Acute penetrating atherosclerotic ulcer presenting as paraplegia and renal failure

Case Report

Acute Penetrating Atherosclerotic Ulcer Presenting as Paraplegia and Renal Failure K. Sudhakar. I. Sathyamurthy K. Jayanthi K. P. Misra Department of Cardiology Apollo Hospitals 21, Greams Lane, Chennai

INTRODUCTION Acute aortic syndrome can present as aortic dissection, intramural hematoma or acute penetrating atherosclerotic ulcer (APAU). The clinical manifestations can be varied based on the etiology. APAU is defined as an acute ulceration of an atherosclerotic lesion that penetrates from the internal elastic lamina into the intima media.1 APAU was first described as a distinct clinical entity by Stanson et al. in 1986.2 The clinical behavior is controversial and advanced techniques of imaging have aided in the early detection of APAU. Here we are reporting a case of acute aortic syndrome diagnosed to have APAU, manifesting as paraplegia and acute renal failure.

CASE REPORT A 45 year old male who developed acute onset of breathlessness during his routine evening walk was diagnosed and treated as accelerated hypertension with heart failure and was referred to our hospitals as his lower limb pulses were found to be absent. On presentation he was found to have weakness of both lower limbs associated with loss of sensation and anuria of 24 hours duration. There was no history of chest pain, back ache or upper limb and facial involvement. He denied any history of trauma. He was a known hypertensive for 4 years. He was obese weighing 95 kgs and was a chronic heavy smoker. Physical examination revealed tachypnea, tachycardia, absent lower limb pulses, high blood pressure and elevated JVP. Systemic examination revealed normal heart sounds, bilateral basal crackles, distended abdomen and flaccid paraplegia associated with sensory loss. Blood investigations revealed elevated serum urea, creatinine, potassium, CPKMB and SGOT. Troponin_T test was positive. ECG revealed left ventricular hypertrophy and hyperkalemic changes with tall T waves. Echocardiogram revealed LVH, no regional wall motion abnormality, normal

LV function with ejection fraction of 62% and no evidence of coarctation of the aorta. The chest X-ray showed cardiomegaly and arterial doppler study revealed grossly reduced flow in both lower limbs and renal flow could not be assessed. Transesophageal echocardiogram (TEE) was planned but could not be done as patient was tachypneic. MRI spine revealed ischemic myelopathy. CT aortogram revealed a large long plaque in the descending thoracic aorta, 2 cm distal to the left subclavian artery with extensive calcification (Figure 1) filling almost the entire lumen with super added thrombus (Figure 2). Coarctation of aorta, aortic aneurysm and dissection of the aorta were ruled out by the CT aortogram. Catheter based intervention, was thought to be risky and so it was deferred. Thrombolysis was done with streptokinase followed by the use of low molecular weight heparin, diuretics, antiplatelets, antihypertensives, statins and antacids. Physiotherapy was initiated. Dialysis was started for the renal failure. He developed high grade fever which continued to persist despite adequate antibiotic coverage. His dyspnea subsided but his paraplegia and renal parameters did not improve. He ultimately died of uncontrolled sepsis. Summarizing the case report, this was a 45 year old obese male, hypertensive and chronic smoker who developed acute dyspnea, paraplegia and acute renal failure, whose CT aortogram revealed a penetrating atherosclerotic ulcer. He received adequate treatment with thrombolysis and anticoagulation but ultimately died of sepsis.

DISCUSSION In the case report we demonstrated the presence of a large immobile thrombus with ulceration as the source of acute aortic syndrome. Aortoarterial thrombosis and ulceration is often associated with atherosclerosis or aneurysm, especially in combination with prothrombotic states. Advancing age,

Correspondence: Dr. I. Sathyamurthy M.D.D.M, FACC, FCCP H.O.D, Department of Cardiology, Apollo Hospitals, 21, Greams Lane, Chennai - 600006 E-mail: [email protected]

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Figure 1. 64 slice CT aortogram revealing densely calcific aorta beyond origin of subclavian artery. Rest of the descending thoracic aorta and subclavian artery are normal.

diabetes mellitus, hypertension and vasculitis are other etiological factors which also contribute. The other causes are hyperhomocystinemia, mucoid vasculopathy especially in south Indians,3 fibro muscular dysplasia causing occlusive arteriopathy,4 antiphospholipid antibody syndrome and intramural hematoma following blunt or penetrating trauma. White clot syndrome is another entity which occurs in patients on prolonged heparin therapy, where a combination of platelet factor, IgG antibodies and fibrin causes thrombocytopenia and paradoxical thrombus formation.5 Women on oral HRT are also prone to develop aortic thrombus and ulceration. The area around the left subclavian artery is a vulnerable location. Aorto-occlusive disorders are also precipitated by low flow states secondary to heart failure.6 The enigma in this patient is that despite the acute presentation there was extensive calcification suggesting an underlying chronic process without symptoms. Apart from routine blood investigations, ECG and echo, TEE is the most appropriate initial imaging modality. CT aortogram is the confirmative modality though. MRI is also reliable. Intravascular ultrasound imaging is also confirmative but is not practiced extensively in India. Management depends on etiology, clinical manifestations and nature of thrombus and ulcer. Anticoagulation with Heparin followed with LMWH is mandatory and thrombolysis can be done with any effective agent. Endovascular stent grafting with AAA graft is preferred in large hyper mobile thrombi7 and Fogarty’s balloon tip catheter removal is preferred in small thrombi. Thromboaspiration can also

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Figure 2. 64 slice sagital section at the level of calcific plaque revealed nondilated descending thoracic aorta, densely calcific and lumen filled with superadded thrombus.

be done but is considered as an adventurous procedure due to risk of dislodgement. Following any therapy, anticoagulation should be continued and the patient should be reassessed after 2 weeks with TEE or MRI and anticoagulation should be continued until the thrombus completely resolves. In a retrospective study reported from the division of Radiology and Cardiovascular surgery, Mayo Clinic, 105 patients with PAU of the descending thoracic aorta were identified in their database and were reviewed by a vascular radiologist to confirm PAU and perform serial measurements. This study concluded that PAU can be managed nonoperatively in an acute setting.8

CONCLUSION Acute aortic syndrome is a heterogeneous group of disorders which may have varied clinical manifestations and needs to be detected early. TEE is the most appropriate initial imaging modality and CT aortogram is confirmative. Treatment can be done with surgery, balloon tip catheter removal, thrombolysis, endovascular stent grafting or thrombo aspiration based on etiology, presentation, size and location of thrombi and patient’s condition. Evidence based recommendations and guidelines are lacking due to lack of any large series.

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Acute Penetrating Atherosclerotic Ulcer

REFERENCES 1.

5.

Vilacosta I, San Roman JA. Acute aortic syndrome. Heart 2001;85:365–368. 2. Stanson AW, Kazmier FJ, Hollier LH, et al. PAU of the thoracic aorta. Ann Vascular Surgery 1986; 1:15–23. 3. Sandhyamani S. Mucoid vasculopathy. Vascular lesions in an autopsy study. Mod Pathol 1993; 16:333–341. 4. Siegel RJ, Dunton SF. Systemic occlusive arteriopathy with sudden death in a 10 yr old boy. Hum Pathol 1991; 22:197–200.

Cho KR, Stanson AW, Potter DD, et al. Penetrating atherosclerotic ulcer of the descending thoracic aorta and arch. 2004;127(5): 1393–99. 6. Braunwald, Zipes, Libby textbook of cardiovascular medicine. 2001; 40:1450. 7. Eggerbrecht, Holger.A, Baumgart, et al. Multiple PAU of abdominal aorta and treatment by endovascular stent grafting. Heart 2001;85:526. 8. A retrospective case study on PAU by Mayo clinic. J Thorac cardiovascular surgery 2004; 127:1393–1401.

ASIAN

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Case Report

Non-Expansion of Carotid Stent due to Detached Stent Sheath—An Unusual Complication of Carotid Angioplasty Treated by Surgery Sarat Chandra K, Ritesh Kumar, Manas Panigrahi Department of Cardiology Nizam’s Institute of Medical Sciences, Hyderabad

INTRODUCTION Carotid artery stenting has become a fairly established mode of treatment for patients with symptomatic and asymptomatic carotid artery disease.1,2,3,4 After the advent of distal protection devices the incidence of complications has come down.5 We report here a case of carotid angioplasty in which the stent failed to expand and we had to resort to surgery to achieve complete expansion of the stent.

CASE REPORT The patient is a 50-year-old man with severe triple vessel coronary artery disease and critical stenosis of left internal carotid artery (Figure 1). He has multiple risk factors in the form of diabetes, hypertension and smoking. Patient did have symptoms of cerebral ischemia in the form of a transient right hemiplegia two years ago. He was scheduled to undergo coronary bypass surgery and carotid angioplasty with stenting was taken up prior to this. Initially a 7 mm protection device (Angioguard, Cordis) was passed across the lesion. After predilatation with a 3.0 ⫻ 20 mm coronary angioplasty balloon (Figure 2), a Conformex 7.0 ⫻ 40 mm stent (Bard-self expanding Nitinol stent) was positioned across the lesion. However during the retraction of the sheath (after nearly 60% was retracted) over the stent there was a sudden resistance and “release” and it was noticed that most of the stent had expanded except over a short length about the junction of distal two thirds to proximal one third (Figure 3). This non-expanded portion of the stent was in the common carotid artery. At the site of the original lesion the stent had fully expanded. A radio opaque marker was found at the point of non-expansion. The shaft of the catheter along with the remaining portion of the sheath was removed. An attempt was made to expand the stent by using a 7 mm balloon but to no avail. Patient was asymptomatic and stable throughout. It was felt that there was a manufacturing

defect and that leaving the stent in that position may lead to stent thrombosis with possible disastrous consequences. Neuro-surgery consultation was taken and a decision was made to do an emergency arteriotomy. Surgery was performed after the ACT had come down to 150 seconds. A lateral neck incision was made and after clamping the common carotid, internal carotid and external carotid arteries, arteriotomy was done in a longitudinal fashion. A ring like structure was found consistricting the stent and once it was cut the stent immediately expanded. A small portion of the ring was left behind as the stent had fully expanded. The removed portion is shown in Figure 4. Fluoroscopy done one day later shows fully expanded stent (AP and lateral views, Figures 5 & 6). Patient recovered from surgery but needed ventilator support transiently for a few hours on the second post operative day due to pulmonary edema. He progressively improved and was discharged after one week. There was no neurologic deficit at any stage. He later underwent bypass surgery without any difficulty (after 4 weeks). He is doing well at 4 month follow up.

DISCUSSION Carotid artery stenting is a fairly established procedure with a large number of patients having already been randomized to stenting versus endarterectomy and it has been shown to be associated with comparable results. The most important trial in this context is the Sapphire trial in which the primary end point (death/stroke/MI at 30 days plus ipsilateral stroke or death from neurologic causes within 30 days to 1 year) was 12% in the stent arm versus 20.1% in the endarterectomy arm.6 In our case non-expansion of the carotid stent due to a constricting ring of material which got disconnected from the outer sheath and remained on the stent was responsible for the complication. We have not been able to find any such instances reported in English literature. The problem was successfully managed with the help of the surgeon.

Correspondence: Dr. K. Sarat Chandra, Department of Cardiology, Nizam’s Insitute of Medical Sciences, Punjagutta, Hyderabad – 500 082 E-mail: [email protected]

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Figure 4. Photograph of the ring excised at surgery

Figure 1. Angiogram showing critical narrowing of ostium of left internal carotid artery

Figure 5. Flouroscopy showing the expanded stent in the AP view

Figure 2. Picture shows a severe waist on the balloon dilating the carotid Lesion

Figure 3. Flouroscopy shows non-expansion of the carotid stent at the site where a ring was left behind

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Figure 6. Flouroscopy showing the expanded stent in the lateral view (a tiny bit of the ring was left behind as it was posterior to the stent).

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REFERENCES 1.

Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95: 376–81. 2. Ohki T, Marin MI, Lyon RT, et al. Exvivo human carotid artery bifurcation stenting: Correlation of lesion characteristics with embolic potential. J Vasc Surg 1998; 27: 463–71. 3. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000; 101: 70–80.

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4.

Naylor AR, Bolia A, Abbott RJ, et al. Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: stopped trial. J Vasc Surg 1998;28:326–34. 5. Grube E, Gerckens U, Yeung AC, et al. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation 2001; 104: 2436–41. 6. Yadav JS, Mark HW, Richard E, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351: 1493–501.

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Case Report

Malignant Ventricular Arrhythmias due to Aconitum Napellus Root Vitthal D. Maheshwari, Puneet Saxena, Dinesh Choudhary Department of Medicine, SMS Medical College & Hospital, Jaipur, Rajasthan

BRIEF REPORT

DISCUSSION

A 25 year old male was admitted in the hospital with complaints of violent vomiting, diarrhea and choking sensations for 6–8 hours. At the time of arrival, patient was drowsy, pulse was feeble, and rate was 100/min irregular. Blood pressure was 60 mmHg systolic. Temperature was normal. Respiratory rate was 28/min. Pupils showed typical ‘hippus’ in response to light (alternate dilatation and contraction). JVP was normal. On CVS examination heart sounds were faint and no murmur was audible. Lungs were clear. No focal neurological deficit was found. Rest of the physical and systemic examination was normal. ECG showed bidirectional and polymorphic ventricular tachycardia with pseudoinfarction pattern (Figure 1, Figure 2). Trop-T test was negative and cardiac enzymes were also within normal range. Chest X-ray, 2D-echo and routine blood chemistry were also within normal range. Arrhythmias were refractory to D.C. cardioversion. IV amiodarone was started. It took 12 hours to achieve sinus rhythm (Figure 3). A history of ingestion of extract prepared from herb was revealed to suppress the dry and irritant cough which was on gas chromatography found to be root of Aconitum napellus.

Aconitum napellus is a plant with purple flowers and is found throughout the world. It has long been known to be a poison.1 The roots and seeds are freely available for treating musculoskeletal pain. They contain highly toxic C-19 diterpene and norditerpene alkaloids of aconitine, mesoaconitine, and the less toxic hypoaconitine. These compounds activate voltage-dependent Na⫹-channels in the heart and brain.2,3 The margin of safety between analgesic and toxic doses is very low. In the past, the plant was implicated in some cases of murder. Typical manifestations of poisoning are gastrointestinal, neurological, and cardiovascular with malignant ventricular arrhythmias.4 Treatment is essentially supportive. This initially consists of gastric lavage followed by oral activated charcoal. The ideal therapy for aconiteinduced arrhythmias is unknown, although anecdotal reports of resolution of the arrhythmias using flecainide, amiodarone, lignocaine, atropine, mexiletine, procainamide and phenytoin have been published.4 Cardiopolmonary bypass and ventricular assist devices have been used for refractory cardiac arrest.5,6 Aconite cardiotoxicity usually resolves within 24 hrs. No gross or histological cardiac abnormalities have been observed in the few autopsied cases.7

Correspondence: Dr. Vitthal D. Maheshwari, D-68, Shanti Path, Patrakar Colony, Jawahar Nagar, Jaipur E-mail: [email protected]

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Figure 1. ECG showing bidirectional ventricular tachycardia with pseudoinfarction pattern. (ECG on admission)

Figure 2. ECG showing polymorphic ventricular tachycardia (Torsades de pointes). (ECG after 2 hours)

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Cardio Vascular Images

Figure 3. ECG showing sinus rhythm. (ECG after 12 hours) pseudoinfarction pattern. (ECG on admission)

REFERENCES 1. Chan Ty, Tomlinson B, Tse LK, et al. Aconitine poisoning due to Chinese herbal medicines: A review. Vet Hum Toxicol. 1994;36:452-455. 2. Heuback JF, Schule A. Cardiac effects of Lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species. Planta Med. 1998;64:22–26. 3. Ameri A., The effects of Aconitum alkaloids on the central nervous system. Prog Neurobiol. 1998;56:211–235.

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4.

Tai YT, But PP, Young K, et al. Cardiotoxicity after accidental herb induced aconite poisoning. Lancet. 1992;340:1254–1256. 5. Fatovich DM. Aconite: a lethal Chinese herb. Ann Emerg Med 1992; 21:309–311. 6. Fitxpatrick AJ, Crawford M, Allan RM, et al. Aconite poisoning managed with a ventricular assist device. Anaesth Intens Care 1994;22: 714-717. 7. Dickness P, Tai YT, But PP, et al. Fatal accidental aconitine poisoning following ingestion of Chinese herbal medicine: a report of two cases. Forensic Sci Int. 1994;67:55–58.

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Case Report

All those Tachy’s are not Ventricular Zehra Jaffery, Karthik Ananthasubramaniam Department of Internal Medicine and Heart and Vascular Institute Henry Ford Hospital Detroit MI 48202

PRESENTATION A 70 year old woman with history of hypertension, diabetes and recent negative stress test less than 6 months ago presented with stuttering but worsening exertional chest pain since past 1 day. She had no electrocardiographic changes suggestive of myocardial ischemia and her cardiac enzymes were normal. She was started on aspirin, heparin and beta blockers. In view of her presentation and risk factors she underwent cardiac catheterization which revealed two vessel disease, 70% occlusion in a very small diagonal branch and 50% in 1st ostial marginal branch. Medical management was suggested. Her echocardiogram revealed an ejection fraction of 60% with no wall motion or valvular abnormalities. On the night prior to discharge, telemetry alarms were sounded for runs of wide complex tachycardia, felt to be of ventricular origin (Figure 1). Medical personnel rushed to her bedside but the patient was asymptomatic, moving around and conversing. The house staff planned to increase beta blockers, pending definitive evaluation the following day. Subsequent detailed evaluation of the tracing revealed a “false alarm” due to pseudo-ventricular tachycardia due to patient movement artifact.

DIAGNOSIS Closer observation of the tracings revealed the continued presence of normal QRS complexes at the cycle length of baseline rhythm within the apparent wide complexes (marked by arrows; Figure 2). This resulted in the recognition that the wide complexes were electrocardiographic artifacts. Other signs to indicate an artifactual nature of the recording were the absence of symptoms or any kind of hemodynamic deterioration during telemetry monitoring. The possibility of artifact as a cause of electrocardiographic finding should always be considered in an otherwise asymptomatic patient who is hemodynamically stable. In our patient cursory overview of the telemetry

tracings by the telemetry, nursing and house staff personnel suggested ventricular tachycardia, potentially influencing therapeutic decisions and causing alarm. Closer scrutiny, clearly showed QRS complexes buried in the wide amplitude, repetitive electrical activity. A study reported misdiagnosis of artifact as ventricular tachycardia to be 94% among internists, 58% among cardiologists and 38% among electro physiologists, with a large proportion of these physicians recommending invasive procedures for evaluation or therapy.1 An electrocardiographic algorithm for differentiation of tremor-induced pseudo-VT has been suggested. In tremorinduced pseudo-VT, one of the frontal leads (leads I, II, and III) may present with sinus rhythm with normal P, QRS and T waves (“Sinus” sign). This is because one of the upper limbs may be free from tremor in certain patients. The second, regular or irregular tiny spikes may be identified among wide-QRS complexes (“Spike” sign). These may coincide with the actual sinus cycle length in another lead and were the clue in our patient. There is another electrocardiographic clue: “Notch” sign, referring to notches superimposed in the wide-QRS-like complex artifact, coinciding with the cycle length when sinus rhythm was recorded. Sensitivity, specificity, negative and positive predictive values are 100%, 97.3%, 100%, and 98.4%, respectively for identification of pseudo-VT.2

MANAGEMENT Artifacts on electrocardiograms may be misdiagnosed as various kinds of cardiac arrhythmias. These electrocardiographic changes may cause unnecessary panic and increase the use of health care resources and can potentially result in unnecessary therapeutic strategies and invasive procedures.3 Physicians should always keep artifact in the differential diagnosis of EKG abnormalities. Our patient was discharged as scheduled with no additional intervention.

Correspondence: Karthik Ananthasubramaniam, Henry Ford Hospital, Heart and Vascular Institute, 2799 West Grand Blvd, K-14, Detroit MI 48202 E-mail: [email protected]

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All those Tachy’s are not Ventricular

Figure 1. Rhythm strip of electrocardiographic artifact that mimicked Ventricular Tachycardia. Narrow QRS complexes (marked) clearly buried within the wide amplitude repetitive activity.

REFERENCES 1.

Knight BP, Pelosi F, Michaud GF, et al. Physician interpretation of electrocardiographic artifact that mimics ventricular tachycardia. Am J Med 2001; 110:335-338 2. Huang CY, Shan DE, Lai CH, et al. An accurate electrocardiographic algorithm for differentiation of tremor-induced pseudo-ventricular

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tachycardia and true ventricular tachycardia. Int J Cardiol 2006; 111:163-165 3. Knight BP, Pelosi F, Michaud GF, et al. Clinical consequences of electrocardiographic artifact mimicking ventricular tachycardia. N Engl J Med 1999; 341:1270-1274

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Case Report

Mobile Intracardiac Thrombi: Clinical Scenarios and Management Strategies V Bhatia, R Sapra, A Mittal, AK Pandey, R Gupta, R Kachru, P Arora, A Parida, G Singh, U Kaul Department of Cardiology, Fortis Hospital, Noida

INTRODUCTION Mobile clots are rare findings and need to be dealt with caution. Echocardiography remains a simple noninvasive way to closely monitor such patients for complications and treatment responses. We present a short series of four patients we encountered with such undesirable clots. Patient Number 1: A 74 years old male, diabetic and hypertensive suffered a massive left Middle Cerebral Artery territory hemorrhagic infarction with midline shift. He was managed conservatively elsewhere and 4 days later referred to our center for sudden onset breathlessness. Examination revealed sinus tachycardia, tachypnea, BP-90/60 mmHg, loud P2 and right-sided neurological deficit. There was no evidence of deep vein thrombosis. Trans- Thoracic Echocardiography (TTE) revealed a worm like mass moving freely between the Right Atrium (RA) and Right Ventricle (RV) (Figure 1). There was paradoxical motion of the interventricualr septum and pulmonary artery systolic pressure (PASP) by TR jet was estimated at 60 mmHg. Thrombolytic therapy was ruled out in view of recent extensive hemorrhage within the infarcted area. Surgical removal was not possible as this would require placing the patient on cardiopulmonary bypass and thus require heparin. The best option seemed to be the extraction of the clot using a basket device. Even as this was being contemplated the patient deteriorated clinically in the form of worsening breathlessness and developed cardiogenic shock. He was immediately put on assisted ventilation and maximal ionotropic support. TTE revealed that the entire clot had embolized into the pulmonary vasculature and was no longer seen in the RA or RV (Figure 2). He had a rapidly progressive downhill course and succumbed soon after. Patient Number 2: A 34 years old lady, known diabetic for 4 years, non-hypertensive, dyslipidemic and with a family history of premature coronary artery disease presented with gradual onset breathlessness of four months

duration. She was in NYHA class IV on admission with complaints of orthopnea, paroxysmal nocturnal dyspnea and oliguria. Clinical examination revealed bi-ventricular failure. ECG revealed NSR, poor R wave progression in anterior leads and chest X ray was suggestive of cardiomegaly, pulmonary venous hypertension along with right-sided pleural effusion. A TTE done showed global hypokinesia, depressed LV systolic function (LVEF⫽30%), PASP by TR jet of 55 mmHg and a mobile, protruding clot with central echogenicity at the LV apex (Figure 3). Apart from decongestive therapy she was started on low molecular weight heparin and warfarin (INR 2–2.5). Serially TTE were done and revealed the gradual resolution of the thrombus over a period of 3 weeks (Figure 4). Her CAG revealed normal coronaries and a diagnosis of Dilated (? Diabetic) Cardiomyopathy (DCM) was considered. There were no adverse thromboembolic events. She is faring well on medical therapy on follow up. Patient Number 3: A 28 years old female who in the 3rd trimester presented with loss of fetal movements and breathlessness. On examination she had central cyanosis, grade 3 clubbing and a single second heart sound. Her obstetric ultrasound revealed evidence of intrauterine fetal death and her 2 D Echo and color Doppler revealed a large ventricular septal defect with right to left shunting, severe pulmonary arterial hypertension and evidence of a large friable and mobile thrombus in the main pulmonary artery (Figure 5). Labor was induced and the patient delivered a stillborn fetus. She was put on LMWH and warfarin and advised long-term warfarin therapy. She belonged to a farflung area and despite being advised regular follow up did not turn up for the same. Patient Number 4: A 40 years old male, normotensive, nondiabetic, smoker suffered an extensive anterior wall myocardial infarction and was thrombolyzed with 1.5 MU of Streptokinase (window period 5 hours). He was referred to us 2 days later for post MI angina. Pre CAG TTE revealed severe hypokinesia of the mid and apical IVS along with

Correspondence: Prof. Upendra Kaul, Director & HOD, Dept. of Cardiology, Fortis Hospital, B–22, Sector–62, NOIDA (UP) E-mail: [email protected], [email protected]

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Mobile Intracardiac Thrombi

Figure 1. Sub-costal view shows a worm like mass (double arrows) extending from RA to RV across tricuspid valve.

Figure 3. PLAX view shows mobile clot with central echogenicity (double arrows) at LV apex.

Figure 2. Sub-costal view reveals complete embolization of the mass.

Figure 4. Echo 3 weeks later shows resolution of the clot seen at LV apex.

a mobile and fleshy clot at the LV apex. CAG revealed 100% mid LAD occlusion for which he underwent PTCA and stenting to LAD along with weight-adjusted Tirofiban. Post procedure he was put on LMWH and warfarin added from day one. A pre-discharge TTE revealed that though still mobile the fleshy appearance had improved and the clot had reduced in size. Regular monthly follow up, revealed resolution of the clot over a 4-month period. There were no thromboembolic events and patient has been advised to continue warfarin until 6 months of the initial event.

DISCUSSION

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The embolic potential of a thrombus usually depends upon three echocardiographic characteristics, namely mobility, protrusion and central echogenicity apart from the clinical setting. Haughland et al1 showed that the risks of embolization in the presence of these characteristics are 60%, 40% and 50% respectively. The following discussion tries to highlight issues pertaining to such thrombi and how to deal with them.

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Figure 5. PSAX view at aortic valve level shows a friable thrombus in the main pulmonary artery.

Patient 1 fits into the category of so called “floating right heart thrombi” (FRHTS). Chartier et al2 have reported possibly the largest follow up series on FRHTS. These are rare entities but probably under diagnosed in patients with PE. They are usually worm like,4 may be spherical or grape like also,2 originate in the lower extremity venous circulation and are in transit to the pulmonary arteries. They require emergency treatment, especially as they carry a high mortality rate, in excess of 40%.3 Four treatment options are available for such patients 1. Surgical embolectomy during cardiopulmonary bypass-seems the surest way of safely removing the mass with least risk of embolism. 2. Intravenous thrombolysis with recombinant tissue plasminogen activator, Urokinase or Streptokinase. Lytic therapy has several advantages, it accelerates thrombus lysis and pulmonary reperfusion, reduces pulmonary hypertension, improves RV function and helps to increase both RV and LV output and to reverse cardiogenic shock. Thrombolysis also helps dissolve clots at several locations: intracardiac, the pulmonary or systemic embolus and the venous thrombosis.5 3. Intravenous heparin alone, with the dose adjusted to keep the activated partial thromboplastin time at 2 to 3 times normal; or LMWH which has several theoretical and practical advantages. 4. Interventional techniques are performed when surgery and thrombolytics are contraindicated. Briefly, the thrombus is trapped in a basket device (Cook, Inc),

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advanced to the right atrium via the femoral approach and then withdrawn into the inferior vena cava. Subsequently, a caval filter is then placed above the entrapped thrombus via the jugular vein. The basket is then removed, leaving the thrombus below the filter.6 After a period of intravenous heparin therapy, patients can be discharged on oral anticoagulation, adjusted to maintain an INR between 2–3. Chartier reported a series of 38 patients encountered over 12 years with FRHTS. Thirty two were in NYHA class IV and 20 in cardiogenic shock. Echocardiography usually demonstrated signs of cor pulmonale: right ventricular overload (91.7% of the population), paradoxical interventricular septal motion (75%) and pulmonary hypertension (86.1%). The thrombus was typically wormlike (36 of 38 patients). It extended from the left atrium through a patent foramen ovale in 4 patients. PE was confirmed in all but 1. Mortality was high (17 of 38 patients) irrespective of the therapeutic option chosen: surgery (8 of 17), thrombolytics (2 of 9), heparin (5 of 8), or interventional percutaneous techniques (2 of 4). The in-hospital mortality rate was significantly linked with the occurrence of cardiac arrest. Conversely, the outcome after discharge was usually good, because 18 of 21 patients were still alive 47.2 months later (range, 1 to 70 months). Heart failure due to DCM is associated with an increased risk of thromboembolism (average at 2.0–2.5 events per 100 patients per year). In the absence of randomized trials, limited evidence exists to support the use of anticoagulant treatment for patients with heart failure due to dilated cardiomyopathy in sinus rhythm, even if these subjects

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Mobile Intracardiac Thrombi

appear to be at higher risk than those with ischemic cardiomyopathy and comparable degree of left ventricular dysfunction. Women with left ventricular ejection fraction ⬍ 25% constitute a remarkable exception to this rule and anticoagulation is strongly indicated for them. Unless there are contraindications, anticoagulant treatment is mandatory for patients with heart failure and atrial fibrillation. As studies on preventive treatment in atrial fibrillation have indicated, a target INR between 2.0 and 3.0 seems appropriate. Patients with intraventricular thrombi present a difficult therapeutic challenge in as much as no strong evidence exists that anticoagulant treatment significantly decreases the risk of embolization particularly in patients with flat thrombus. Therapy should thus probably be limited to patients with pedunculated or floating thrombus7 as in patient number 2. Pregnancy in Eisenmenger syndrome (ES) carries high fetal and maternal morbidity and mortality. ES is characterized by a consumptive coagulopathy as well as a prothrombotic state leading to complications. Thrombi in the distal pulmonary circulation are known but, large thrombi in the proximal pulmonary arteries are unusual, more so their direct visualization. It is postulated that local thrombus formation within the pulmonary arteries occurs as a direct consequence of pulmonary hypertension (sluggish flow in the dilated pulmonary arteries and polycythemia might be contributory) rather than venous thromboembolism. Acute worsening of symptoms with right heart failure leading to death in weeks to months, or occasionally sudden death, may occur. A similar etiology may cause fetal loss. Anticoagulation is the traditional treatment. In case of hemodynamic disturbance or acute worsening of symptoms, the thrombus has to be removed using thrombolytic therapy or mechanical means. Thrombolytic therapy may be considered up to 2 weeks after the onset or on worsening of symptoms. The major complication is bleeding and the advantage is the ease of therapy.8

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As far as the issue of mobile or protruding clots in the setting of Acute MI is concerned, though small series as one by Kremer et al 9 have shown use of thrombolytic agents to be safe and not associated with increased risk of systemic embolization, the larger consensus is to treat such patients with Heparin and oral anticoagulants. The European Society of Cardiology guidelines10 on management of ST elevation MI clearly state “If the thrombi are mobile or protuberant, they should be initially treated with intravenous heparin or LMWH and subsequently with oral anticoagulants for at least 3–6 months”.

REFERENCES 1. Haugland JM, Asinger RW, Mikell FL, et al. Embolic potential of left ventricular thrombi detected by two – dimensional echocardiography. Circulation 1984;70:588–98. 2. Chartier L, Bera J, Delomez M, et al. Free-floating thrombi in the right heart: Diagnosis, management, and prognostic indexes in 38 consecutive patients. Circulation 1999;99:2779–83. 3. European working group on echocardiography. The European cooperative study on the clinical significance of right heart thombi. Eur Heart J 1989;10:1046–59. 4. Panidis IP, Kotler MN, Mintz GS, et al. Clinical and echocardiographic features of right atrial masses. Am Heart J 1984;107:745–58. 5. Leclereq F, Messner – Pellene P, Beigbeder JY, et al. Thrombus flottant de l’oreillette droite et embolie pulmonaire grave: intere de al thrombolyse intraveineuse. Arch Mal Coeur 1994;87:805–11. 6. Loubeyre C, Chartier L, Beregi JP, et al. How should pulmonary embolism associated with mobile right atrial thrombus de treated? Is there a place for interventional cardiology? Eur Heart J 1995; 16 (suppl):268. 7. Kansaria JJ, Salvi VS. Eisenmenger syndrome in pregnancy. Journal Post Grad Med 2000;46:101–03. 8. Gensini GF, Rostagno C. Anticoagulant therapy in patients with dilated cardiomyopathy. Am Ital Med Int. 1998;13(4):227–32. 9. Kremer P, Fiebig R, Tilsner V, et al. Lysis of left ventricular thrombi with Urokinase. Circulation 1985;72:112–18. 10. The Taste Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST segment elevation. Eur Heart J 2003;24:28–66.

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D r u g s fo r H e a r t

Bivalirudin: A New Promising Direct Antithrombin Anupam Bhambhani, Bernhard Meier Swiss Cardiovascular Center, Bern University Hospital, Bern, Switzerland ABSTRACT The deadliest manifestations of ischemic heart disease are initiated and propagated by intra-coronary thrombin generation. Thrombin is resistant to inactivation by heparin when it is bound to fibrin, fibrin degradation products or subendothelial collagen. Recognition of these limitations has led to development of a new class of antithrombin agents which directly target the active sites on the surface of thrombin molecule and are therefore designated as direct antithrombins. These agents do not need mediation of antithrombin III for their action and are not inhibited by platelet factor 4. This report focuses on bivalirudin, a new agent of promising impact on both interventional as well as non-interventional cardiology. It is a short acting anticoagulant which bivalently and directly inhibits thrombin (coagulation factor II). It binds the active (catalytic) site and the fibrinogen-binding site (exosite I). This provides high affinity and specificity for thrombin. Slow cleavage at the Arg3-Pro4 bond results in recovery of thrombin activity after discontinuation of bivalirudin. Bivalirudin inhibits both protease activated receptor 1 and 4 (PAR 1 and PAR 4) thereby effectively inhibiting acute thrombin mediated platelet aggregation. Clinical efficacy has been assessed and proved in over 20 published patient series focussing on patients with acute coronary syndrome with or without myocardial infarction, patients undergoing percutaneous coronary interventions, patients receiving various adjunctive anti-platelet medications, patients with heparin induced thrombocytopenia or patients undergoing cardiac surgery. In contrast to the well established unfractionated heparin, bivalirudin lacks the risk of heparin induced thrombocytopenia. It shows a tendency to lower bleeding risks without reduction of efficacy when compared with the two-pronged treatment with unfractionated heparin and glycoprotein IIb/IIIa inhibitors. KEYWORDS Direct thrombin inhibitor, bivalirudin, percutaneous revascularization, platelet receptors, GP IIb/IIIa inhibitor, ecarin clotting time, heparin-induced thrombocytopenia

INTRODUCTION The deadliest acute manifestations of ischemic heart disease are initiated and propagated by intra-coronary thrombin generation. The pivotal role of thrombin (coagulation factor II) in the coagulation cascade has made it a popular target for discovery of new direct and indirect antithrombins. It is the central molecule that controls the balance between hemostasis and fibrinolysis. Thrombin converts the soluble plasma-protein fibrinogen into the insoluble protein fibrin by proteolytic cleavage of fibrinopeptides A and B from the former.1 The linear fibrin monomers are then cross-linked by factor XIIIa, which is itself activated by thrombin. This network of insoluble, cross-linked fibrin polymer results in a blood clot. Moreover, thrombin can release strong vasoconstrictors like endothelin 1, it catalyzes the proliferative effects of various growth factors2 thereby mediating endothelial cell and smooth muscle cell proliferation after injury to the vessel wall, and it also activates the platelet thrombin receptor,3 playing the role of a potent activator of platelet aggregation.

Indirect antithrombins are ineffective in patients with antithrombin III deficiency, due to their mechanism of action through antithrombin III. Moreover, thrombin is resistant to inactivation by antithrombin III when it is bound to fibrin, fibrin degradation products4 or subendothelial collagen. Fibrin binding of thrombin causes a 240 fold decrease in the heparin catalysed rate of thrombin inhibition.5 This protection occurs due to formation of a heparin-thrombinfibrin complex. This reaction limits accessibility of heparincatalyzed inhibitors to thrombin by inducing conformational changes at the active site of the thrombin. Recognition of these limitations of the so-called indirect antithrombins like heparin and the relatively recent molecule fondaparinux pentasaccharide, a factor Xa antagonist, has led to the development of a new class of antithrombin agents which directly target the active sites on the surface of thrombin molecule and are therefore designated as direct antithrombins. These agents do not need mediation of antithrombin III for their action and are not inhibited by platelet factor 4. The first agent of the class was hirudin,

Correspondence: Bernhard Meier, Professor and Chairman of Cardiology, Swiss Cardiovascular Center, Bern University Hospital 3010 Bern E-mail: [email protected]

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