Male patient, 23 years-old, sought medical treatment for malaise, nausea, vomiting,
and
retrosternal burning pain for three days (09/25/2013). Two weeks before seeking medical
attention, the patient was diagnosed with a heart disease after an evaluation done
one
month before his complaint of malaise, for a research of dyspnea during physical effort
with progressive worsening. He stated to have been a cocaine user in the past, but
had
been clean for seven years.
Transthoracic two-dimensional echocardiogram (09/11/2013) showed: left atrium diameter
58
mm; left ventricle diameters (diast./syst.) 81 mm/ 72 mm, LVEF= 24%; accentuated diffuse
ventricular hypokinesis; restrictive filling pattern; moderate to severe mitral
insufficiency. The patient was prescribed: enalapril 1 omg, furosemide 40 mg,
spironolactone 25 mg, and carvedilol 6.25 mg daily.
Lab exams (09/19/2013) revealed: urea 48 mg/dL, creatinine 1.82 mg/dL, sodium 140
mEq/L,
potassium 4.8 mEq/L.
During the physical exam (09/25/2013), the patient presented regular overall condition,
acyanotic, afebrile, and hydrated; heart rate was 92 bpm; blood pressure was 80x60
mmHg,
arterial saturation 98%; pulmonary auscultation was normal; heart auscultation showed
the presence of third sound and regurgitant systolic murmur +++/6+ in mitral area;
abdominal exam was normal, and there was no edema in the lower limbs.
Electrocardiogram showed overload of the left chamber.
Lab exams (09/25/2013) revealed: CKMB 1.61 ng/mL, troponin I 0.447 ng/mL, urea 60
mg/dL,
creatinine 2 mg/dL, C-reactive protein 2.65 mg/L, sodium 139 mEq/L, potassium 4.3
mEq/L,
PT (INR) 1.3, PTT (rel) 0.87, hemoglobin 16.8 g/dL, hematocrit 49%, leukocytes
9100/mm3 (61% neutrophils, 1% eosinophils, 1% basophils, 30% lymphocytes,
and 7% monocytes), platelets 286000/mm3.
Toxicology screen (results obtained on October 10th) was positive for
benzodiazepine and ecstasy, negative for amphetamines, methamphetamines, cocaine,
opioids, barbiturates, and marijuana.
Chest X-Ray (09/29/2013) showed pronounced cardiomegaly with lung fields without
condensation (Fig. 1)
Figure 1
Chest X-Ray. Severe cardiomegaly, free lung fields.
A new echocardiographic evaluation (09/27/2013) showed aortic diameter of 27 mm, left
atrium diameter of 57 mm, mean right ventricle diameter of 31 mm, left ventricle
diameters (diast./syst.) 80/73, ejection fraction 20%, and septum and posterior wall
thickness of 9 mm. The left ventricle was diffusely hypokinetic, more pronounced in
the
inferior wall; there was accentuated mitral insufficiency by failure of coaptation
of
cusps, as well as indirect sings of pulmonary hypertension by the movement analysis
of
the sigmoid of the pulmonary valve; pericardium was normal. (Figures 2, 3, and 4)
Figure 2
Echocardiogram. A) Longitudinal parasternal view. Enlargement of left
ventricle and atrium; B) Apical four chamber view. Enlargement of the
ventricle with auto contrast in apical position.
Figure 3
Echocardiogram. A) Longitudinal parasternal view with Doppler. Severe mitral
insufficiency. B) Apical four chamber view and one-dimensional
echocardiogram of the left ventricle demonstrating paradoxical movement of
the interventricular septum.
Figure 4
Echocardiogram. Restrictive ventricular filling.
MRI (09/27/2013) showed: right atrium with normal dimensions, right ventricle with
pronounced dilatation (indexed end diastolic volume = 131 mL/m2, indexed end
systolic volume = 97 mL/m2) with depressed systolic function (EF=25%), and
accentuated enlargement of the left atrium and left ventricle, diameters (diast./syst.
96/83 mm and indexed end diastolic volume = 282 mL/m2, indexed end systolic
volume = 218 mL/m2), ejection fraction 23%, basal, mean and apical septal
hypokinesis, inferior akinesia and akinesia in mid-basal and inferolateral segments.
There was late mesocardial enhancement in all the mid-basal and apical septal walls
and
in the subepicardial of the mid-basal and inferolateral segments. The findings were
considered of a pattern non-secondary to ischemic event. Septum thickness was 9 mm
and
lateral wall thickness was 4 mm. There was also pericardial effusion with no filling
restrictions. (Figure 5)
Figure 5
A) Cardiac MRI. Dilated left ventricle and atrium, presence of pericardial
effusion, with no diastolic restriction. B) Cardiac MRI. Presence of late
mesocardial enhancement in the septum and transmural in the inferior
wall.
Abdominal ultrasound (10/02/2016) showed hepatomegaly of the right lobe, ectasia of
the
vena cava and hepatic veins, gallbladder with sludge, normal pancreas, spleen with
increased volume, topical kidneys, preserved dimensions (right kidney 10.5 cm and
left
kidney 11.5 cm, preserved thickness and bilateral hyperechogenicity.
Initially, the patient responded well to treatment, but with a lot of agitation and
anxiety. However, he later progressed with a worsening of the dyspnea and hypotension
attributed to a probable infection of pulmonary focus, requiring the use of vasopressor
amines at maximum doses, orotracheal intubation for mechanical ventilation and passage
of the intra-aortic balloon. He was initially treated with piperacillin and tazobactam,
with therapeutic amplification to vancomycin and meropenem and colistin and fluconazole
on October 15th. He progressed to dysfunction of multiple organs, including
kidney failure requiring continuous hemodialysis.
Table 1. Laboratory evolution
On October 15th, there was a need for a progressive increase of
vasopressors. Dialysis was recommended for kidney insufficiency and hyperkalemia,
but the patient did not tolerate it, and, after two hours, dialysis was stopped on
the night of October 17th 2013, and he received an association of
vasopressors as well as a correction of metabolic disorders. Despite high doses of
vasoactive drugs, with noradrenaline 3.0 mcg/kg/min, vasopressin 0.04 UI/min,
dobutamine 20 mcg/kg/min, intra-aortic balloon 1:1, the patient went into
cardiorespiratory arrest in pulseless electrical activity, and died at 00:45 on
October 18th, 2013.
Clinical aspects
This is the case of a young male patient with dilated cardiomyopathy of unknown
etiology. Didactically, we can investigate heart failure seeking anatomical and
functional alterations.
1
From the
anatomical perspective, the syndrome can stem from alterations in the myocardium,
endomyocardium, or pericardium. From the functional perspective, it can be caused
by
conduction disorders (tachyarrhythmia and bradyarrhythmia) or load disturbances
(volume overload, systemic hypertension, valve and structural diseases). Myocardial
injuries are the most the common causes. In this stratum lies the ischemic etiology.
Although there are no classic risk factors for stable coronary disease in this case,
ischemic etiology must be considered due to the history of illicit drug use. In
young individuals, in the context of acute coronary syndromes, there are mechanisms
other than classic coronary plaques, such as vasospasm, intracoronary
thrombosis
2
or spontaneous
dissection.
3
Other
myocardial injuries are not infrequent as a cause for ventricular dilatation, by
myocarditis (infectious or not), direct toxicity (use of recreational drugs), or
genetic dysfunctions (sporadic or familial). Guidelines for cardiac failure also
contemplate infiltrative diseases (by malignancy or not) or hormonal and nutritional
metabolic alterations.
1,2
From the epidemiological perspective, because this was a young patient with no
history of hypertension, dyslipidemia, diabetes, or smoking, the possibility of
chronic coronary disease is slim. We must keep in mind that the clinical history is
of a subacute disease, with classic symptoms of heart failure that started only one
month before, with a quick decline of ventricular function and patient stability.
Any case of new cardiac failure with major dysfunctions must include myocarditis
among its differential diagnoses.
4
The patient's history of illicit drug stands out, and brings hypotheses of direct
damage to the myocardium due to the drugs, which provoked coronary dysfunctions,
especially microcirculation. There is no history of previous viral conditions or
family history of heart disease.
The physical exam is not sufficiently detailed to converge the etiological diagnostic
hypotheses, but it proves that there is heart failure due to the presence of B3, one
of the major criteria of Framingham.
5
In the lab exams, the normality of plasma level of sodium, even
without adequate treatment time, can corroborate the subacute character of the
disease.
In the complementary investigation, electrocardiogram shows an overload of the left
chambers, not a typical pattern of any etiology. It is important to remember that
in
infiltrative diseases such as amyloidosis, for example, there is a reduction in QRS
voltage,
6
which does not
occur in this case. There are also no alterations related to previously described
ischemia, such as inactive areas. Even though the report does not mention serology
for Chagas disease, it is known that Chagas patients who progress with a worse
diagnosis, usually present alterations in the ECG with right bundle branch block and
blockage of the anterior superior division of the left branch.
7
Echocardiogram confirms the diagnostic hypothesis of heart failure, showing an
extremely dilated left ventricle, with segmental dysfunction in the inferior wall
and important systolic ventricular dysfunction. There are no alterations described
in the endomyocardium, which rules out restriction by endomyocardial fibrosis,
common in tropical countries. There are also no alterations described in the
pericardium, or data that suggest constriction. We also ruled out primary valve
alterations. Thin wall thickness does not match infiltrative and restrictive
diseases, and there were no restrictive diastolic patterns. Moreover, these diseases
rarely come with systolic dysfunction, and diastolic dysfunction is usually
predominant.
6
Thus, extreme
dilatation with segmental dysfunction suggests myocardial damage, be it by ischemia,
inflammation, or even primary dilated cardiomyopathy (DCM).
MRI findings confirm myocardial disease, with no anatomic alterations of the
pericardium or endomyocardium, and show late mesocardial enhancement in practically
the entire septal wall and late subepicardial enhancement in the inferolateral wall,
in the mid and basal segments. The inferior wall, akinetic and with late
enhancement, is extremely thin, hindering characterization regarding a transmural
pattern versus mesocardial pattern. Late enhancement in the MRI represents a
persistency in the impregnation by contrast, and suggest the presence of areas of
myocardial fibroses. When this scar is transmural, that is, covers the whole
myocardial wall thickness, we describe it as an ischemic pattern of enhancement.
Transmural enhancement can also occur by myocarditis, but we cannot rule out
ischemia with this pattern. On the other hand, non-transmural enhancement
(mesocardial or subepicardial) does suggest another etiology, such as myocarditis
or
non-ischemic cardiomyopathies, considering ischemic processes occur from the
endocardial to the epicardium.
6
With inflammatory diseases such as myocarditis, Lake Louise criteria have been
recently published, which have increased the accuracy of the diagnostic exam.
Together with late enhancement, we have another two criteria: T2 weighting and early
enhancement, both of which evidenced acute inflammation and muscle wall
edema.
8
Late enhancement in
isolation, as in this case, reduces exam specificity to 46% in myocarditis,
accepting an ample differential diagnosis.
8
Another condition that often presents late mesocardial
enhancement in wide areas is primary DCM itself, representing a poor prognosis for
this disease.
6
Regarding the doubt
faced by the team in relation to the inferior wall, it was not possible to establish
a precise diagnosis with this exam. Due to the use of drugs, the patient may have
presents inferior wall ischemia, and progressed with DCM by direct toxicity of other
myocardial regions. The patient may also have had DCM from a previous viral
myocarditis or idiopathic DCM and presents the inferior alteration due to the
extreme thinning of this regions.
Table 1
Lab exams
Exam
30 set
01 out 2013
15 out
17 out
Hemoglobin (g/dL)
12.6
13
10.3
8.7
Hematocrit (%)
38%
42
36
29
Leukocytes (/mm3)
6880
8590
17770
31440
Segmented (%)
69
75
68
57%
Metamyelocytes (%)
1
1
Rod cells (%)
18
22
Eosinophils (%)
1
1
1
1
Linocuts (%)
30
18
9
16
Monocytes (%)
7
5
2
3
Platelets/mm3
286000
168000
291000
228000
Sodium (mEq/L)
136
132
146
144
Potassium (mEq/L)
3.5
3.4
6.6
4.2
CK MB (ng/L)
0.83
Troponin I (ng/L)
0.406
Urea (mg/dL)
48
53
120
122
Creatinine (mg/dL)
1.85
1.91
3.62
2.01
PCR (mg/L)
28.8
136.25
119.59
Arterial Lactate (mg/dL)
11
11
53
99
Arterial gasometry
pH
7.19
7.15
pCO2 (mm Hg)
45.7
39.6
pO2 (mm Hg)
110
124
Sat. O2 (%)
98.4
98
HCO3 (mE/L)
16.8
13.2
Excess Base (mEqL)
- 10.7
- 14.2
AST (U/L)
20
366
1074
ALT (U/L)
30
64
960
Gamma GT (U/L)
118
104
206
FA (U/L)
66
84
76
Total bilirubin (m/dL)
2.51
3.24
Direct bilirubin (MG/dl)
1.26
2.24
PT (INR)
1.3
2.2
1.8
PTT (rel)
0.93
0.92
0.85
Density
1.032
Proteins (g/L)
3.31
Epithelial cells /mL
3000
Leukocytes/mL
8000
Erythrocytes/mL
23000
PCR: P reactive protein; AST: Aspartate aminotransferase; ALT: Alanine
aminotransferase; Gama GT: Gamma-glutamyl transpeptidase; FA: Alkaline
Phosphatase; PT: Prothrombin time; PTT: Partial thromboplastin time.
After MRI results, the assisting team obtained tox screen results: positive for
ecstasy and benzodiazepines. Regarding the patient's statement of being recently
clean of illicit drugs, a false positive is unlikely at this point because the blood
was collected before the ingestion of most medications that may have generated
crossed reactions in the results. Moreover, there are reports of considerable
agitation and anxiety from the patient throughout his stay, which can represent a
state of withdrawal from the previously used substances.
By conflating the several collected data, clinical history, and complementary tests,
we can suppose that our differentials were restricted to ischemic/toxicologic
cardiomyopathy caused by cocaine and ecstasy, leading to the differential diagnosis
of viral/inflammatory myocarditis and chronic phase of primary DCM.
In a case such as this one, of subacute heart failure refractory to clinical
treatment, it is recommended to perform a endomyocardial biopsy as a grade 1
recommendation and evidence level B in the Statement
9
of the American and European Societies published in
2007.
The incredibly fast evolution of the condition made it impossible to perform an
endomyocardial biopsy at that moment.
Cardiomyopathy associated to cocaine use is not yet fully understood. The incidence
is under 1% of DCMs, according to a study from the John Hopkins
University.
10
In
comparison to ecstasy, the cardiovascular pathophysiology related to cocaine is
better described in the literature. Its most notable effect is the nora-adrenergic
stimulatory action, which inhibits the reuptake of noradrenaline in the synaptic
clefts.
11
That promotes a
sympathetic discharge with vasoconstriction (alpha effect), and an increase in
cardiac frequency and contractility (beta effect).
11
Coronary risks become higher because there is more
oxygen consumption with a reduction of supply. Moreover, it was demonstrated, in
this context, an increase in thrombotic diathesis from platelet activation, release
of fibrinogen and Von Willebrand factor, as well as an increase of tissue
plasminogen activator inhibitors activity.
12,13
This combination
of factors increases the chance of intracoronary thrombosis.
13
Additionally, Wilbert-Lampen et
al.
14
have demonstrated an
increased release of endothelin in cocaine users, a powerful vasoconstrictor that
contributes to endothelial dysfunction in these patients. A study published in 1996
proved endothelial dysfunction in these patients as well as a worse flow response,
even without the context of acute intoxication, showing that endothelial alterations
in chronic users are persistent.
15
We can thus conclude that, even without atherosclerotic plaque, microcirculation
dysfunction, the potential of vasospasm and intracoronary thrombosis, and the
imbalance between oxygen supply and consumption provoked by the drug allow the
occurrence of acute myocardial infarction and, consequently, the appearance of
ischemic cardiomyopathy.
Although classically described and very important, alterations in coronaries and
microcirculation in cocaine users do not sufficiently explain cases of drug-related
DCM. Some hypotheses of direct toxic damage to the myocardium include lymphocytic
infiltrate, as well as an increase in intracellular levels of calcium due to the
beta-adrenergic stimulus, generating necrosis of the cardiomyocyte. Recently, an
Italian group demonstrated indications of the theory of oxidative stress generated
by the drug, propagating the myocardial lesion, as an activity of oxidative enzymes
and direct cellular damage markers.
16
Methylenedioxymethamphetamine, known as 'ecstasy', acts in the same way as
methamphetamines, except it is also linked to serotonin receptors.
17
Most amphetamine related DCM
patients are male, and the few reported cases were presented early with severe
dysfunction. In one of the few studies on this theme, Yeo et al.
18
observed an increased prevalence
of methamphetamine users in a young population (<45 years old) with idiopathic
DCM, generating a hypotheses that the drug may be a causal factor or an accelerator
of the disease. A recent review discussed the etiology of cardiomyopathy in
methamphetamine use.
19
The
variables that potentially cause dysfunctions are countless. Tachycardia, the state
of hyper stress, and catecholaminergic release are included. The same
pathophysiology of cocaine generates ischemia. There are also hypotheses described
regarding oxidative stress, pathway activation resulting in apoptosis, an increase
of calcium and intracellular free fatty acids.
19
(Dr. Fernando Faglioni Ribas)
Final comments and diagnostic hypothesis: Assuming this was a case of
DCM by a direct drug cardiotoxicity and related ischemic alterations, regardless of
the substance that caused them, the prognosis with such dilatation and fibroses is
limited.
5
Unfortunately,
the patient did not have a satisfactory outcome with the instituted therapeutic
measures, perhaps due to precipitating infectious factors, but that probably would
not result in the same way were it not for the established cardiac dysfunction. An
alarming increase in the number of illicit substance users
20
makes it pivotal that doctors have deep knowledge
of the pathophysiology of these diseases, their prevention and treatment.
(Dr. Fernando Fagliono Ribas)
Necropsy
During the necropsy, the heart showed accentuated dilatation with hypertrophy and
wall thickness close to normal (1.5 cm - normal up to 1.2 cm), that is, the so
called "eccentric" hypertrophy that accompanies dilatation (Figure 6), in which there
is a addition of sarcomeres in series.
The heart weighed 1038 g (normal between 350 and 400 g). There was myocardial
fibroses more located in the diaphragmatic wall (posterior, inferior) of the left
ventricle, accompanied by other areas of fibroses in all the chamber's walls -
especially in the medomural region - or by ischemic-pattern necrosis in
organization, with characteristics suggestive of an approximately two-week
evolution, especially in the subendocardial region (Figure 7). Coronary arteries did
not show significant obstruction or
thrombus (Figure 8).
Figure 6
Cross section of the heart showing acute dilatation and areas of
myocardial fibroses with whitish coloration; the arrow shows the largest
one, in the diaphragmatic wall (posterior, inferior) of the left
ventricle.
Figure 7
Histologic sections of the heart. A) area of fibrosis, stained in blue
(Masson’s trichrome staining method, objective magnification=1x; B)
microinfarction area in organization (staining by hematoxylin and eosin,
objective magnification=10X).
Figure 8
Histologic section of the coronary artery showing that the light does not
present a significant level of obstruction (Movat pentachromic staining
method, objectioev magnification=1X).
Considering the main cause of large cardiac dilatations is aortic valve
insufficiency,
21
it is
important to highlight that, in this patient, there was no such dysfunction. On the
other hand, there was insufficiency of both atrioventricular valves, possibly as a
result of dilatations and valve rings. In the other organs, there were signs of
severe congestive heart failure, with chronic passive congestion of the lungs and
liver and acute lung edema, which led to cardiogenic shock, with prerenal acute
renal failure (because there was no acute tubular necrosis) and hepatocyte necrosis
in the centrilobular region. Shock was the final factor that lead to the patient's
death.
The patient had a history of bronchopneumonia, which must have been adequately
treated, because, during the necropsy, there were only focal areas with compatible
aspects with suspected resolved bronchopneumonia.
(Dr. Paulo Sampaio Gutierrez)
Comment
The main question brought by this case is the difficulty, even with the necropsy,
of
establishing a differential diagnosis between ischemic heart disease and idiopathic
DCM. The dilatation is enormous, with a weight over 1,000 grams.
21
There is no aortic insufficiency.
Morphological pattern of the myocardium is, to a certain extent, indicative of
ischemia, with fibrosis and areas of necrosis in organization, with a tendency to
be
transmural in the diaphragmatic wall, as shown by the MRI and the necropsy. The
aspect is compatible to a healed myocardial infarction. The other areas of ischemia
may be secondary to the heart failure caused by such infarction. On the other hand,
coronary arteries do not have any obstructive lesion; thus, the case can also fit
as
a case of DCM, with the necrosis, in this case, also being secondary to the increase
in the myocardial mass. Considering the absence of coronary obstruction and the
fibroses pattern that is not completely transmural, this last possibility may seem
the most adequate. To explain it, even without excluding the possibility that it
might be idiopathic, corresponding to a myocarditis that did not evolve or to
spontaneous vasospasm, we must consider the hypothesis of the drug use. The patient
reported to have been a cocaine user, even if in the past, and
methylenedioxymethamphetamine ('ecstasy') was found in his blood. There are reports
that both drugs can cause infarction by vasospasm or even fixed obstructive
lesions
22,23
and have also been associated to DCM.
24
(Dr. Paulo Sampaio Gutierrez)
Main disease: DCM (though we cannot completely rule out the possibility
of an ischemic disease), possibly related to drug use.
Cause of death: cardiogenic shock.
(Dr. Paulo Sampaio Gutierrez)
Editor da Seção: Alfredo José Mansur
(ajmansur@incor.usp.br)
Editores Associados: Desidério Favarato
(dclfavarato@incor.usp.br)
Vera Demarchi Aiello (anpvera@incor.usp.br)