can then also be

available within water. In addition, molds and bacteria can

convert dimethylarsinic acid into both trimethylarsine and

dimethylarsine in water. Once in water, trimethylarsine and

dimethylarsine can volatilize into the atmosphere. Therefore,

different forms of Arsenic can be found in the soil, sediments,

water, atmosphere and the food chain. (Reviewed in:[7]).

Non-occupational human exposure to arsenic in the environment is

primarily through the ingestion of food and water[8,9]. Arsenic has

been detected in groundwater in several countries of the world, with

concentration levels exceeding the WHO drinking water guideline

value of 10 g/L (WHO) as well as the national regulatoryμ

standards (e.g. 50 g/L in India and Bangladesh) [10, 11]. Arsenicμ

in groundwater is often associated with geologic sources. Today,

arsenic contamination of drinking water is a major worldwide

public health problem. A very large number of people in India and in

different parts of the world (countries like Bangladesh, Chile,

Taiwan, Mexico, Thailand, Germany and parts of China) are being

highly affected due to the intake of arsenic contaminated ground

water [8, 10-12]. A signi�cant fraction of the population living in the

districts of West Bengal, India, (e.g. Malda, Murshidabad, Nadia,

Bardhaman, Hooghly, 24-Parganas, and Kolkata) are also under

heavy environmental exposure to arsenic and suffer from the

effects of chronic

arsenic toxicities

i n i t i a t i n g a n

a larming ly h igh

incidence of skin, bladder and lung cancer and also ‘Blackfoot’

disease (arsenic induced oxidative stress leading to microvascular

damage and gangrene of foot) [13-16].

The daily intake of total arsenic from food and beverages is

generally between 20 and 300 μg/day. Foodstuffs such as meat,

poultry, dairy products and cereals have higher levels of inorganic

Arsenic [17]. Pulmonary exposure may contribute up to

approximately 10 μg/day in a smoker and about 1 μg/day in a non-

smoker, and more in polluted areas. The concentration of

metabolites of inorganic arsenic in urine ranges from 5 to 20 μg of

Arsenic/liter, but may even exceed 1000 μg/liter. In workplaces

with up-to-date occupational hygiene practice, exposure generally

does not exceed 10 μg/m (8-h time-weighted average).3

Concentrations as low as 0.5 ppm Arsenic may trigger the initial symptoms of exposure [18].

The symptoms of small-to-moderate exposure to arsenic may appear immediately or only after several hours and

include headaches, vertigo and nausea. Subsequently, problems related to oxygen transfer in the body due to

interferences with the hemoglobin, along with possible impairment of renal functions occur.

Roxarsone organoarsenic compoundis an that is widelyused in the poultry, pork, and cattle industry as a foodadditive to increase weight gain and improve feedef�ciency. The drug was also approved in the UnitedStates for use in pigs.Roxarsone is marketed** as 3-Nitroby Zoetis, a former subsidiary of P�zer. In 2006,approximately of Roxarsone wereone million kilogramsproduced in the U.S.**Use of Roxarsone was discontinued in the US since 2011

A few important facts pertinent to ArsenicPoisoning:

1. Every person is exposed daily to Arsenic becausemost drinking waters and foods contain traceamounts of arsenic.

2. The body can tolerate small doses of Arsenicwithout noticeable immediate physiologicaleffects.

3. Arsenic atoms may be present in compounds in thetrivalent or the pentavalent form.

4. Arsenic may be atoms, inconnected to carbonwhich case the compound is called orORGANICmay be connected to other types of atoms, when itwill be called INORGANIC. Inorganic arseniccompounds are in general much more toxic thanorganic compounds.

5. Many Arsenic compounds will impart a garlic-likesmell to a food or to the breath of the person whoconsumes them.

6. Since the chemical properties of Arsenic are verysimilar to the properties of phosphorous, andbecause phosphorous compounds are critical innumerous biochemical functions in the body,Arsenic is toxic in all biochemical reactions thatinvolve phosphorous.

Overview of the human exposure to arsenic

- human exposure to arsenic inNon-occupationalthe environment is primarily through the ingestionof food and water.

- The daily intake of total arsenic from food andbeverages is generally between 20 and 300µg/day.

- such asFoodstuffs meat, poultry, dairy productsand cereals have higher levels of inorganicarsenic.

- may contribute up toPulmonary exposureapproximately and about10 µg/day in a smoker 1µg/day in a non-smoker, and more in pollutedareas.

- The concentration of metabolites of inorganicarsenic in urine ranges from 5 to 20 μg ofarsenic/liter, but may even exceed 1000 μg/liter.

- In workplaces with up-to-date occupationalhygiene practices, exposure generally does notexceed 10 μg/m3 (8-h time-weighted average).

14

Exposure to small doses of Arsenic compounds over a long period of time can result in lung, skin or liver cancer, or

cancer of the lymphatic system [19], and damage to organs, such as the esophagus, as also confusion and

disorientation. Arsenic mainly enters via drinking water or food that has been taken but it can also penetrate into the

body through the skin or the lungs [20]. Most Arsenic compounds are soluble in water to some extent and thus are

easily transported in the blood stream and assimilated by the body. The water solubility also helps to remove some

of the Arsenic via the urine and the excrement. The urine and other excrements may change to darker red-brown or

even greenish color [21]. Notably, a signi�cant portion of the ingested Arsenic is absorbed by various bodily

tissues and is retained over an extended period of time. Some of the Arsenic that enters the body is excreted out of

the body rather rapidly but a fraction of it accumulates in various organs including the blood vessels in addition to

the hair and the nails. The fraction of Arsenic that is retained in the body depends on the speci�c Arsenic compound

that has entered, the portal that it entered through, i.e. ingestion or inhalation, and other components present in the

food that were consumed together. While such arsenic based toxic wastes are liberated very slowly, nevertheless

they cause physiological damage in various organ systems [22].

Recent clinical research has shown that arsenic trioxide, administered intravenously, could induce cancer

remission in some people with refractory acute promyelocytic leukemia [23, 24]. There are highly suggestive but

inconclusive epidemiological evidences that support the increased incidence of arteriosclerotic lesions, ischemic

heart disease and thereby increased mortality risk among arsenic-exposed persons [25, 26]. Arsenic can trigger

multiple abnormal electrocardiographic patterns not limited to ventricular tachyarrhythmia [27, 28]. While the

carcinogenic and cancer therapeutic potentials of arsenic have widely been studied, there is a relatively smaller

attention to arsenic induced CVDs [29].

Arsenic and Cardiovascular diseases

Being long considered a potent human

health hazard due to its neoplastic

ou tcomes, Arsen ic a lso shows

increasing epidemiological evidence of

links between Arsenic exposure and

risks of CAD and CVDs. As mentioned

earlier, Arsenic is a major risk factor for

the endemic peripheral artery disease

characterized by severe arteriosclerosis

and subsequent gangrene of affected

extremities, so-called “Blackfoot”

disease (BFD) . In addition,[30, 31]

systemic vascular disease have been epidemiologically linked to chronic Arsenic exposure. High mortality from

ischemic heart disease was �rst reported in copper smelter workers who were exposed to arsenic . In the[32]

United States epidemiological studies correlated between standard mortality ratios for cardiovascular diseases

and arsenic levels in food and drinking water [33, 34]. In our experimental system, acute exposure of inorganic

arsenic induced tachycardia in isolated amphibian hearts ,similar to adrenalin ,and could be blocked by a beta

blocker - atenolol (Figure 1). Ischemic heart disease and cerebral infarction are considered late clinical

manifestations of generalized atherosclerotic process and ultrasound studies in the super�cial carotid artery

indicated a dose response relationship between carotid atherosclerosis and chronic exposure to arsenic [33, 35,

36]been observed after careful adjustment of the statistical data for major CVD risk factors, signifying arsenic

exposure as a potential independent risk factor for atherosclerosis, CAD, and increased incidences of

cardiovascular morbidity and mortality.

Figure 1 : Arsenic induce tachycardia in isolated amphibian heart.Brief exposure of inorganic Arsenic (Na-Arsenate) induce tachycardia that could becounteracted by beta blockers in isolated amphibian heart.

15

Chronic low dose exposure to Arsenic induce endothelial dysfunction

The endothelium, being most sensitive to systemic or micro-environmental stress, is one of the prime target of

chronic arsenic toxicity. Naturally occurring and highly toxic inorganic form of arsenic rapidly induces reactive

oxygen species (ROS) formation and thereby induce proliferation response in vascular smooth muscle cells. The

net effect of such activity is attenuation of endothelium-dependent conduit artery dilation via downregulation of

endothelial NO synthase- events that are temporally matched to the accumulation of oxidants across the vessel

wall. Reduced expression of endothelial nitric oxide synthase (eNOS) leading to diminished bioavailability of

vasodilating nitric oxide (NO) is a hallmark of endothelial dysfunction.

A number of earlier publications indicate that Arsenic imposes serious threats to cardiovascular health and co-

morbidity. Reports of chronic arsenic exposure induced CVD related mortality, endothelial dysfunction,

dysregulated lipid metabolism are available, and some other detailed mechanistic studies are also starting to

emerge [1,37-41]. Moreover, in a recent study, it was shown that even habitual �sh intake, although generally

re�ect healthier dietary habits with favorable effects on the endothelial function, can actually increase the chronic

exposure levels of Arsenic and subsequently lead to deleterious alteration in the arterial �ow mediated dilation

(FMD) – a clinical indicator of endothelial dysfunction [42]. Chronic low exposure to arsenic induce Cyclin D1

dependent NFkB/BCL3 mediated pathways leading to cellular proliferation [43]. In addition, other associated

deleterious effects of chronic Arsenic exposure includes generation and persistence of proactive platelet, induction

of dyslipidemia and increase in endothelial adhesion of activated monocytes initiating a pro-atherogenic condition

[38, 44].

Our recent studies indicate that a range of ultra-low concentrations of Arsenic (10nM – 10μM) exposure

signi�cantly down-regulate the mRNA levels of eNOS in addition to signi�cantly diminished expression of Krüppel-

like Factor 2 (KLF2) and Krüppel-like Factor 4 (KLF4) in HUVEC (not shown), and in primary human aortic

endothelial cells respectively. Krüppel-like factors 2 and 4 are pivotal laminar �ow inducible transcription factors

that modulate several genes critical for maintaining an antithrombotic endothelial surface [45, 46]. KLF2 is also a

key determinant of the anti-in�ammatory and anti-atherogenic vascular environment [47-49], and a potent inducer

of endothelial nitric oxide synthase (eNOS) [50]. KLF2 blocks expression of the procoagulant Tissue Factor [51]

and also inhibits thrombin-induced activation of endothelial cells by decreasing expression of the thrombin-

activated protease activated receptor type 1 (PAR-1), Conversely, TNF- , IL-1 , and oxidative stress, repress KLF2α β

expression in the endothelial cells (EC)[52]. KLF4 is also an independent regulator of EC function, and is protective

against atherosclerosis [53].According to reports, Krüppel-like factors (KLFs) are important mediators of

monocyte differentiation and activation as well. KLF2 is a negative regulator of proin�ammatory genes both in the

ECs and monocytes and expression of KLF2 in monocytes is reduced following exposure to TNF- or LPS and inα

monocytes from patients with coronary artery disease [54]. Krüppel-like factor 4 is also involved in myeloid cell

differentiation [55] and is a critical regulator of macrophage polarization. In vitro exposure of mouse macrophages

to LPS, proin�ammatory cytokines, or oxLDL, results in decreased KLF4 levels [53, 56]. Mouse macrophages

de�cient in KLF4 have enhanced foam cell formation in response to oxLDL [53]. Our preliminary observations

shows brief exposure of inorganic Arsenic in nanomolar concentration induce signi�cant down-regulation of

several other endothelial regulator genes resulting in increased expression of VCAM-1, and E-selectin

(unpublished observations, not shown) in HUVEC.

To determine whether the reduced eNOS expression in Arsenic exposed endothelial cells and other peripheral blood

mononuclear cells (not shown), could be linked to a reduced expression of endothelial KLF4 (and KLF2: not

shown), we examined nuclear KLF4 levels by immuno�uorescence microscopy, normalizing the digitized nuclear

KLF4 �uorescence to nuclear DNA (as measured by DAPI �uorescence). We observed signi�cantly reduced KLF4

expression in Arsenic exposed primary human aortic endothelial cells when compared to the KLF4 expression in

untreated control cells (Figure 2a. ***p < 0.001).

16

Interestingly, when the nuclear levels of histone H3,

as an internal control, was measured using identical

parameters no such dose or time dependent effect of

Arsenic exposure on the endothelial cells was

observed (Figure 2b.). We confer that the vascular

micro-environment during Arsenic exposure is

pathologically modi�ed characterized by a

diminished expression of the anti-in�ammatory and

anti-atherogenic transcriptional regulator KLF2 and

KLF4 in addition to signi�cant reduction in eNOS

production and increased expression of endothelial

adhesion molecules, like VCAM-1 and E-selectin.

Here, we provide a comprehensive set of data

showing the effects of low dose Arsenic exposure

(10μM) at different time point on cultured primary

human aor tic endothelium from descending

thoracic aorta (Figure 2).

Arsenic-induced molecular and cellular events

related to atherogenesis : In vitro studies on

cultured human endothelial cell indicate that arsenic

can initiate oxidative damage, activation of

transcription factors, and gene expression relevant

to endothelial dysfunction and CVD (Figure 3).

Chronic exposure to Arsenic is also a potential risk

factor for type 2 diabetes.

Exposure to inorganic Arsenic induces pre-diabetic

effects by altering or deregulating lipid metabolism,

gluconeogenesis and insulin secretion in healthy

individuals. It worsens glucose metabolism in

established diabetics. Alteration of insulin resistance

might be not the sole reason of diabetic effects

caused by inorganic Arsenic [57].

Arsenic exposure, cardiovascular diseases and

global HIV incidences : Card iovascu lar

abnormalities are common in HIV-infected

individuals but often go unrecognized or untreated,

which results in increased cardiovascular-related morbidity and mortality and reduced quality of life. Clinicians

may mistakenly attribute signs of cardiovascular abnormalities to pulmonary or infectious causes, an error that

can delay appropriate treatment.Despite a dramatic improvement in survival in the antiretroviral therapy (ART) era,

there remains an increased risk of thromboembolic and cardiovascular co-morbidities in those treated [58-60].

The core mechanism(s) that contribute to this increased risk of CVD in HIV disease have not been fully elucidated,

but may be partially related to chronic immune activation [61, 62]. Systemic indices of in�ammation and

Figure 3:Schematic view of plausible arsenic induced oxidativedamage and endothelial dysfunction. Arsenic interacts with G ProteinCoupled Receptors (GPCR) to initiate signal ampli�cation schemesregulating NOX-dependent redox signaling. Downstream signaling fordysfunction was (partially adapted from: States JC, et al., Toxicol Sci.2009.[1]).

Figure 2 : Arsenic exposure reduce Krüppel-like Factor 4 expression inhuman aortic endothelial cells in a time and dose dependent manner.Human primary aortic endothelial cells were grown in sterile chamberslides, and exposed to 10•M of Arsenic at the indicated time points. Thecells were subsequently immunostained and digital images were recordedby epi-�uorescence microscopy (EVOS•FL, Life Technologies) using a100X objective (20X images for large scale data acquisition and analyses)for the detection and analysis of nuclear KLF4 (Panel a) and Histone H3(Panel b.) as internal control. Quantitative �uorescence intensity ratio(KLF4:DAPI) data of 100 cells at each time point from 3 independentexperiments are presented to the right of each panel. The data werecompared using a two tailed Mann Whitney test. ***p

17

coagulation have been linked to cardiovascular risk in HIV infection [63] and PET CT scans have demonstrated

metabolic evidence of aortic in�ammation in treated HIV infection [64].

Endothelium is a highly reactive sur face,

responding to a myriad of micro-environmental

stress-inducing factors resulting from infection

tissue injury, and in�ammation [65]. ECs serve as

selective micro environmental barriers for the

exchange of �uid and macromolecules from the

vascular compartment to the tissue.In addition, the

bidirectional relationship that follows between the

coagulation pathways and vascular in�ammation

modulating endothelial homeostasis is widely

recognized [66, 67].

We showed in one of our recent reports that eNOS

and KLF2 are signi�cantly downregulated inducing

endothelial dysfunction alongwith a dramatic

increase in the subendothelial migration of CD8 T

cells and in�ammatory monocytes in the aortic

endothelium of Rhesus macaque who are acutely

infected with simian immunode�ciency virus (SIV)-

the HIV homologue infecting non-human primates

[68]How such downregulation affects the formation

and sustenance of the immunological synapse bond

is of extreme importance in de�ning the immune

lifeline of an affected individual. An immediate future

extension of our present line of research in this �eld

is to analyze such effects based on mathematical

and probabilistic models that will also highlight the

quantitative importance of all affecting factors.

Association of chronic low dose exposure to

inorganic Arsenic and Arsenicals, endothelial

dysfunction, CVD, and endemic HIV infections

opens up future avenues of research into a relatively

poorly understood topic with major implications for

human health. While the data acquisition on the

world prevalence of HIV and cardiovascular

diseases is thorough, the data on chronic exposure

to Arsenic is still incomplete for most part of the world. But, we know a large sum of the world population, mostly

unknowingly, is exposed to Arsenic irrespective of the socioeconomic status or geographical location of their

country. This is a fact which generally indicate that the HIV infected population who are on continued anti-retroviral

therapy (ART) with controlled viremia, are also exposed to low, moderate or high levels of environmental Arsenic

that might be an additional trigger in initiating their accelerated endothelial dysfunction and atherosclerotic lesions.

Determination of the true risk of CVD in HIV and measuring the synergistic effects of Arsenic exposure that further

complicates the pathogenesis of CVD will become increasingly important in the long-term management of HIV-

infected patients receiving antiretroviral therapy.

Figure 4 : Global Arsenic exposure (A), Cardiovascular/other diseases(B), HIV/AIDS Prevalence in 2013 (C), and the projected overlaps (lowerpanel).

18

Arsenic Modelling and Transport

As described above, Arsenic is now widely accepted to have not only a dual role as a causative and a curative agent

primarily for non-infectious disease proliferation [69] but also as a secondary instigator of population infection

[70]. While conventional biology is typically a �rst resort, probabilistic prediction of affectation and disease

proliferation often stretch beyond the realms of experimental data, especially in predicting what levels of �uctuation

of the affecting parameters could instigate a certain threshold of arsenic in�icted persecution. As an example,

consider this - if the water arsenic toxicity factor increases by 5% over the next 3 years while the glutathione

depletion factor decreases by 7% leading to an overall increase in protein inactivation by 8% (considering only a

few token factors) during the same time span, what will be the increase in arsenic af�icted atherosclerosis and CVD

during this time? To address such questions in a non-invasive method, computer based data analysis and

statistical modeling is the new genre of science in this interdisciplinary arena.

Techniques from statistical mechanics, thermodynamics and nonlinear mechanics, together with native computer

simulation, has started unearthing lots of features that have so far remained outside the conventional research

purview. In a recent ensemble modeling approach, a mathematical model has been studied that predicts

intracellular arsenic �ow rates under varying mutant conditions, focusing on the toxicity mechanism of arsenic.

This data based analysis clearly highlight an array of important conclusions like a) protein based arsenic pro�les

have short-term implications while glutathione based arsenic compounds have long term rami�cations; b) arsenic

dynamics is mostly a transient mechanism that probabilistically escapes the vacuole via natural export

mechanism. While this work was studied on a yeast substrate, more indicative suggestions towards the protein-

versus-glutathione debate have been advised. While this line of modeling directly assesses the microbiological

origin of its affectation, secondary infections in the form of (Buruli) ulcerous swellings, believed to be arsenic

in�icted, have recently been studied using data from chosen African countries [70]. The results from this study

indicate without con�rming as much the importance of environmental implication of arsenic disease propagation.

Similar results were obtained a while ago by a South African modeling group who studied the optimal control of

arsenic transmission dynamics targeting infection [71]. While the data analysis resultsmycobacterium ulceran

[70] indicated the roots of the proliferation mode, this more recent kinetic equation based nonlinear modeling [71]

traced the mitigation mechanism as an optimal combination of environmental and health education together with

water puri�cation protocols.

Modeling attempts at arsenic retention processes in wetland areas is another line of complementary research that

focuses on the role of trace elements in arsenic effect proliferation. Analyzing a model representing arsenic

propagation dynamics in constructed wetlands targeting a quantitative prediction of the mutual relationship

between iron and arsenic retention ef�ciency increase, the model results indicate a maximum arsenic retention

ef�ciency of 85-95% [72]. What all such effects ultimately culminate at is in the population response to exposure of

chemical carcinogens at low to high exposure levels often leading to a mutation of a single-cell DNA, hastening a

terminal illness. A consummate detailing of such “carcinogenesis modeling” can be availed from a self-suf�cient

overview by Vineis, et al. [73]. Of the �ve models discussed here, only Model 4 indirectly alludes to arsenic

affectation of carcinoma, another indication of insuf�cient research in this �eld.

The above highlighted areas are only the tips of the proverbial iceberg. More concerted efforts combining

complementary inter- and cross- disciplinary efforts are needed to tackle this problem, an approach that has taken

pace off late.

Concluding Remarks

Studies summarized in this mini-review suggest that chronic Arsenic exposure induces pathophysiological events

relevant to the atherogenic potential including impaired vascular nitric oxide homeostasis, low Krüppel-like factor

2, 4 expression, and enhanced expression of endothelial adhesion molecule like VCAM-1. These detrimental

changes in the endothelial microenvironment, collectively expressed as endothelial dysfunction are the key

molecular events in the cardiovascular system which are surprisingly common to Arsenic exposure and in the HIV

infected patients on long-term ART. Based on the accumulating epidemiological evidences and experimental data,

we conclude, arsenic exposure could be considered as an important modifying factor in the understating and

intervention strategies of atherosclerosis and related cardiovascular diseases in virologically controlled HIV

patients on ART, at least under certain circumstances (including genetic background, diet, co-exposure and

geographical location). Also, we would argue that the considerable overlap with the worldwide exposure of

Arsenic, incidences of HIV infection positively reinforce the initiation, persistence, and progress of HIV infection

itself and the pathogenesis of related cardiovascular complications. While mathematical modeling of arsenic

poisoning, infection and its impact on carcinogenesis is a vital and newly adopted line of research, the sheer

paucity of material in gelling together known biological observations against data and mathematical models clearly

indicates the need for more detailed and target driven studies. Over the next couple of years, such cross-platform

research is expected to hold center stage in throwing light in this �eld.

____________________________________________________________________________________

Conflict of Interest Statement :

All other authors declare that they have no competing interests.

Authors' contribution :

AP and SP designed, performed, analyzed experiments, and SP, AKC, and AP wrote the manuscript with collaborations from GP, and AKC. All

authors contributed to general design and discussion of the project and reviewed and approved the manuscript.

Acknowledgements :

SP acknowledge the Fasenmyer Foundation; the CWRU Center for AIDS Research; the Cleveland Immunology Consortium (CLIC) for supporting

this study without having any role in study design, data collection or analysis, the preparation of the manuscript or the decision to publish it.

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Struma Cordis - A Case ReportBhabani Prasad Chattopadhyay , Sanhita Chatterjee ,

1 2

Sudakshina Chanda , Kunal Sarkar , Sanjeev Garg3 4 5

Abstract : A case of Pyrexia of unknown origin on admission was provisionally thought to be suffering from

infective endocarditis. A space occupying lesion in the LVOT causing signi�cant gradient across it was observed

that led ultimately to surgical exploration. The excised specimen on gross examination revealed multiple grayish

white tissue bits measuring 2 cm x1.5cm. Microscopic examination revealed nodular areas composed of thyroid

follicles of varying sizes �lled with colloid . There was moderate lymphocytic in�ltration into the stroma. The �bro-

muscular wall of left ventricle surrounding the stromal tissue was unremarkable. Mass in the LVOT is rare and

presence of thyroid tissue in it in is further rarer. The authors on net searching could not �nd any such case

reporting from Indian subcontinent. In this background we are presenting this case report of clinical signi�cance.

Key Words : Struma cordis, LVOT(Left Ventricular Out�ow Tract).

Introduction : Ectopic thyroid in the heart is rare. The infrequent case reports in this context available

predominantly narrates location of ectopic thyroid in the right ventricle and inter ventricular septum. Presence of

ectopic thyroid tissue in the left ventricle is more rare and till date there are few such reports. Till 2011 out of 33

case reports of intracardiac ectopic thyroid only three were located in the LVOT and rest of the 30 cases were

localized either in the RV or in the IVS .The authors on net searching could not �nd any such case reporting from1

Indian subcontinent. In this background we are presenting this case report.

Clinical Summary : A 61 year old gentleman presented with pyrexia of unknown origin along with complaint of

discomfort and pain in chest on exertion of 4 weeks duration .It was insideous in onset but progressive in nature.

He was treated outside with antibiotics without proper investigations before reaching our Institute. Due to non-

responsiveness to antibiotics outside he was re-evaluated and thoroughly investigated. In our Institute he was

provisionally diagnosed to be suffering from Infective Endocarditis. Cardiac Echo-doppler study revealed round

Space Occupying Lesion in the LVOT and aortic cusp and that caused haemodynamically signi�cant obstruction in

the LVOT. Vegetation/Tumour were considered in the differential diagnosis. Surgical exploration and excision of the

mass in the LVOT was done and sent for histopathological examination.

Corresponding address : Dr. B. P. Chattopadhyay. Department of Cardiology, Medical College and Hospital, 88,

College Street, Kolkata-73. E-mail add: bhabani07@yahoo.co.in

22

1. Associate Professor, Medical College and Hospital, Kolkata, 2. Consultant Pathologist, Medica Superspeciality Hospital, Kolkata, 3. ConsultantPathologist, Medica Superspeciality Hospital, Kolkata, 4. Vice Chairman, Cardiac Surgeon, Medica Superspeciality Hospital, Kolkata, 5. ConsultantCardiologist, Medica Superspeciality Hospital, Kolkata

23

Investigation Summary :

Haemoglobin-11.3g/dl Total Leucocyte Count 14,500mm N86%, L10%, M2%, E2% ESR78 mm/1st hour C-_3

Reactive Protein was elevated (18). Widal test (tube agglutination) was negative for enteric fever. Repeated Blood

Cultures were negative. ECG12 leads revealed Left Ventricular Hypertrophy and strain pattern. Digital X-Ray Chest

PA View was within normal limits.

Echodoppler study (Fig1) revealed mass in the non-coronary cusp causing obstruction at the level of Left

Ventricular Out�ow Tract and the aortic valve. Flow velocity was observed to be 4.19 m/sec and the peak systolic

gradient across the LVOT was 70.4 mm of Hg (Fig2).Vegetation of infective endocarditis and intra cardiac tumour

were kept under consideration of the differential diagnosis.

Fig 1 : 2D Echo-Image of LVOT Mass Fig 2 : Gradient across the LVOT

128 slice MDCT Coronary Angiography (Fig 3) revealed normal epicardial coronaries but the Cardiac CT revealed

SOL in the LVOT (23 X 22 mm). Probablity of vegetation/tumor was kept under consideration. In view of the

negative blood culture and signi�cant haemodynamic obstruction to LV out�ow surgical excision was done and

specimen was sent for histopathological examination.

Fig 3 : Cardiac CT ..Round Filling defect in the LVOT Fig 4 : Thyroid Tissue within the ventricular wall

24

Histo-Pathological Examination of the excised specimen : Gross examination revealed : Multiple grayish white bits

of tissue measuring 2 cm x1.5cm. Microscopic examination revealed nodular areas composed of thyroid follicles

of varying sizes �lled with colloid. There was moderate lymphocytic in�ltration into the stroma. The �bro-muscular

wall surrounding the stromal tissue was unremarkable .

After availability of histopathological diagnosis Serum T3,T4,TSH level assay was done and was within normal

limits.

Fig 5 : ventricular wall and adjoining thyroid tissue

Discussion :

Development of the Thyroid Gland:Embryologically the development of the thyroid gland and the tongue are closely

related .Before the ventral ends of the �rst and second branchial arches join with counterparts of opposite side,

three endodermal elevations appear -a pair of lingual swellings and unpaired median swelling called Tuberculum

Impar between the �rst and second arches.The endodermal cells dorsal to the tuberculum impar proliferate to form

a surface elevation called median thyroid rudiment. Thereafter the cells evaginate caudally through the substance

of the tongue to form the thyroglossal duct which goes further down in the median plane lying successively

anterior to the laryngeal bones, hyoid bone and tracheal cartilage where it divides to become bilobed. The middle

isthmus and two rudimentary lateral lobes develop. The fourth pharyngeal pouch complex fuse with the two

rudimentary lateral lobes which arrests fur ther caudal migration and the thyroglossal duct star ts

regressing.Before complete regression the duct divides and subdivides into a series of double cellular plates on

either side of the median plane.When colloid materials accumulate between the two layer of cells the latter are

converted to primary thyroid follicles .Subsequent budding result in formation of the secondary follicles. The

parafollicular cells or C cells and parathyroid glands develop from the Ultimobranchial body of the caudal

pharyngeal complex(mostly from 4th branchial arch).

Developmental Anomalies:There may be developmental anomalies of the thyroid gland which include

thyroglossal cyst/�stula, lingual thyroid, accessory thyroid, agenesis of thyroid and Ectopic thyroid. Ectopic

thyroid is the presence of thyroid tissue away from its normal anatomical position anywhere in the body.When it is

located in the heart it is called Struma Cordis.

Review of Literature on struma cordis :

Struma cordis i.e. ectopic thyroid tissue in the heart is extremely rare and was �rst reported in 1941 . The review1

article1 on ectopic thyroid by J. Besik et al is an exhaustive one. In the year 1986 one case of heterotopic thyroid

gland causing haemodynamically signi�cant LVOT obstruction was reported .In the same year another case2

25

report of ectopic thyroid in the right ventricle was reported. In the year 2000 another case report entitled “Ectopic3

Thyroid tissue in the left ventricular out�ow tract”. was published .4

Conclusion : Mass in the LVOT is rare and most often is due to vegetation in relation to infective endocarditis.

Tumour in the LVOT is rare and presence of thyroid tissue in it is very very infrequent. However echocardiologists

and clinicians should keep this possibility in mind to avoid missing the diagnosis.

References :

1. Josef Besik, Ondrej Szarszoi et al : Intracardiac Ectopic Thyroid (Struma Cordis) : Journal of Cardiac Surgery 2014, Vol29 Page 155-158

2. Kantelip B, Lusson J R, De Riberolles et al : Intracardiac Ectopic Thyroid. Hum Pathol.1986:17:1293-1296.

3. Pollice L, Caruso G : Struma Cordis-Ectopic Thyroid in the right ventricle Archive Pathol Lab Med May 1986, Vol 110(5) Page 452-53

4. Baykut D, Fiegen U, Krian A : Ectopic Thyroid tissue in the left ventricular out�ow tract. Ann Thorac Surg 2000 Feb Vol 69 Issue 2 Pages 620-

621

26

Abstract : Shape memory alloys are special type of alloys that can regain their original shape when heated.

Development of renual cardiological devices like IVC �lter, DSD closure device, Nitinal heart valve with this alloy

has brought a radical change in the �eld of cardiology. Presently a project is underway to develop a dedicated

bifurcation wire with this alloy.

Key-words : Shape memory alloys, dedicated bifurcation wire.

Introduction : Interventional Cardiology, Paediatric Interventional Cardiology, Interventional Radiology,

Interventional Neuro-Radiology are relatively newer branches of medical science and have some common

denominators. All these subspecialities concentrate in identi�cation of vascular narrowing (stenosis) and

restoration of normal calibre by balloon dilatation and /or deployment of Stents/Stent grafts (for aneurysms).

Techniques of identi�cation of structural holes in vessels or organs and techniques of minimally invasive repair of

the holes by occluders (e.g. ASD / VSD/ PDA closing devices), covered stents (for perforations)etc. are replacing

extensive surgeries. Closure of undesired vessel and aneurysm by coils etc are also very common. All these

techniques and technologies have brought memorable changes in shape of interventional cardiology. Considering

the economic potential of the devices, implants, hardwares and accessories, the big Multi National Corporate

Houses have invested a lot for research in the �eld of Interventional Cardiology and allied branches. This has led to

ever expanding innovations in Interventional Cardiology and allied subjects in last few decades. It has changed the

dimensions and equations of Cardiovascular Medicine and Surgery as well. The paradigm shift to minimally

invasive approach in treating structural defects whenever possible is a consequence of it. Amongst many

innovations, application of Shape Memory Alloy (SMA) in Interventional Techniques has made these disciplines

�ourish to a signi�cant extent. Till date nearly 3000 patents of SMA based research works are pending all over the

world.

Background Concepts : Minoo Masani stated that Change is the only unchanging thing in the world. On application

of force on some object or body there is change in length, volume or shape .On removal of force it may regain

original length, volume and shape. The property by virtue of which a body regains its original length ,volume and

shape after removal of the deforming force is called elasticity. Within elastic limit ,the extension of an elastic body is

directly proportional to the force responsible for the extension. Bodies possessing the property of elasticity are

called elastic bodies. Plasticity is the property of remaining deformed even after removal of the deformimng force.

Rigid bodies retain their shape under in�uence of limited deforming force beyond which it is broken.

Pseudoelasticity or superelasticity is a property by virtue of which a deformed body can restore or regain its

original shape following exposure to stimulus like heat or cold. Shape Memory Alloy possess the property of

pseudoelasticity.

Superelasticity, or pseudoelasticity, is a unique property of shape memory alloys (SMAs), wherein up to 13%

deformation strain can be sustained and the material can recover its original shape after removing the stress. The

Memorable Change in Shape of interventional Cardiologyby Shape Memory Alloys (SMA)

B. P. Chattopadhyay , Sunip Bannerjee , S. Das , A. S. Tripathi1 2 3 4

1. Assocociate Professor, Medical College and Hospital, Kolkata (Corresponding author). 2. Head of the Dept. of Cardiology, Medica SuperspecialtyHospital, Mukundapur, Kolkata. 3. Associate Professor, School of Medical Science and Technology, IIT, Kharagpur. 4. Ph.D. Student, School ofMedical Science and Technology, IIT, Kharagpur

27

shape memory effect occurs in SMA and is de�ned as when a material can remember its original shape upon

heating or cooling.

What is Shape Memory Alloy? An Alloy is a mixture or combination of two or more metallic elements. Mixture of

Nickel and Titanium gives rise to an alloy named Nitinol. This is a shape memory alloy(SMA). There are many other

SMAs . SMA constitute a group of alloys which has the ability to recover a previously de�ned shape or length when

subjected to an appropriate thermo-mechanical load i.e. they can recover apparent permanent strainsi.e. original

shape when they are heated above a certain temperature(transformation temperature). The SMAs have two stable

phases - the high-temperature phase, called austenite and the low-temperature phase, called martensite. This

phenomenon of recovery of original shape results from a change of one crystalline phase to another in response

to heat. This is known as thermo elastic transformation from martensitic (cooled) to austentite (heated) phase.

When change in reverse direction is also possible that is called two way memory. At temperatures below the

transformation temperature shape memory alloys are martensitic, In this condition. their microstructure is

characterized by self-accommodating twins , The martenensite is soft and can be deformed quite easily by de-“ ”

twinning. Heating above the transformation temperature recovers the original shape. Due to this property and

added biocompatibility there are many biomedical applications of SMA in dentistry(orthodontics),orthopaedics,

neurosurgery and intervention in vascular �elds including cardiology.

Shape Memory Alloy has many properties . On subjecting to force or load the length of metals can be increased or1-3

decreased and the shape can be deformed. The external force applied on the metal is equivalent to the Stress on the

metal. The difference between the original length and �nal length (L1-L2) divided by the original length is called

strain (L1-L2)/L1. Restoration of the original length or shape usually does not occur spontaneously without

application of force or energy from outside. The alteration in length and shape is usually unidirectional and

apparently permanent. Deformation done at low temperature(e.g.10 degree Celsius) can be corrected and original

length or shape may be restored at higher temperature(e.g.37 degree Celsius.

Application of SMA in interventional cardiology : The �rst cardiovascular device developed with shape memory

was the inferior vena cava (IVC) �lter(Fig1). The purpose of this device is to �lter clots that travel upstream to the

lungs. The �lter traps these clots. The insertion of the �lter inside the inferior vena cava is done by exploiting the

shape memory effect. In its original shape in the martensitic state the �lter is deformed (in compressed form and

packaged within the container catheter). When the catheter releases out the �lter within IVC, it faces warm blood.

As a result, the �lter returns to its former shape (austentite phase). This is a landmark change in treatment modality

of recurrent pulmonary thrombo-embolism in patients of deep vein thrombosis.

Like the IVC �lter peripheral and coronary stents made up of SMA (Fig4) have been successfully used. Stents

which are commonly used for coronary arteries are Balloon Expandable whereas stents used for peripheral

arteries and aneurysms (stent graft) are usually self expandable. Balloon Expandable stents are manufactured in

the crimped state and expanded to the vessel diameter by in�ating the stent with a balloon (thus plastically

deforming the stent). Self-expandable stents are manufactured targeting the vessel diameter and are crimped and

constrained to the smaller diameter until the release at the target area, where the constraint is removed and the

stent is deployed. Balloon Expandable stents resist the balloon expansion process, whereas self expandable stents

assist vessel expansion. Balloon Expandable stents are usually made up of stainless steel, platinum, chromium

etc. and self expandable stents are usually made up of nitinol. Self expanding stent is intended to be used for the

treatment of stenotic or occlusive lesions in iliac or femoro-popliteal arteries to establish patency and to maintain

patency. Covered stents provide a circumferentially occlusive boundary between the stent and the vessel and they

are used for stenting vessels that are at risk for rupturing (or have already ruptured/are aneurismal. Trials are

28

Fig 1 : IVC FILTER Fig 2 : ASD CLOSURE DEVICE

Fig 3 : NITINOL HEART VALVE

Fig 4 : NITINOL STENT

undergoing for treating Bifurcation, trifurcation, tapered lesions with specially designed stents made up of SMA.

The stent is pre-compressed in its martensitic state and as the stent is exposed to the warm blood, it tends to

recover its original shape, expanding itself. APPOSITION I to APPOSITION V trials are de�nitive trials on coronary4,5

stents made up of SMA. These studies sought to

investigate whether self-expanding stents are more

effective than balloon-expandable stents for reducing

stent malapposition at 3 days after implantation in

patients with ST-segment elevation myocardial

infarction undergoing primary percutaneous coronary

intervention. This randomized study in acute MI using

OCT as primary endpoint showe