Case report
A case study of likely wild-type cardiac transthyretin amyloidosis causing rapid deterioration
Journal of the Intensive Care Society 2017, Vol. 18(2) 138–142 ! The Intensive Care Society 2016 Reprints and permissions: sagepub.co.uk/ journalsPermissions.nav DOI: 10.1177/1751143716682263 journals.sagepub.com/home/jics
Thomas Davies1, Aarash Saleh1, Gerry Coghlan2, Carol Whelan2,3 and Banwari Agarwal1
Abstract We present the case of an 88-year-old gentleman who presented to hospital septic with bilateral leg cellulitis, pulmonary oedema and hypotension. He had no history of heart disease but had had bilateral carpal tunnel releases. His condition deteriorated with refractory hypotension in spite of fluid filling, inotropic and vasopressor support. His echocardiogram showed an infiltrative cardiomyopathy with a speckled myocardium, severe concentric left and right ventricular increased wall thickness, diastolic dysfunction, biatrial dilatation and restrictive physiology in keeping with cardiac amyloidosis. He developed atrial fibrillation and worsening respiratory failure due to fluid overload and was intubated and ventilated but continued to decline and passed away. The degree of heart failure in the absence of ischaemia, the patient’s advanced age, echocardiographic findings and past history of carpal tunnel syndrome in a male are strongly indicative of a diagnosis of wild-type cardiac transthyretin amyloidosis. We discuss the key features and intensive care management of this disease.
Keywords Amyloidosis, heart failure, transthyretin, critical care
Case presentation An 88-year-old white British gentleman presented to the accident and emergency department with a sixweek history of worsening painful erythema and swelling of the lower legs and shortness of breath. He had a past medical history of mild chronic obstructive pulmonary disease, gout, osteoarthritis, transient ischaemic attack and bilateral carpal tunnel releases 10 years earlier. He lived alone and was independently mobile with a Zimmer frame. In the three weeks prior to admission, he was treated with oral antibiotics by his GP who suspected cellulitis of the legs. On admission he was tachypnoeic, hypotensive and pyrexial. His blood pressure was 84/52 mmHg, with a heart rate of 100 beats/min and temperature of 38.4 C. Examination in the emergency department revealed marked erythema and oedema of both legs and bibasal chest crepitations. The initial diagnosis was sepsis due to leg cellulitis and he was commenced on intravenous fluid resuscitation at 250 ml/h, intravenous gentamicin and flucloxacillin and high flow oxygen. His electrocardiogram showed atrial fibrillation (AF), right bundle branch block and left axis deviation.
Initial blood tests showed acute kidney injury and raised inflammatory markers with urea 19.2 mmol/l, creatinine 209 mmol/l, haemoglobin 108 g/l (mean cell volume 90.3 fl), white cell count 10.79 109/l (neutrophilia 9.57 109/l), CRP 75, serum lactate level 4.3 mmol/l, N-terminal pro-brain natriuretic peptide 2769 pg/ml and a mild coagulopathy–international normalised ratio 1.6, platelets 206, d-dimer 675. Basal interstitial changes with an enlarged heart were seen on chest radiograph. A blood culture was taken that later grew (1) Serratia marcescens and (2) Staphylococcus capitis. These organisms may represent contaminants as they are unusual organisms to find in blood cultures, particularly in combination, and in a patient from the community. 1
Intensive Care Department, Royal Free Hospital, London, UK Cardiology, Royal Free Hospital, London, UK 3 National Amyloidosis Centre, Royal Free Hospital, London, UK 2
Corresponding author: Thomas Davies, Intensive Care Department, Royal Free Hospital, 4th Floor, Pond Street, London NW3 2QG, UK. Email: [email protected]
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The patient was admitted under the medical team who on examination noted worsening respiratory function following initial fluid resuscitation with bilateral crepitations throughout chest and a raised jugular venous pulse. They suspected there was underlying cardiac failure and fluid resuscitation was slowed. The following day he remained hypotensive with a systolic blood pressure consistently below 100 mmHg in spite of 5.7 l of fluid and he was transferred to the intensive care unit (ICU) for inotropic support. In the ICU LiDCOTMplus haemodynamic monitoring was employed and intravenous fluid administration was guided by clinical assessment of volume status and stroke volume variation. A repeat chest radiograph revealed worsening airspace opacity on the right (Figure 1) indicative of pulmonary oedema. A transthoracic echocardiogram performed on ICU showed an infiltrative cardiomyopathy with a speckled myocardium, severe concentric left and right ventricular increased wall thickness, biatrial dilatation, diastolic dysfunction and restrictive physiology in keeping with cardiac amyloidosis1 (Figures 2 to 4). The left ventricle end diastolic diameter was 33 mm, interventricular septal thickness 26 mm, posterior wall thickness 20 mm with a left atrial diameter of 41 mm and an area of 21 cm2. In the presence of AF, the clinical usefulness of conventional Doppler indexes is limited. However, the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/E0 ) has been reported to be accurate in the estimation of left ventricular (LV) filling pressure and is recommended for the evaluation of LV diastolic function in AF.2,3 In this gentleman the measured E/E0 ratio was 13, which in the context of AF predicts an elevated LV filling pressure.2 Mitral annular plane systolic excursion was 5 mm indicating impaired longitudinal function with an ejection fraction of 10%. Right ventricular function appeared to be severely impaired and estimated pulmonary artery
systolic pressure was 28 mmHg. There was a small pericardial effusion but no evidence of tamponade. Dynamic LV outflow tract obstruction was ruled out with a peak velocity over the aortic valve of 1.03 m/s and a peak gradient of 4.24 mmHg. There was no significant valve disease; trace mitral and aortic regurgitation was evident with no tricuspid regurgitation. Based on the clinical suspicion of cardiac amyloidosis on the echocardiogram, serum and urine electrophoresis were carried out which later showed the absence of a plasma cell dyscrasia. Following the echocardiogram, dobutamine was started and it was titrated (maximum dose reached 18 mcg/kg/min) to ensure adequate inotropic effect whilst avoiding excessive tachycardia which would reduce time for ventricular filling in diastole. Despite this he developed a rapid ventricular response and was loaded with digoxin which adequately controlled the ventricular response to around 80–90/min.
Figure 1. Chest radiograph on day 3 showing worsening airspace opacity particularly on the right.
Figure 3. In diastole the left ventricular cavity remains constricted causing a filling defect.
Figure 2. Transthoracic echocardiogram (apical four-chamber view) showing concentric left ventricular hypertrophy, thickened interatrial septum and biatrial dilatation. Hypertrophic restriction of the left ventricular cavity is evident. LA: left atrium; LV: left ventricle; RA: right ventricle; RV: right ventricle.
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Figure 4. Tissue Doppler recording from the lateral mitral annulus.
Noradrenaline was used as a vasopressor to maintain adequate systemic vascular resistance (maximum dose reached 0.38 mcg/kg/min). Over the next few hours following his admission to ICU, his blood pressure became labile and he developed confusion. He was tracheally intubated and ventilated. However, he continued to deteriorate with increasing inotrope and vasopressor requirements and 24 h into his ICU admission he had two cardiac arrests with pulseless electrical activity both of which terminated after adrenaline and cardiopulmonary resuscitation. At this point further intervention was agreed to be futile and he passed away shortly after. A post-mortem examination was considered but declined by his family and a cause of death was determined as septic shock due to leg cellulitis on the background of cardiac failure secondary to a suspected wild-type transthyretin (ATTR) cardiac amyloidosis.
Discussion Amyloidosis is a disease characterized by the extracellular deposition of insoluble fibrillar proteins in the tissues and organs including the heart.4,5 There are three major subtypes of cardiac amyloid: light chain amyloidosis, hereditary transthyretin amyloidosis and wild-type transthyretin amyloidosis formally known as senile systemic amyloidosis. Wild-type ATTR cardiac amyloidosis is almost exclusively a disease of elderly males caused by the deposition of wild-type transthyretin fibrils predominantly in the myocardium leading to progressive heart failure, arrhythmia and conduction defects.6 The prevalence of wild-type ATTR cardiac amyloidosis is not known but postmortem studies have shown that the finding of
amyloid deposits (wild-type transthyretin) is relatively common in the elderly.7 The natural history of wild-type ATTR cardiac amyloidosis is not well documented as it 4 is rarely diagnosed before death.8 Typically it presents with symptoms and signs of biventricular cardiac failure for which the differential diagnosis is large. Common ECG findings in wild-type ATTR cardiac amyloidosis are that of conduction abnormality (especially right bundle branch block) and AF/flutter. Small QRS complexes often seen in AL cardiac amyloidosis are not typical in wild-type ATTR cardiac amyloidosis.8,9 Echocardiography shows an infiltrative cardiomyopathy: thickening of left and right ventricular walls and the interatrial septum, atria are dilated and Doppler echocardiography shows restrictive physiology.10 Another less common clinical presentation is with carpal tunnel syndrome, a recent case series found that 48% of patients with wild-type ATTR cardiac amyloidosis gave a history of carpal tunnel syndrome at presentation.11 Wild-type ATTR cardiac amyloidosis is underdiagnosed and its clinical importance is underestimated,12 especially as the prognosis of patients with wild-type ATTR cardiac amyloidosis is better than other subtypes of cardiac amyloidosis.8,13 Until recently, the gold standard for diagnosis of wild-type ATTR cardiac amyloidosis required the combination of transthyretin amyloid on a tissue biopsy specimen and wild-type transthyretin gene sequencing9,14 which is clearly difficult in this patient population. New techniques such as Tc-DPD scintigraphy have been shown to be a sensitive imaging tool for detecting transthyretin cardiac amyloid15,16 but unfortunately they are not practical options for
Davies et al. patients in severe cardiac failure and our patient was too unwell to undergo this. Restrictive physiology and diastolic dysfunction are the hallmarks of this disease. During late diastole, LV filling is passive and dependent on the compliance of the ventricle. Wild-type ATTR cardiac amyloidosis causes an infiltrative cardiomyopathy leading to a stiffened myocardium with reduced compliance. This leads to impeded, brief ventricular filling and abnormal relaxation resulting in severe diastolic dysfunction and cardiac failure. Management of this restrictive physiology in acute decompensated heart failure is based around decreasing systemic and pulmonary congestion, lowering ventricular filling pressure and augmenting systolic pump function. Pulmonary congestion can be reduced by improved LV filling and controlling blood volume. The steep gradient of the diastolic pressure– volume relationship means that a small change in left ventricular end diastolic volume (LVEDV) results in a significant change in left ventricular end diastolic pressure (LVEDP).17 Diuretics and nitrates can be used to reduce blood volume returning to the heart and decrease LVEDV, i.e. preload. These medications were not started in this patient due to severe hypotension and worsening haemodynamic instability. Reduced systolic function is usually uncommon in cardiac amyloidosis until the more severe stages of the disease18; however, one study has shown that left ventricular ejection fraction is more frequently impaired in wild-type ATTR cardiac amyloidosis than other subtypes, as it was in this gentleman.19 Inotropic therapy is important in patients with concurrent impaired systolic function and a low cardiac output state with signs of end organ dysfunction. Treatment with inotropes will improve contractility increasing cardiac output and decrease LVEDP improving diuresis. The choice of inotropic agent was further complicated in this patient by the presence of superimposed sepsis. Dobutamine is a synthetic catecholamine that increases cardiac output and reduces LVEDP. It is widely used in the treatment of severe heart failure and current guidelines recommend it as the first line agent, in combination with a vasopressor, for septic patients with a low cardiac output.20 Nevertheless, this is based on a paucity of outcome data and increased mortality in septic shock has been associated with the use of dobutamine.21 Levosimendan, a calcium sensitizer, has theoretical advantages in sepsis (calcium sensitization, reduction in apoptosis and inflammatory response) when compared to dobutamine. Furthermore, it enhances cardiac lusitropy and has been shown to be more effective in improving LV diastolic function than dobutamine.22,23 Small studies evaluating the use of levosimendan in sepsis have had promising results,24–26 though the recent LeoPARDS trial found that the addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction
141 or lower mortality.27 Milrinone is a phosphodiesterase 3 inhibitor with positive inotropic and lusitropic effects that has also been used in sepsis. However, little convincing evidence of benefit exists and it causes more significant vasodilatation which has been associated with worsening of hypotension in patients with congestive cardiac failure and superimposed sepsis.28 Adrenaline is an endogenous catecholamine with both inotropic and vasopressor properties. In cardiogenic shock, it has been shown to be as effective as dobutamine combined with noradrenaline in terms of global haemodynamic effects but with an increased side effect profile.29 It is, however, recommended as second line to noradrenaline for use as a vasopressor in septic shock.20 In this case, dobutamine was used to improve cardiac index with noradrenaline as a vasopressor to counteract peripheral vasoplegia due to concurrent sepsis and the vasodilatory effect of dobutamine. Arrhythmias such as AF have been shown to be common in cardiac amyloidosis and especially in wildtype ATTR cardiac amyloidosis.9,19 In AF, there is loss of atrial contribution to filling (‘atrial kick’) and often a rapid ventricular response shortening diastolic filling times. This further impairs diastolic function and therefore maintenance of sinus rhythm, if possible, is important. Our patient was in AF throughout and digoxin was used to achieve adequate rate control following the development of a fast ventricular rate after dobutamine administration. In patients with amyloidosis, digoxin should be used with caution as it binds amyloid fibrils leading to a higher risk of digoxin toxicity.30 Currently, no specific disease-modifying therapies are available but promising new agents are being investigated in a number of clinical trials. While there is presently no proven therapy it is recommended that all patients with wild-type ATTR cardiac amyloidosis are referred to the National Amyloidosis Centre for surveillance and inclusion in ongoing trials.10 We were unable to confirm the diagnosis in this gentleman with Tc-DPD scintigraphy in the absence of a plasma cell dyscrasia. However, the clinical picture of biventricular cardiac failure, with increased biventricular wall thickening and restrictive physiology on echocardiography, AF and a past history of carpal tunnel syndrome strongly suggests wild-type ATTR cardiac amyloidosis. Although there is no specific treatment at present, diagnosis is paramount to guide management of the associated cardiac physiology. Consent Published with written consent from the patient’s next of kin.
Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Patel K, Knight D, Whelan C, et al. Assessment of restrictive cardiomyopathy – Guideline of British Society of Echocardiography. Available at: http://www. bsecho.org/assessment-of-restrictive-cardiomyopathy/ (2014, accessed 23 November 2016). 2. Sohn DW, Song JM, Zo JH, et al. Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 1999; 12: 927–931. 3. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009; 10: 165–193. 4. Merlini G, and Westermark P. The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies. J Intern Med 2004; 255: 159–178. 5. Falk R, Comenzo R, and Skinner M. The systemic amyloidoses. N Engl J Med 1997; 337: 898–909. 6. Westermark P, Bergstro¨m J, Solomon A, et al. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid 2003; 10: 48–54. 7. Cornwell G, Murdoch W, Kyle R, et al. Frequency and distribution of senile cardiovascular amyloid. Am J Med 1983; 75: 618–623. 8. Ng B, Connors L, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 2005; 165: 1425–1429. 9. Pinney J, Whelan C, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013; 2: e000098. 10. Dubrey S, Falk R, and Hawkins P. Amyloid diseases of the heart: assessment, diagnosis and referral. Heart 2011; 97: 68–70. 11. Kyle R, Gertz M, and Linke R. Amyloid localized to tenosynovium at carpal tunnel release. Immunohistochemical identification of amyloid type. Am J Clin Pathol 1992; 97: 250–253. 12. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008; 40: 232–239. 13. Kyle R, Spittell P, Gertz M, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996; 101: 395–400. 14. Dungu J, Whelan CJ, Gibbs SDJ, et al. Patterns of late gadolinium enhancement in 94 patients with AL or transthyretin. J Cardiovasc Magn Reson 2012; 14: O87. 15. Hutt D, Quigley A-M, Page J, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid
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scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging 2014; 15: 1289–1298. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016; 133: 2404–2412. Pirracchio R, Cholley B, De Hert S, et al. Diastolic heart failure in anaesthesia and critical care. Br J Anaesth 2007; 9: 707–721. Selvanayagam JB, Hawkins PN, Paul B, et al. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol 2007; 50: 2101–2110. Rapezzi C, Merlini G, Quarta C, et al. Systemic cardiac amyloidoses. Circulation 2009; 120: 1203–1212. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580–637. Wilkman E, Kaukonen KM, Pettila V, et al. Association between inotrope treatment and 90-day mortality in patients with septic shock. Acta Anaesthesiol Scand 2013; 57: 431–442. Parissis JT, Panou F, Farmakis D, et al. Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. Am J Cardiol 2005; 96: 423–426. Dominguez-Rodriguez A, Samimi-Fard S, GarciaGonzalez MJ, et al. Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty. Int J Cardiol 2008; 128: 214–217. Mathieu S, and Craig G. Levosimendan in the treatment of acute heart failure, cardiogenic and septic shock: a critical review. J Intens Care Soc 2011; 12: 15–24. Morelli A, Teboul J-L, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 2006; 34: 2287–2293. Alhashemi JA, Alotaibi QA, Abdullah GM, et al. Levosimendan vs dobutamine in septic shock. J Crit Care 2009; 24: e14–e15. Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 2016; 375: 1638–1648. Varriale P, and Ramaprasad S. Short-term intravenous milrinone for severe congestive heart failure: the good, bad, and not so good. Pharmacotherapy 1997; 17: 371–374. Levy B, Perez P, Perny J, et al. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med 2011; 39: 450–455. Rubinow A, Skinner M, and Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981; 63: 1285–1288.
A case study of likely wild-type cardiac transthyretin amyloidosis causing rapid deterioration
Journal of the Intensive Care Society 2017, Vol. 18(2) 138–142 ! The Intensive Care Society 2016 Reprints and permissions: sagepub.co.uk/ journalsPermissions.nav DOI: 10.1177/1751143716682263 journals.sagepub.com/home/jics
Thomas Davies1, Aarash Saleh1, Gerry Coghlan2, Carol Whelan2,3 and Banwari Agarwal1
Abstract We present the case of an 88-year-old gentleman who presented to hospital septic with bilateral leg cellulitis, pulmonary oedema and hypotension. He had no history of heart disease but had had bilateral carpal tunnel releases. His condition deteriorated with refractory hypotension in spite of fluid filling, inotropic and vasopressor support. His echocardiogram showed an infiltrative cardiomyopathy with a speckled myocardium, severe concentric left and right ventricular increased wall thickness, diastolic dysfunction, biatrial dilatation and restrictive physiology in keeping with cardiac amyloidosis. He developed atrial fibrillation and worsening respiratory failure due to fluid overload and was intubated and ventilated but continued to decline and passed away. The degree of heart failure in the absence of ischaemia, the patient’s advanced age, echocardiographic findings and past history of carpal tunnel syndrome in a male are strongly indicative of a diagnosis of wild-type cardiac transthyretin amyloidosis. We discuss the key features and intensive care management of this disease.
Keywords Amyloidosis, heart failure, transthyretin, critical care
Case presentation An 88-year-old white British gentleman presented to the accident and emergency department with a sixweek history of worsening painful erythema and swelling of the lower legs and shortness of breath. He had a past medical history of mild chronic obstructive pulmonary disease, gout, osteoarthritis, transient ischaemic attack and bilateral carpal tunnel releases 10 years earlier. He lived alone and was independently mobile with a Zimmer frame. In the three weeks prior to admission, he was treated with oral antibiotics by his GP who suspected cellulitis of the legs. On admission he was tachypnoeic, hypotensive and pyrexial. His blood pressure was 84/52 mmHg, with a heart rate of 100 beats/min and temperature of 38.4 C. Examination in the emergency department revealed marked erythema and oedema of both legs and bibasal chest crepitations. The initial diagnosis was sepsis due to leg cellulitis and he was commenced on intravenous fluid resuscitation at 250 ml/h, intravenous gentamicin and flucloxacillin and high flow oxygen. His electrocardiogram showed atrial fibrillation (AF), right bundle branch block and left axis deviation.
Initial blood tests showed acute kidney injury and raised inflammatory markers with urea 19.2 mmol/l, creatinine 209 mmol/l, haemoglobin 108 g/l (mean cell volume 90.3 fl), white cell count 10.79 109/l (neutrophilia 9.57 109/l), CRP 75, serum lactate level 4.3 mmol/l, N-terminal pro-brain natriuretic peptide 2769 pg/ml and a mild coagulopathy–international normalised ratio 1.6, platelets 206, d-dimer 675. Basal interstitial changes with an enlarged heart were seen on chest radiograph. A blood culture was taken that later grew (1) Serratia marcescens and (2) Staphylococcus capitis. These organisms may represent contaminants as they are unusual organisms to find in blood cultures, particularly in combination, and in a patient from the community. 1
Intensive Care Department, Royal Free Hospital, London, UK Cardiology, Royal Free Hospital, London, UK 3 National Amyloidosis Centre, Royal Free Hospital, London, UK 2
Corresponding author: Thomas Davies, Intensive Care Department, Royal Free Hospital, 4th Floor, Pond Street, London NW3 2QG, UK. Email: [email protected]
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The patient was admitted under the medical team who on examination noted worsening respiratory function following initial fluid resuscitation with bilateral crepitations throughout chest and a raised jugular venous pulse. They suspected there was underlying cardiac failure and fluid resuscitation was slowed. The following day he remained hypotensive with a systolic blood pressure consistently below 100 mmHg in spite of 5.7 l of fluid and he was transferred to the intensive care unit (ICU) for inotropic support. In the ICU LiDCOTMplus haemodynamic monitoring was employed and intravenous fluid administration was guided by clinical assessment of volume status and stroke volume variation. A repeat chest radiograph revealed worsening airspace opacity on the right (Figure 1) indicative of pulmonary oedema. A transthoracic echocardiogram performed on ICU showed an infiltrative cardiomyopathy with a speckled myocardium, severe concentric left and right ventricular increased wall thickness, biatrial dilatation, diastolic dysfunction and restrictive physiology in keeping with cardiac amyloidosis1 (Figures 2 to 4). The left ventricle end diastolic diameter was 33 mm, interventricular septal thickness 26 mm, posterior wall thickness 20 mm with a left atrial diameter of 41 mm and an area of 21 cm2. In the presence of AF, the clinical usefulness of conventional Doppler indexes is limited. However, the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/E0 ) has been reported to be accurate in the estimation of left ventricular (LV) filling pressure and is recommended for the evaluation of LV diastolic function in AF.2,3 In this gentleman the measured E/E0 ratio was 13, which in the context of AF predicts an elevated LV filling pressure.2 Mitral annular plane systolic excursion was 5 mm indicating impaired longitudinal function with an ejection fraction of 10%. Right ventricular function appeared to be severely impaired and estimated pulmonary artery
systolic pressure was 28 mmHg. There was a small pericardial effusion but no evidence of tamponade. Dynamic LV outflow tract obstruction was ruled out with a peak velocity over the aortic valve of 1.03 m/s and a peak gradient of 4.24 mmHg. There was no significant valve disease; trace mitral and aortic regurgitation was evident with no tricuspid regurgitation. Based on the clinical suspicion of cardiac amyloidosis on the echocardiogram, serum and urine electrophoresis were carried out which later showed the absence of a plasma cell dyscrasia. Following the echocardiogram, dobutamine was started and it was titrated (maximum dose reached 18 mcg/kg/min) to ensure adequate inotropic effect whilst avoiding excessive tachycardia which would reduce time for ventricular filling in diastole. Despite this he developed a rapid ventricular response and was loaded with digoxin which adequately controlled the ventricular response to around 80–90/min.
Figure 1. Chest radiograph on day 3 showing worsening airspace opacity particularly on the right.
Figure 3. In diastole the left ventricular cavity remains constricted causing a filling defect.
Figure 2. Transthoracic echocardiogram (apical four-chamber view) showing concentric left ventricular hypertrophy, thickened interatrial septum and biatrial dilatation. Hypertrophic restriction of the left ventricular cavity is evident. LA: left atrium; LV: left ventricle; RA: right ventricle; RV: right ventricle.
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Figure 4. Tissue Doppler recording from the lateral mitral annulus.
Noradrenaline was used as a vasopressor to maintain adequate systemic vascular resistance (maximum dose reached 0.38 mcg/kg/min). Over the next few hours following his admission to ICU, his blood pressure became labile and he developed confusion. He was tracheally intubated and ventilated. However, he continued to deteriorate with increasing inotrope and vasopressor requirements and 24 h into his ICU admission he had two cardiac arrests with pulseless electrical activity both of which terminated after adrenaline and cardiopulmonary resuscitation. At this point further intervention was agreed to be futile and he passed away shortly after. A post-mortem examination was considered but declined by his family and a cause of death was determined as septic shock due to leg cellulitis on the background of cardiac failure secondary to a suspected wild-type transthyretin (ATTR) cardiac amyloidosis.
Discussion Amyloidosis is a disease characterized by the extracellular deposition of insoluble fibrillar proteins in the tissues and organs including the heart.4,5 There are three major subtypes of cardiac amyloid: light chain amyloidosis, hereditary transthyretin amyloidosis and wild-type transthyretin amyloidosis formally known as senile systemic amyloidosis. Wild-type ATTR cardiac amyloidosis is almost exclusively a disease of elderly males caused by the deposition of wild-type transthyretin fibrils predominantly in the myocardium leading to progressive heart failure, arrhythmia and conduction defects.6 The prevalence of wild-type ATTR cardiac amyloidosis is not known but postmortem studies have shown that the finding of
amyloid deposits (wild-type transthyretin) is relatively common in the elderly.7 The natural history of wild-type ATTR cardiac amyloidosis is not well documented as it 4 is rarely diagnosed before death.8 Typically it presents with symptoms and signs of biventricular cardiac failure for which the differential diagnosis is large. Common ECG findings in wild-type ATTR cardiac amyloidosis are that of conduction abnormality (especially right bundle branch block) and AF/flutter. Small QRS complexes often seen in AL cardiac amyloidosis are not typical in wild-type ATTR cardiac amyloidosis.8,9 Echocardiography shows an infiltrative cardiomyopathy: thickening of left and right ventricular walls and the interatrial septum, atria are dilated and Doppler echocardiography shows restrictive physiology.10 Another less common clinical presentation is with carpal tunnel syndrome, a recent case series found that 48% of patients with wild-type ATTR cardiac amyloidosis gave a history of carpal tunnel syndrome at presentation.11 Wild-type ATTR cardiac amyloidosis is underdiagnosed and its clinical importance is underestimated,12 especially as the prognosis of patients with wild-type ATTR cardiac amyloidosis is better than other subtypes of cardiac amyloidosis.8,13 Until recently, the gold standard for diagnosis of wild-type ATTR cardiac amyloidosis required the combination of transthyretin amyloid on a tissue biopsy specimen and wild-type transthyretin gene sequencing9,14 which is clearly difficult in this patient population. New techniques such as Tc-DPD scintigraphy have been shown to be a sensitive imaging tool for detecting transthyretin cardiac amyloid15,16 but unfortunately they are not practical options for
Davies et al. patients in severe cardiac failure and our patient was too unwell to undergo this. Restrictive physiology and diastolic dysfunction are the hallmarks of this disease. During late diastole, LV filling is passive and dependent on the compliance of the ventricle. Wild-type ATTR cardiac amyloidosis causes an infiltrative cardiomyopathy leading to a stiffened myocardium with reduced compliance. This leads to impeded, brief ventricular filling and abnormal relaxation resulting in severe diastolic dysfunction and cardiac failure. Management of this restrictive physiology in acute decompensated heart failure is based around decreasing systemic and pulmonary congestion, lowering ventricular filling pressure and augmenting systolic pump function. Pulmonary congestion can be reduced by improved LV filling and controlling blood volume. The steep gradient of the diastolic pressure– volume relationship means that a small change in left ventricular end diastolic volume (LVEDV) results in a significant change in left ventricular end diastolic pressure (LVEDP).17 Diuretics and nitrates can be used to reduce blood volume returning to the heart and decrease LVEDV, i.e. preload. These medications were not started in this patient due to severe hypotension and worsening haemodynamic instability. Reduced systolic function is usually uncommon in cardiac amyloidosis until the more severe stages of the disease18; however, one study has shown that left ventricular ejection fraction is more frequently impaired in wild-type ATTR cardiac amyloidosis than other subtypes, as it was in this gentleman.19 Inotropic therapy is important in patients with concurrent impaired systolic function and a low cardiac output state with signs of end organ dysfunction. Treatment with inotropes will improve contractility increasing cardiac output and decrease LVEDP improving diuresis. The choice of inotropic agent was further complicated in this patient by the presence of superimposed sepsis. Dobutamine is a synthetic catecholamine that increases cardiac output and reduces LVEDP. It is widely used in the treatment of severe heart failure and current guidelines recommend it as the first line agent, in combination with a vasopressor, for septic patients with a low cardiac output.20 Nevertheless, this is based on a paucity of outcome data and increased mortality in septic shock has been associated with the use of dobutamine.21 Levosimendan, a calcium sensitizer, has theoretical advantages in sepsis (calcium sensitization, reduction in apoptosis and inflammatory response) when compared to dobutamine. Furthermore, it enhances cardiac lusitropy and has been shown to be more effective in improving LV diastolic function than dobutamine.22,23 Small studies evaluating the use of levosimendan in sepsis have had promising results,24–26 though the recent LeoPARDS trial found that the addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction
141 or lower mortality.27 Milrinone is a phosphodiesterase 3 inhibitor with positive inotropic and lusitropic effects that has also been used in sepsis. However, little convincing evidence of benefit exists and it causes more significant vasodilatation which has been associated with worsening of hypotension in patients with congestive cardiac failure and superimposed sepsis.28 Adrenaline is an endogenous catecholamine with both inotropic and vasopressor properties. In cardiogenic shock, it has been shown to be as effective as dobutamine combined with noradrenaline in terms of global haemodynamic effects but with an increased side effect profile.29 It is, however, recommended as second line to noradrenaline for use as a vasopressor in septic shock.20 In this case, dobutamine was used to improve cardiac index with noradrenaline as a vasopressor to counteract peripheral vasoplegia due to concurrent sepsis and the vasodilatory effect of dobutamine. Arrhythmias such as AF have been shown to be common in cardiac amyloidosis and especially in wildtype ATTR cardiac amyloidosis.9,19 In AF, there is loss of atrial contribution to filling (‘atrial kick’) and often a rapid ventricular response shortening diastolic filling times. This further impairs diastolic function and therefore maintenance of sinus rhythm, if possible, is important. Our patient was in AF throughout and digoxin was used to achieve adequate rate control following the development of a fast ventricular rate after dobutamine administration. In patients with amyloidosis, digoxin should be used with caution as it binds amyloid fibrils leading to a higher risk of digoxin toxicity.30 Currently, no specific disease-modifying therapies are available but promising new agents are being investigated in a number of clinical trials. While there is presently no proven therapy it is recommended that all patients with wild-type ATTR cardiac amyloidosis are referred to the National Amyloidosis Centre for surveillance and inclusion in ongoing trials.10 We were unable to confirm the diagnosis in this gentleman with Tc-DPD scintigraphy in the absence of a plasma cell dyscrasia. However, the clinical picture of biventricular cardiac failure, with increased biventricular wall thickening and restrictive physiology on echocardiography, AF and a past history of carpal tunnel syndrome strongly suggests wild-type ATTR cardiac amyloidosis. Although there is no specific treatment at present, diagnosis is paramount to guide management of the associated cardiac physiology. Consent Published with written consent from the patient’s next of kin.
Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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