Painless Aortic Dissection

Author’s Accepted Manuscript Painless Aortic Dissection, a Case Report and a Focused Review of the Literature Tariq S. Marroush, Andrew R. Boshara, Kesav C. Parvataneni, Robert Takla, Nancy A. Mesiha www.elsevier.com

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S0002-9629(16)30610-3 http://dx.doi.org/10.1016/j.amjms.2016.11.005 AMJMS322

To appear in: The American Journal of the Medical Sciences Received date: 7 September 2016 Revised date: 18 October 2016 Accepted date: 1 November 2016 Cite this article as: Tariq S. Marroush, Andrew R. Boshara, Kesav C. Parvataneni, Robert Takla and Nancy A. Mesiha, Painless Aortic Dissection, a Case Report and a Focused Review of the Literature, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2016.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Painless Aortic Dissection, a Case Report and a Focused Review of the Literature.

Tariq S. Marroush MDa; Andrew R. Boshara MDa; Kesav C. Parvataneni MDb, Robert Takla MD, MBAc; Nancy A. Mesiha MDb. a.

Department of Internal Medicine, St. John Hospital and Medical Center, Detroit, Michigan, USA, address: 19251 Mack Ave Suite 335 Grosse Pointe Woods, MI 48236

b.

Department of Cardiovascular diseases, St. John Hospital and Medical Center, Detroit, Michigan, USA. Address: 22101 Moross Road VEP, 2nd floor, Cath Lab, Detroit, MI 48236

c.

Department of emergency medicine, St. John Hospital and Medical Center, Detroit, Michigan, USA, Address 22101 Moross Rd, Grosse Pointe, MI 48236

Emails: Tariq Marroush: [email protected] Andrew Boshara: [email protected] Kesav Parvataneni [email protected] Robert Takla: [email protected] Nancy Mesiha: [email protected] Key Terms: Painless, aortic, dissection, stroke, heart failure Short title: Painless aortic dissection Address for correspondence: Tariq Marroush M.D St. John Hospital and Medical Center, Internal Medicine Residency Program: 19251 Mack Ave Suite 335 Grosse Pointe Woods, MI 48236 Phone: 507-491-4529 FAX: (313) 343-7784 E-mail: [email protected] Conflict of interest: Dr. Takla is on speakers’ bureau for AstraZeneca and Janssen; all other authors declared no conflict of interests.

Abstract Painless aortic dissection (PAoD) was previously linked to poor outcomes. We recently encountered a case of PAoD presenting with dyspnea, the clue to diagnosis was the presence of a loud aortic diastolic murmur. A systematic review of the literature revealed 86 other cases, 62% of which occurred in men with a mean age of 65 years. Left sided neurological deficits were the most common presentation, followed by dyspnea and bilateral lower extremity deficits. Pulse asymmetry was found in 53% of patients as 29% had right-left asymmetry and 24% had upper-lower asymmetry. Cumulatively, 88% of the cases were type A dissection and 51% of the patients died. Erroneous application of fibrinolysis and anticoagulation occurred in multiple instances. PAoD is rare but potentially fatal; a high index of suspicion and a thorough cardiovascular examination are needed to establish the diagnosis prior to applying possible harmful intercentions such as fibrinolysis, vasodilation or anticoagulation.

Introduction

Aortic dissection (AD) is a frequently lethal condition with an annual incidence of 5 to 30 cases per million people [1], resulting in about 10,000 deaths among Americans every year [2]. AD is associated with hypertension and genetic connective tissue abnormalities that may culminate in medial degeneration, intimal tear and false lumen formation [3]. Multiorgan ischemia, exsanguinations and tamponade may complicate aortic dissection summiting in shock and death. Unfortunately, the diagnosis is challenging and is often delayed or even missed, which may render the poor prognosis even poorer [4], this is mostly related to the rarity of the condition and the wide array of its differential diagnoses. Aortic dissection is generally classified based on the acuity of symptoms as either acute when the diagnosis is made within two weeks of onset of symptoms or chronic if the diagnosis is made later [1]. Anatomic classifications depend on the entry and the extension of the dissection; in 1965, De Bakey suggested a classification of three types where type I starts at the ascending aorta and extends to the aortic arch or beyond, type II is limited to the ascending aorta and type III starts in the descending aorta, normally distal to the left subclavian artery [5]. Stanford classification, on the other hand, simplifies the dissection for therapeutic purposes into type A that involves the ascending aorta and type B that starts after the origin of the left subclavian artery, type A is considered a surgical emergency, and type B is treated medically more often [1].

The classic and most common presentation of type A aortic dissection is a sudden onset of a tearing chest pain whereas type B dissection may present with severe abdominal pain; however, a wide range of presentation exists. Atypical presentations may complicate the picture, and are associated with frequent delay in diagnosis and subsequently increased mortality and morbidity especially in patients who present without pain [6, 7]. This, in addition to the potential mimicry between type A aortic dissection, myocardial infarction and cerebrovascular accidents, each of which has a different treatment, make precise diagnosis crucial as misdiagnosis with the potential inappropriate application of anticoagulation or thrombolytics may be disastrous [8]. Timely diagnosis and triage, on the other hand, are of utmost importance [9], since every hour of delay translates into a 1% increase in mortality [10]. The data about painless AD is scarce and based mainly on the International Registry of Acute Aortic Dissection (IRAD) [6] and case reports. Driven by a recently encountered case of painless type A aortic dissection, in which the presence of aortic regurgitation murmur led to the diagnosis 12 hours into presentation, and due to the serious complications of missing or delaying the diagnosis, we review the related literature and highlight key features that may help the clinician to consider this entity and establish the diagnosis.

Case Presentation: A 53 year-old African-American man with a history of hypertension and alcohol misuse presented to our hospital complaining of a 2 weeks history of a progressive shortness of breath.

The patient was previously placed on nifedipine but was not compliant with medications and had not seen a physician in years. He was normally an active person until his symptoms started two weeks prior to presentation with a progressively worsening dyspnea on exertion, paroxysmal nocturnal dyspnea and frothy sputum-producing cough. He denied any chest, neck, back or abdominal pain.

On presentation, his blood pressure was 265/85 mmHg, heart rate was 117 beat per minute and respirations were 22 per minute. He was found to be hypoxic on ambient air with a pulse oximetry of 85%. Physical examination revealed crackles on both lung bases. The cardiac auscultation was notable for what was thought to be a systolic murmur audible throughout the precordium. The jugular veins were distended bilaterally with an estimated jugular venous pressure of 12 centimeters. Pulses were normal and symmetric in all four extremities and carotid upstrokes were also normal. The patient was alert and oriented to place, time and person and able to move all four extremities with full strength, sensation was also preserved. Chest X-ray showed attenuation over the mid and lower lung fields with prominence of the cardiac silhouette mimicking heart failure and electrocardiogram (EKG) showed sinus tachycardia with a heart rate of 115, QRS duration was 90 milliseconds and the axis was 98 degrees, with signs of old septal infarcts.

Laboratory investigations were notable for elevated creatinine kinase at 1154 units/liter (reference range below 195 units/liter) and a mildly elevated Pro-BNP level at 446 pg/ml (reference range below 137pg/ml). The patient’s initial working diagnosis was presumed to be an acute exacerbation of heart failure, and he was treated with furosemide injection and continuous Nitroglycerine infusion. He reported a significant improvement in his symptoms in congruence with an improvement in lung exam findings. Upon further examination, the murmur was found to be diastolic in nature, 3/4 in intensity, covering the precordium and associated with a systolic ejection murmur, this was concerning for a possible derangement to the aortic valve potentially in the context of type A AD causing the cardiac decompensation. The patient underwent an urgent transthoracic echocardiography to better assess the cardiac anatomy; an unexpected dilatation of the aortic root measuring 4.9 cm was seen (figure 1) in association with a severe aortic insufficiency of a trileaflet aortic valve with a normal separation and malcoaptation of the cusps. The aortic regurgitation peak gradient was measured at 103.13 mmHG and the pressure half time was 84 milliseconds (figure 2). Aortic regurgitation jet was less evident by color Doppler, potentially because of aorta-left ventricular pressure equilibrium (figure 3). An intimal flap was also noticed when examining the abdominal aorta. These findings were concerning for an acute AD and a contrast-enhanced computed tomography angiogram of the chest, abdomen and pelvis showed a Stanford type A AD extending from the aortic root to the common iliac arteries, with involvement of the innominate artery (figure 4 and 5). After controlling the blood pressure, the patient was transferred to another hospital where he underwent successful emergent surgical repair and was discharged in a stable condition.

Methods We reviewed PubMed and Google Scholar for cases of painless aortic dissection, using the keywords: painless, aortic, dissection.

The data was gathered by two authors, the references in each paper were also reviewed and pertinent case reports were included. A number of cases were excluded because of the presence of pain. We included 86 cases indexed in PubMed in the final analyses in addition to our patient’s case; the total number analyzed was 87 cases.

The data was checked for accuracy, the results are expressed in percentages of the available data.

Results The majority of cases occurred in males (62%) (table 1). The mean age was 64.8 years with 85% of the patients older than 50 years. A history of hypertension was elicited in 64% of the patients, coronary artery disease in 12%, and aortic aneurysm in 9%, while 14% of the patients had no known past medical history. The most common presentation was left sided neurological deficits with intact consciousness in 21% (table 2), followed by dyspnea in 18% and bilateral lower extremities neurological deficits in 15%. Left-sided neurological deficits with or without altered consciousness were seen in 29% of the patients and altered consciousness with or without other neurological deficits was present in 26% of the patients. Overall, 76% of the patients presented with a form of neurological deficit.

On examination, 32% of the patients were hypertensive upon presentation, while 29% were hypotensive. Nineteen percent were bradycardic and 2% were febrile. Pulse deficits were present in 53% of the patients as 29% had right-left asymmetry and 24% had upper-lower asymmetry. Abnormal cardiac auscultation was found in 52% of the patients with 30% having the classic aortic regurgitation murmur.

Radiologic investigation revealed an abnormal chest X-ray in 75% of the patients, with widened mediastinum being the most common finding (35%), followed by a normal chest X- ray in 25% and increased tortuosity of the aorta in 23%. The classic double calcium sign was only seen in 2% of the patients.

The dissection type was reported to be Stanford type A in 88% of the cases and type B in 12%. Pericardial tamponade developed in 12% of the reviewed cases, of these, only 17% survived. Mortality rate overall was found to be 51%.

Discussion and literature review:

The painless presentation of AD may seem counterintuitive when taking into consideration the traditional teaching that dissection presents with the unique abrupt chest pain that radiates to the back. The first reported case of painless aortic dissection dates back to 1964 when, in a case similar to our patient’s, Cohen et al. suspected the diagnosis based on the presence of aortic regurgitation murmur [11]. In 1986, Gerber et al. reported three cases of painless aortic dissection presenting as acute neurological deficits [12]. Aortic dissection is generally underdiagnosed, even in its painful presentation. Misdiagnosis was reported initially in about one third of the patients, with the acute coronary syndrome being the most common initial diagnosis [13, 14]. The exact incidence of painless aortic dissection remains unknown; the reported percentage in the IRAD of 6.4% [3] may represent an underestimation as it does not account for undiagnosed cases or those ending with death prior to diagnosis. Other series reported that up to one third of the patients did not complain of pain upon presentation [15]. Different theories have been suggested to explain the absence of pain. The pain usually develops when the adventitia is involved as it is the only innervated layer of the vessel wall and thus pain will not be elicited if it is preserved [16]. Cerebral ischemia may alter the pain threshold or blunt the response to it [12]; in one report of 102 consecutive cases of AD, 29% of patients had neurologic deficits, only one third of them had prominent pain on presentation [17]. Furthermore, patients with diabetes, advanced age, previous aneurysm, or previous aortic surgery may have damaged innervation to the aorta and hence a decreased pain stimulation [12].

Hypertension constitutes a major risk factor for AD as it plays a pivotal role in medial degeneration and formation and propagation of the false lumen [1]. Patients with type B dissection are more frequently hypertensive on presentation compared to type-A [9], with as many as 25-60% of patients with type-A-dissection presenting with hypotension [3, 18]. This may be secondary to the higher incidence of heart failure, aortic regurgitation, cardiac tamponade and the involvement of the baroreceptors. The presence of hypotension is an ominous sign and confers a higher rate of morbidity and mortality [19].

The relatively high percentage of patients presenting with bradycardia is related to the involvement of the right common carotid artery owing to its proximity to the arch, this stimulates the carotid reflex and may result in syncope in some instances [9]. This proximity is also attributed to the high incidence of right hemispheric ischemia and hence left sided neurological deficits [20]. Patients with painless aortic dissection were found to constitute about 1.7% of the patients diagnosed with an acute ischemic stroke within the thrombolytics window [21], and cerebrovascular insults were found to be more common in painless presentation compared to the painful counterpart [7].

Patients presenting with heart failure almost invariably have aortic valve involvement leading to aortic regurgitation [22], the classic murmur was auscultated in 44% of patients with type A dissection [3] and was reported in about one third of the cases that we reviewed. The presence of this unique murmur should raise the suspicion about aortic dissection in the right

clinical context, particularly if the patient is not known to have a murmur [22]. This finding was the clue to the diagnosis in both our case and the first described case in the literature. Pericardial tamponade is a major cause of death in aortic dissection and it should be immediately detected [24], its incidence is higher among patients with painless aortic dissection compared to their counterparts with painful presentation [7].

Diagnosis: The American College of Cardiology and the American Heart Association suggested a 3 steps algorithm to evaluate patients with suspected aortic dissection (figure 4) [23]. This proved to be highly sensitive [25]. It is mainly based on a high clinical suspicion and directed physical examination and should be implemented when evaluating any patient with high risk clinical features (syncope, multiple vascular findings, and aortic insufficiency murmur).

Physical examination: Physical examination is an integral part of assessing cardiovascular complaints as it offers an inexpensive, readily available tool to evaluate patients and an opportunity to detect unexpected pathologies. Its implementation is integral to the aforementioned algorithm prior to pursuing advanced imaging modalities [26]. IRAD reports the most common physical findings in patients presenting with AAD to be elevated blood pressure in 49%, auscultation of aortic insufficiency murmur in 32% and pulse deficit in 15% [3]. Unfortunately, the importance of physical examination has been deemphasized in the surge of technology and the need to evaluate patients quickly [26]. Multiple reports have pointed at the lack of critical skills at

different levels of practice (medical students, residents, fellows, specialists) with cardiovascular auscultation being especially poor among residents of different specialties [27, 28]. Further research has shown that this deficit, although significant, could be at least partially rectified with dedicated teaching [29]. The lack of such abilities becomes particularly problematic if it results in misdiagnosing aortic dissection and proceeding with thrombolysis and aggressive anticoagulation. These interventions are vital to the treatment pathway of ailments with similar presentation such as myocardial infarction and ischemic stroke and have significantly improved outcomes of these conditions; however, they may be catastrophic in AD. The erroneous use of tPA was reported in both painless [30, 31, 32] and painful AD [33] and resulted in poor outcome. In another case, the diagnosis of PAoD was made inadvertently right before applying tPA [34]. The presence of ST-elevation myocardial infarction pattern on EKG was reported in 3.2% of patients eventually diagnosed with AD and 4.8% of patients diagnosed with Type A AD due to coronary osteal involvement that may lead to myocardial ischemia [3, 35], on the other hand, EKG changes related to left ventricular hypertrophy were observed in 26% of patients diagnosed with AD owing to the frequent association with hypertension , this may complicate the diagnosis and result in erroneous application of thrombolysis or referral to primary angioplasty [3]. Early mortality in case of applying thrombolysis in patients with AD was reported to be as high as 70% [36].

Radiology: Chest-X-ray is rarely normal in thoracic AD. Abnormalities, however, are mostly nonspecific. The double calcium sign represents a separation of more than 1 cm between the calcified intima and the aortic wall, this sign is specific but rarely seen [18], on the other hand, the presence of mediastinal widening and tortuous aorta, although nonspecific, merits further investigation [37].

Echocardiography and ultrasonography:

Transthoracic echocardiography is known to have limitation in the detection of AD, particularly when the lesion is limited to the descending aorta [38], its wide availability, however, makes it an excellent tool to assess patients with acute cardiovascular presentations[39], and its sensitivity has shown to be high when assessing the ascending aorta [40]. Its use is especially warranted to evaluate patients presenting with shock, and in the presence of physical findings concerning for tamponade [41]. Echocardiography, especially in the suprasternal view has also shown to be effective in detecting arch involvement, an invariable finding in patients with AD presenting with hemiplegic findings, neck ultrasonography may also detect the extension to the carotids if present [21, 42, 43, 44]. When it is emergently available, transesophageal echocardiogram (TEE) represents a sensitive and specific diagnostic tool with accuracy comparable to computed tomography and magnetic resonance [48]. The advantages of TEE include the ability to reach the diagnosis in minutes [45, 46], being readily available, the ability

to assess the aortic valve [47], and the avoidance of contrast dye in patients with impaired renal function. Biomarkers:

Multiple biomarkers have been investigated in aortic dissection, the majority of which is not available for clinical use [48]. D-dimer level has been shown to be highly sensitive for aortic dissection and is a useful tool to rule its presence out with a negative predictive value approaching 97% [49, 50], exceptions are young patients and totally thrombosed false lumen. The drawback is that the specificity is quite low and may be elevated in different other cardiovascular pathologies. Troponin and CK MB levels are not always helpful distinguishing aortic dissection from MI [51].

Study limitations:

This study represents only the reported cases of aortic dissection, and although it is the largest series reported in the literature, many cases may pass unrecognized and unreported. Further research is needed to investigate this phenomenon and to help distinguish the cases that are concerning for aortic dissection.

Conclusion: Painless AD is a rare entity with an ominous prognosis; diagnosis is difficult and based on a high clinical suspicion and focused physical examination. It should be considered when assessing patients with acute onset neurological deficits, new onset heart failure and multiple concomitant vascular phenomena.

When appropriate, this entity should be ruled out prior to the application of thromblytics, antiplatelets and anticoagulants to avoid the drastic consequences of missing the diagnosis.

A comprehensive cardiovascular examination is crucial to making the diagnosis, with special consideration being given to pulse deficit, arterial bruits and murmurs of new onset. Bedside echocardiography provides a useful tool to assess the cardiovascular system in the emergency setting and other radiological and laboratory findings may be helpful if interpreted correctly and advanced imaging should be pursued when clinical suspicion is high.

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Figure legends: Figure 1: Parasternal long axis view showing dilatation of the aortic root. AO=aorta, AV=aortic valve, LV=left ventricle. Figure 2: Aortic regurgitation jet obtained from apical five-chamber view showing a pressure half time of 84 milliseconds. Figure 3: Aortic regurgitation jet by color Doppler, AO=aorta, LV=left ventricle, LA=left atrium, ARJ=aortic regurgitation jet. Figure 4: Right, 3D reconstruction of the aorta, Left: Longitudinal CTA showing full-length aortic dissection. AA=aortic arch, TL=true lumen, FL=false lumen, arrows point at the intimal flap. Figure 5: Transverse CTA showing the involvement of both the aortic root and the descending aorta with aortic root dilatation. TL=true lumen, FL=false lumen, arrows point at the intimal flap. Figure 6: Reprinted from 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary, Vol.55 / No.14, Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, 2010, with permission from Elsevier.

Table 1: Clinical characteristics of patients with painless aortic dissection: Age: mean±SD=64.8±14.1 <50

13 (15%)

50-60

20 (23%)

60-70

21 (24%)

70-80

18 (21%)

>80

15 (17%)

Gender Male

54 (62%)

Females

33 (38%)

Associations Hypertension

47 (64%)

No previous history

10 (14%)

Coronary artery disease

9 (12%)

Aortic aneurysm

7 (9%)

Smoking

5 (7%)

Diabetes

5 (7%)

Atrial fibrillation

4 (5%)

COPD

3 (4%)

Aortic replacement

2 (3%)

Aortic stenosis

1 (1%)

Rheumatoid arthritis

1 (1%)

Spondyloarthritis

1 (1%)

Marfan

1 (1%)

N/A

13

Physical Exam Heart rate Bradycardia

11 (19%)

Tachycardia

9 (15%)

Normocardia

39 (66%)

N/A

28

Blood pressure Hypotensive

21 (29%)

Hypertensive

23 (32%)

Normotensive

28 (39%)

N/A

15

Peripheral pulse Symmetric

24 (47%)

R-L asymmetry

15 (29%)

U-L asymmetry

12 (24%)

N/A

36

Heart murmur None

21 (48%)

Aortic regurgitation

13 (30%)

Diminished

5 (11%)

Other

4 (9%)

Pericardial rubs

1 (2%)

N/A

43

Chest X-ray Mediastinal wideneing

20 (35%)

Normal CXR

14 (25%)

Increased tortuosity of the aorta

13 (23%)

Cardiomegaly

7 (12%)

Pulmonary infiltrates

6 (11%)

Pleural effusion

4 (7%)

Double calium

1 (2%)

N/A

30

SD: standard deviation, N/A: not available, R-L: right-left, U-L: upper lower.

Table 2: Presenting symptoms, dissection type and outcome Presentation Left sided deficits/intact consciousness

18 (21%)

Dyspnea

16 (18%)

Bilateral lower extremity deficits

13 (15%)

Altered consciousness

12 (14%)

Altered consciousness with left sided deficits

7 (8%)

Right sided deficits/intact consciousness

5 (6%)

Altered consciousness with right sided deficits

2 (2%)

Amnesia

4 (5%)

Dysphonia

3 (3%)

Generalized weakness with fever

2 (2%)

Vomiting

2 (2%)

Facial swelling

1 (1%)

Vision loss

1 (1%)

Dysarthria

1 (1%)

Dissection type Type A

75 (88%)

Type B

10 (12%)

N/A

2

Outcome Death

36 (49%)

Survival

38 (51%)

N/A

13