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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