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"Myocardial or Pericardial disease : that is the question"

Case Presentation: The scene of crime...

On February 2012, a 40 year-old man was admitted to our Outpatient Clinic complaining dyspnea at rest, NYHA class IV,  persistent orthopnoea and was forced to sleep with additional pillows (three pillow orthopnoea) or sit in a chair for many hours during the night.
His physical examination evidenced arrhythmic muffled heart sounds (90 bpm), peripheral swelling, jugular veins distension, liver enlargement until 4 cm from ribs, no rales or pathological  murmurs or pericardial friction rubs,  absence of  dysmorphic facial features; BP 90/60 mmHg. Echocardiography at the admission showed a severe circumferential pericardial effusion with right atrial collapse and initial compression of right ventricle, the heart had a swinging motion within the pericardial sac, severe biatrial enlargement in contrast with normal size of ventricles, a plethora of inferior vena cava (IVC) and blunted respiratory changes were also observed. We also detected moderate ascites. We promptly performed an echo-guided pericardiocentesis, with removal of about 650 cc of yellow fluid.
The microbiologic/serologic/biochemical/cytologic/immunologic examination of the aspirate showed a sterile serofibrinous exudate (glucose 92 mg/dl; LDH 1001 U/L, proteins 3 g/dL).
Blood tests were all normal excluding autoimmune processes and tumors.

Who is guilty?

Cold Case (let’s go back to the past!)

He denied drug and alcohol abuse. No family history of cardiomyopathy was reported.
His previous medical history reveled a drastic loose of weight (about 30 Kilograms) when he was 18 years old. At that time his ECG (figure 3) showed sinus rhythm, atrial anomalies, incomplete right ventricle bundle branch block. His echocardiogram revealed normal dimensions and thickness of all chambers with normal systolic function but early mild dystolic disfunction type II (delayed relaxation, E/A ratio 0.7, deceleration time of 250msec), unusual for his age.
He was fine until January 2011 when he was admitted in another hospital for decompensated heart failure with atrial flutter and mild pericardial effusion with thickened pericardium. During his hospital stay, he also underwent chest TC scan that ruled out the presence of lynphoadenopathies, masses, neoplasia, turbercolosis and detected normal pericardium thickening (without calcifications). He was discharged with bisoprolol (1.25 mg/die), furosemide(25mg/die), and warfarin (according to INR value). An ambulatory ECG revealed alternation of atrial fibrillation and atrial flutter rhythm with several pauses>2.5 sec. At May 2011 he was admitted to our Outpatient Clinic for the first time complaining dyspnea on exertion, NYHA class II, dizziness, orthostatic hypotension, disturbances of sweating associated with shivers. ECG at the admission revealed atrial flutter at 3:1 or 4:1 conductions ratios and ventricular rate of about 90 bpm, right-axis deviation (+105°) and diffuse repolarisation anomalies. Echocardiography demonstrated: normal ventricular cavity sizes with preserved systolic function and intense  interventricular septal thickening (maximum medium-apical thickness was 15mm), thickened interatrial septum with no shunt and moderate pericardial effusion. There was also thickening of mitral and tricuspid valve and gross atrial dilatation. Dilated inferior vena cava and blunted respiratory changes.

Figure 1 (A and B). Illustration in subcostal view of severe pericardial effusion, a diastolic echo-free space of 38 mmin width (A) and in apical four chamber view of swinging heart due to large circumferential effusion, severe biatrial enlargment and normal ventricles.

Figure 2 (A and B). Illustration in subcostal view of pericardiocentesis: puncture of the pericardial sac (the arrow shows the insertion of the needle, A) followed by the injection of air gas microbubbles to define the tip of needle before fluid removal (the arrow show the microbubbles, B).

Figure 3. ECG at 18 years old  showed sinus rhythm, atrial anomalies; incomplete right bundle branch block.

Figure 4. Echocardiography at 18 years old showed normal dimensions and thickness of all chambers with normal systolic function but early mild dystolic disfunction type II (delayed relaxation, E/A ratio 0.7, DT 250msec)

Figure 5. ECG at the admission (May 2011) revealed atrial flutter at 3:1 or 4:1 conductions ratios and ventricular rate of about 90 bpm. Right-axis deviation (+105°) and diffuse repolarisation anomalies.

Doppler mitral valve inflow spectra revealed grade III of distolic dysfunction (E 48 cm/sec, A 23 cm/sec, E/A=2, DT 140 m/sec) without any significant respiratory variation. Tissue Doppler imaging from the septal mitral annulus showed decreased systolic and early diastolic velocities (S’ 6.4 cm/sec, E’ 6 cm/sec).

Figure 6. Long axis view of moderate pericardial effusion (A). Illustaration in four-chamber view of biatrial enlargment, thinchkened interatrail septum, intense interventricular septal thickening. There is also thickening of mitral valva (B). Doppler imaging of mitrale valve inflow showing restrictive filling pattern (C). Tissue Doppler imaging of septum with decrease of systolic and diastolic velocities (D)





Who is guilty?

What is the differential diagnosis in this patient ?

What further investigations (if any) would you perform ?

Try to solve our Cold Case… the importance of evidence collection!

Chest radiography and routine blood test, including markers of inflammation (CRP, ESR) and of myocardial lesions (creatine kinase, troponins) were normal failing to aid diagnosis. Spirometry showed moderate obstruction but no restriction. The patient was apyretic. We excluded any neurological or oculistic involvement too after consulting experienced operators. We performed cardio MRI with gadolinium (Gd) that, evenif partialy limitated by the arrythmia, the patient was in permanent atrial fibrillation, showed normal ventricular size with preserved systolic function (LEDV 49ml/mq, LESV 16ml/mq, LV FE 68%), the presence of moderate no haemodynamic pericardial effusion (expecially along inferior-lateral wall) without thickened pericardium. The early gadolinum enanchment (EGE) revealed no myocardial inflammation or oedema.
On the otherhand the late gadolinum enanhment (LGE) pattern showed a diffuse non-ischemic regional distribution expecially involving interventricular septum and anterior wall suggesting an infiltrative disease.

Figure 7. Illustration of cardioMRI showing large no haemodynamic pericardial effusion (along inferior-lateral wall) and LGE

So finally we have the guilty..this is a case of restrictive-infiltrative cardiomyopathy with severe pericardial effusion!

However, as all that glitters is not gold.. all restrictive pathophysiology is not a restrictive-infiltrative cardiomyopathy.. let’s understand why!

In order to define the eziology of this cardiomyopathy, we recommended to the patient to undergo right heart catetherization and endomyocardial byopsy (EMB) but he denied so he carried on with heart failure farmacological therapy (digoxin 0.125 mg per day, spirolactone  50 mg per day, furosemide 25 mg twice per day, bisoprolol 2.5 mg per day, warfarin according to INR value) untill February 2012 when he was admitted to our department for cardiac tamponade (as we previously described at the beginning of our case presentation).

On March 2012, following his last stay in our department and pericardiocentesis, the patient finally accepted to undergo to right heart catetherization and EBM.
Haemodynamic assessment documented increased right atrial pressure (14mmHg) with a typical dip-and-plateau configuration of the right ventricle filling pressure.
There was also a moderate-severe increase of pulmonary capillary wedge (PCWP=22mmHg) with mild post-capillary venous pulmonary hypertension (pulmonary pressures, PA 35/22/27 mmHg) and a severe riduction of cardiac output (CO 2.2 l/min; CI=1.33 l/min/mq)
Interestingly, EBM  revealed an istological pattern of restrictive disease but failed to disclose any amyloid deposition or any other kind of infiltration and ultrastructural analysis showed degenerative alterations propably due to hypertrofic disease. So we started genetic evaluation for the assessment of sarcomeric mutant genes and enrolment the patient for orthotropic heart transplantation.

It is important to recognize that while the term “restrictive cardiomyopathy” is seen as a diagnostic term, it is also used as a descriptive term of a pathophysiologic state.
The “restrictive pathophysiology”, on the other hand, is not an exclusive feature of restrictive cardiomyopathy but can be the final evolution of different diseases (i.e dilated, hypertrofic,left-ventricular non compaction, diabetic, ischaemic cardiomyopathies).
Filling impairment reflects the change of two components of diastole, the chamber stiffness and the relaxation. All diastolic components are affected by the hypertrophy, the inactivation of myofibrils, intersistial fibrosis or amyloid deposition and ischaemia because of coronary flow delayed relaxation. Furthermore, some sarcomeric gene mutations (i.e.Troponin I gene mutations) can develop different phenotype and morphological heterogeneus diseases as hypertrofic, dilatated and restrictive cardiomyopathy. So the clinical and genetic overlap can furthermore make the differential diagnosis challenging.
This allows for some crossover as we attempt to characterize cardiomyopathy cases; for example case of hypertrophic cardiomyopathy with restrictive physiology.
Nevertheless, a misdiagnosis may often lead to inappropriate treatment with a very poor outcome.
To solve tricky case as this, clinicians should sharpen and share characteristics of ideal detectives as:

• Ability in observation
• Ability in “deduction”
• Culture (Knowledge)
• Ability to spot inconsistencies







Notes to editor

Department of Cardiology, Monaldi Hospital, Second University of Naples, Naples, Italy.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.