Myocarditis and

Cardiomyopathies
Dr. Rejane Dillenburg, MD
Pediatric Cardiology
McMaster Childrens Hospital

Acute Myocarditis
definition and criteria

Defined on histology as inflammation of the

myocardium with myocellular necrosis
Gold standard dx: myocardial biopsy

Acute (active) phase: 14 leuc/mm2 + necrosis and

degeneration
Chronic phase: 14 leuc/mm2 without necrosis and
degeneration
No myocarditis: < 14 leuc/mm2

Etiology:

Infections: Cocksackie, adenovirus

Drugs / toxins / autoimmune / systemic diseases

Pathogenesis of myocarditis

3 distinct phases

Viral replication 7-10 days

Autoimmune: role for immunosuppressives
Dilated cardiomyopathy

Immunosuppression

Does it work?

Diagnosis of myocarditis

Recent onset heart failure and LV dysfunction with

no other cause
Clinical features are variable
Hx of flu-like illness or GI sx
Vague onset of tachypnea, dyspnea, tiredness,
general malaise
PE: resting tachycardia, resp distress, arrhythmias,
poor PP and perfusion, muffled heart sounds,
gallop, increased JVP, pulm/syst venous congestion
(rales/hepatomegaly)

Diagnosis of myocarditis

Presentation of myocarditis

Heart failure
Chest pain
Arrhythmias, conduction blocks
Aborted sudden death
Myocardial infarction
Asymptomatic

Outcomes are somewhat related to form of

presentation

KM curve according to presentation of

myocarditis
Myocardial infarction-like

Heart failure

Myocarditis or cardiomyopathy?

Historically, dx of DCM
included:
Clinical symptoms of
heart failure
Cardiac enlargement
(CXR, echo, radionuclide
scan, angiography)
Histopathology
More recently,
echocardiographic criteria
have been developed

Etiology of
DCM

Investigations

Screening tests for dilated LV

Non invasive cardiac

ECG, CXR, Echo

Blood testing

CBC, differential
ESR

Subunit of a thin filament of the contractile

apparatus
Cardiospecific and highly sensitive marker for
myocardial injury
Increases in 3-4 h and remains high 6-14 days

Myocardial biopsy

Lymphocytic myocarditis

Giant cell myocarditis

Giant cell myocarditis

Role of biopsy: problems

The fate of acute myocarditis btw spontaneous improvement and

evolution to DCM. Heart 2001:85:499-504

Role of biopsy: advantages

active myocarditis x non-specific

Treatment

General considerations
Met acidosis, tachycardia, arrhythmias (can be worsened
with digoxin), u/o, vent support
Inotropic agents
Beta-adrenergic agonists (dopamine, dobut)
Phosphodiesterase inhibitors (milrinone)
VAD, ECMO if severely ill
Afterload reducing agents
IV nitroprusside
Chronic: ACE inhibitors (hd and neurohorm effects)
Diuretics
Loop diuretics on continuous infusion
Thiazides
If hypoK: spironolactone (watch for interaction: ACEi
enhance K retention)
Anticoagulation with heparin, when LV FS < 20%
Immunosuppression
Transplant

Beta-blockers and carvedilol

mechanisms of beta-adrenoceptor antagonists in heart failure are not well
delineated
carvedilol is an alpha-1 and beta-blocker (ventricular remodeling, inhibits
excess sympathetic outflow and antioxidant)

J Heart Lung Transplant. 2004 Jul;23(7):832-8.

Carvedilol in children with cardiomyopathy: 3-year experience at a single institution.

Rusconi P, Gomez-Marin O, Rossique-Gonzalez M, Redha E, Marin JR, Lon-Young M, Wolff GS.
Department of Pediatrics, University of Miami School of Medicine, Miami, Florida 33101, USA.
[email protected]
BACKGROUND: Carvedilol reduces mortality and hospitalization in adults with congestive heart
failure. Limited information is available about its use in children. METHODS: We reviewed the
medical records of 24 children with dilated cardiomyopathy and left ventricular ejection fraction of
<or=40%, who were treated with carvedilol as adjunct therapy to angiotensin-converting enzyme
inhibitors, digoxin and diuretics. RESULTS: Carvedilol was initiated 14.3 +/- 23.3 (mean +/- SD)
months after the diagnosis of cardiomyopathy. Mean age at initiation of therapy was 7.2 +/- 6.4
years. The mean initial and maximum doses were 0.15 +/- 0.09 and 0.98 +/- 0.26 mg/kg/day.
Adverse effects occurred in 5 patients (21%). Two patients (8%) required discontinuation of the
drug within 5 weeks of the initial dose. The remaining 22 patients tolerated carvedilol for a mean
follow-up period of 26.6 +/- 14.7 months. Among these 22 patients, mean left ventricular ejection
fraction improved from 24.6 +/- 7.6% to 42.2 +/- 14.2% (p < 0.001), and mean sphericity index
from 0.86 +/- 0.11 to 0.74 +/- 0.10 (p < 0.001). New York Heart Association functional class
improved in 15 patients (68%). One patient (4%) died and 3 (14%) were transplanted.
CONCLUSIONS: Carvedilol, in addition to standard therapy for dilated cardiomyopathy in children
improves cardiac function and symptoms; it is well tolerated, with minimal adverse effects, but
close monitoring is necessary as it might worsen congestive heart failure and precipitate asthma.
Control studies are necessary to assess the effect of carvedilol on mortality and hospitalization
rates.
Carvedilol: mixed beta and alpha blockade (inotropic vasodilator)

Cardiol Young. 2003 Aug;13(4):333-6.

Modulation of neurohormonal activity after treatment of children in heart failure with

carvedilol.
Giardini A, Formigari R, Bronzetti G, Prandstraller D, Donti A, Bonvicini M, Picchio FM.
Pediatric Cardiology, Policlinico "S. Orsola", University of Bologna, Italy. [email protected]
BACKGROUND: In adults with heart failure, neurohormonal overstimulation is related to the
progression of the disease, and influences prognosis. beta-blockers, which modulate
neurohormonal activation, now play an essential role in the pharmacological management of heart
failure in adults, but their use in children is very limited. PATIENTS AND METHODS: To
investigate the effects of carvedilol administration on neurohormonal activation and left ventricular
function, carvedilol was added to standard treatment for heart failure in 9 patients with dilated
cardiomyopathy due to heart muscle disease. Standard treatment has been in place for at least 1
month. The protocol consisted in a baseline evaluation to assess neurohormonal activation, and
echocardiographic evaluation of left ventricular function. This was followed by a final evaluation at
12 months from carvedilol loading. Carvedilol was started at 0.05 mg/kg/day, and increased every
two weeks until the target dose of 0.8 mg/kg/day was reached. RESULTS: Carvedilol
administration was associated with a significant reduction in plasma norepinephrine (p = 0.00001),
dopamine (p = 0.0001), aldosterone (p = 0.00001) and activation of the renin-angiotensin system
(p = 0.0006). Similar reductions in vanilmandelic and homovanillic acid were noted. After 12
months, a positive remodeling took place, with significant reductions in end-diastolic (p = 0.004)
and end-systolic diameters (p = 0.009), and an increase in left ventricular ejection fraction (p =
0.001). No adverse effects needing reduction or interruption in the dosage were noted in the run-in
phase, nor in the period of maintenance. CONCLUSION: Carvedilol is a safe complement to
standard therapy for heart failure in children, allowing a significant reduction of neurohormonal
activation with evident benefits on both ventricular function and the clinical condition.

J Am Coll Cardiol. 2002 Dec 4;40(11):2034-8.

Delisting of infants and children from the heart transplantation waiting list after carvedilol
treatment.
Azeka E, Franchini Ramires JA, Valler C, Alcides Bocchi E.
Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo,
[email protected]
OBJECTIVES: We performed a prospective, randomized, double-blind, placebo-controlled study of
carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional
therapy. BACKGROUND: Little is known about the effects of carvedilol in youngsters with chronic HF and
severe left ventricular (LV) dysfunction. METHODS: We conducted a double-blind, placebo-controlled
study of 22 consecutive children with severe LV dysfunction. The children had chronic HF and left
ventricular ejection fraction (LVEF) <30%. Patients were randomly assigned to receive either placebo (8
patients) or the beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day,
followed-up for six months. RESULTS: During the follow-up and the up-titration period in the carvedilol
group, four patients died and one underwent heart transplantation. In patients receiving carvedilol
evaluated after six months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval
[CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001. Modified New York Heart Association
(NYHA) functional class improved in nine patients taken off the transplant waiting list. All nine patients
were alive at follow-up. In the placebo group, during the six-month follow-up, two patients died, and two
underwent heart transplantation. Four patients persisted with HF symptoms (NYHA functional class IV).
No significant change occurred in LVEF or fractional shortening. CONCLUSIONS: Carvedilol added to
standard therapy may reduce HF progression and improve cardiac function, allowing some youngsters to
be removed from the heart transplantation waiting list.

Amlodipin improves mortality and function in a murine model of myocarditis-dilated cardiomyopathy: The role of microvascular blood
flow ABSTRACT
Journal of Cardiac Failure, Volume 4, Issue 3, Supplement 1, September 1998, Page 47
Geoffrey Puley, Michael J. Sole, Fayez Dawood, Wen-Hu Wen, Michael Dodd and Peter Liu

Immunosuppression

Adult studies on immunosuppression

Immunosuppression

N Engl J Med. 1995 Aug 3;333(5):269-75. Related Articles, Links

Comment in:

N Engl J Med. 1995 Aug 3;333(5):312-3.

N Engl J Med. 1995 Dec 21;333(25):1713-4.
N Engl J Med. 1995 Dec 21;333(25):1713; author reply 1714.
N Engl J Med. 1995 Dec 21;333(25):1713; author reply 1714.

A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial
Investigators.
Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE.
Division of Cardiology, University of Utah, Salt Lake City.
BACKGROUND. Myocarditis is a serious disorder, and treatment options are limited. This trial was designed
to determine whether immunosuppressive therapy improves left ventricular function in patients with
myocarditis and to examine measures of the immune response as predictors of the severity and outcome of
disease. METHODS. We randomly assigned 111 patients with a histopathological diagnosis of myocarditis
and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined
with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of
prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left
ventricular ejection fraction at 28 weeks. RESULTS. In the group as a whole, the mean (+/- SE) left
ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P <
0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly
between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent
confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03
to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at
base line, and a shorter duration of disease, but not the treatment assignment, were positive independent
predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival
between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56
percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less
severe initial disease. CONCLUSIONS. Our results do not support routine treatment of myocarditis with
immunosuppressive drugs. Ventricular function improved regardless of whether patients received
immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory
response had less severe disease.

Myocarditis Treatment Trial Investigators.

Immunosuppression

111 patients, biopsy +, LV EF < 45%

Randomized to

Conventional
Conventional + immunosuppression 24 weeks

Immunosuppresion

Prednisone + cyclosporine
Prednisone + azathioprine

Outcome

Primary: LV EF at 28 wk : no difference
Secondary: mortality: no difference

Mortality rate 20% 1 yr; 56% at 4.3 yr

Immunosuppressive therapy does not

improve outcomes in children

Immunosuppresion

Immunoglobulin

Circulation, 1994;89:252-257: Gamma-Globulin Treatment of Acute Myocarditis in the

Pediatric Population. Drucker et al.
cohort with historical controls; 21 patients, 25 controls
High dose IVIG 2 g/kg over 24 h in addition to anticongestive therapies versus
conventional therapy
F/U 1,3,6,12 mo with significant LV function improvement in cases as compared to
controls.
At presentation,the IVIG and non-IVIG groups had comparable left ventricular
enlargement and poor fractional shortening. Compared with the non-IVIG group,
those treated with IVIG had a smaller mean adjusted left ventricular end-diastolic
dimension and higher fractional shortening in the periods from 3 to 6 months (P=.008
and P=.033, respectively) and 6 to 12 months (P=.072 and P=.029, respectively).
When adjusting for age, biopsy status, intravenous inotropic agents, and angiotensinconverting enzyme inhibitors, patients treated with IVIG were more likely to achieve
normal left ventricular function during the first year after presentation (P=.03).
By 1 year after presentation, the probability of survival tended to be higher among
IVIG-treated patients (.84 versus.60, P=.069). We observed no adverse effects of
IVIG administration.
Conclusions These data suggest that use of high-dose IVIG for treatment of acute
myocarditis is associated with improved recovery of left ventricular function and with
a tendency to better survival during the first year after presentation.

Evidence on IVIG: adult cohort shows no

significant difference in DCM

More on immunosuppression

Myocarditis >>>>> cardiomyopathy

F/U studies: Myocarditis >>> DCM

Variable progression to DCM in different

studies: 14-52%

Progression myocarditis >>> DCM

Persistence of viruses may lead to dilated

cardiomyopathy

Persistent viral genome in myocardium

Viral persistence

Outcomes

How many improve?

Spontaneous improvement

KM for DCM in children

Outcome according to presentation.

Heart 2001;85:499-504

Factors in prognosis

Knowledge of type of presentation may be

helpful
Patients with chest pain or advanced AV
block at onset had good prognosis on long
term, none had DCM

Factors in prognosis

Predictors of outcome
LV function
ECG abnormalities (BBB)
Syncope (unfavourable)

Factors in prognosis
McCarthy

Unfavourable predictors of outcome

Positive serology for Cocksackie B in one

study, not confirmed by others
QRS alterations
A Fib
Low voltages
Histological pattern on biopsy suggested by
one study, not confirmed by same
investigator subsequently

Molecular biologic predictors

Conclusions

Biopsy is gold standard, but needs to be

early and has complications
Immunosuppression: no clear evidence of
benefit
Standard treatment: ACEi, diuretics
Carvedilol improves LV function and delays
tx