Heart Failure: Management

1951CHAPTER 258

Failure (SADHART-CHF) trial, showed that although sertraline was

safe, it did not provide greater reduction in depression or improve cardiovascular status among patients with HF and depression compared

with nurse-driven multidisciplinary management.

Atrial arrhythmias, especially atrial fibrillation, are common and

serve as a harbinger of worse prognosis in patients with HF. When rate

control is inadequate or symptoms persist, pursuing a rhythm control

strategy is reasonable. Rhythm control may be achieved via pharmacotherapy or by percutaneous or surgical techniques, and referral to practitioners or centers experienced in these modalities is recommended.

Antiarrhythmic drug therapy should be restricted to amiodarone and

dofetilide, both of which have been shown to be safe and effective but

do not alter the natural history of the underlying disease. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive

Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) studied

the effects of the novel antiarrhythmic agent dronedarone and found

an increased mortality due to worsening HF. Catheter ablation and

pulmonary vein isolation appear to be safe and effective in this highrisk cohort and compare favorably with the more established practice

of atrioventricular node ablation and biventricular pacing.

Diabetes mellitus is a frequent comorbidity in HF. Prior studies

using thiazolidinediones (activators of peroxisome proliferatoractivated receptors) have been associated with worsening HF. Glucagonlike peptide 1 (GLP-1) agonists such as liraglutide have also been tested

and do not lead to greater post-hospitalization, clinical stability, or

worsening in HF. The role of SGLT-2 inhibitors in HF has been previously discussed.

■ NEUROMODULATION USING DEVICE THERAPY

Autonomic dysfunction is common in HF, and attempts at using

devices to modulate the sympathetic and parasympathetic systems

have been undertaken. Broadly, devices that achieve vagal nerve stimulation, baroreflex activation, renal sympathetic denervation, spinal

cord stimulation, or left cardiac sympathetic denervation have been

employed. While small preclinical and clinical studies have demonstrated benefits, large randomized trials, when conducted, have failed.

The INOVATE-HF study tested vagal nerve stimulation versus optimal medical therapy among individuals with stable HF. Vagus nerve

stimulation did not reduce the rate of death or hospitalization for HF.

However, functional capacity and QOL were favorably affected by

vagus nerve stimulation.

■ CARDIAC CONTRACTILITY MODULATION

Cardiac contractility modulation (CCM) is a device-based therapy for

HF that involves nonexcitatory electrical stimulation to the right ventricular septal wall during the absolute myocardial refractory period to

augment the strength of subsequent myocardial contraction. A series

of small, randomized, prospective clinical trials, as well as a number of

real-world observational registries, have suggested that application of

CCM to selected patients with HF may improve symptoms, functional

capacity, and QOL, although no effect on hard clinical outcomes such

as HF hospitalization or mortality has been established. The predominant benefits of CCM appear to accrue to those with symptomatic

HFrEF (EF 25–45%) and narrow QRS duration (for whom cardiac

resynchronization therapy is not an option), and the approach can be

combined with an implantable defibrillator. The device is currently

available for use in selected patients with HFrEF outside the United

States but is not currently endorsed by clinical treatment guidelines

in the United States or Europe as part of the routine HF treatment

armamentarium.

CARDIAC RESYNCHRONIZATION THERAPY

Nonsynchronous contraction between the walls of the left ventricle

(intraventricular) or between the ventricular chambers (interventricular) impairs systolic function, decreases mechanical efficiency of

contraction, and adversely affects ventricular filling. Mechanical dyssynchrony results in an increase in wall stress and worsens functional

mitral regurgitation. The single most important association of extent of

dyssynchrony is a widened QRS interval on the surface electrocardiogram, particularly in the presence of a left bundle branch block pattern.

With placement of a pacing lead via the coronary sinus to the lateral

wall of the ventricle, cardiac resynchronization therapy (CRT) enables

a more synchronous ventricular contraction by aligning the timing

of activation of the opposing walls. Early studies showed improved

exercise capacity, reduction in symptoms, and evidence of reverse

remodeling. The Cardiac Resynchronization in Heart Failure Study

(CARE-HF) trial was the first study to demonstrate a reduction in allcause mortality with CRT placement in patients with HFrEF on optimal therapy with continued moderate-to-severe residual symptoms of

NYHA class III or IV HF. More recent clinical trials have demonstrated

disease-modifying properties of CRT in even minimally symptomatic

patients with HFrEF, including the Resynchronization–Defibrillation

for Ambulatory Heart Failure Trial (RAFT) and Multicenter Automatic

Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), both of which sought to use CRT in combination

with an implantable defibrillator. Most benefit in mildly symptomatic

HFrEF patients accrues from applying this therapy in those with a QRS

width of >149 ms and a left bundle branch block pattern. Attempts to

further optimize risk stratification and expand indications for CRT

using modalities other than electrocardiography have proven disappointing. In particular, echocardiographically derived measures of

dyssynchrony vary tremendously, and narrow QRS dyssynchrony has

not proven to be a good target for treatment. Uncertainty surrounds

the benefits of CRT in those with ADHF, a predominant right bundle branch block pattern, atrial fibrillation, and evidence of scar in

the lateral wall, which is the precise location where the CRT lead is

positioned.

SUDDEN CARDIAC DEATH PREVENTION IN

HEART FAILURE

Sudden cardiac death (SCD) due to ventricular arrhythmias is the

mode of death in approximately half of patients with HF and is particularly proportionally prevalent in HFrEF patients with early stages

of the disease. Patients who survive an episode of SCD are considered

to be at very high risk and qualify for placement of an implantable

cardioverter-defibrillator (ICD). Although primary prevention is challenging, the degree of residual left ventricular dysfunction despite

optimal medical therapy (≤35%) to allow for adequate remodeling

and the underlying etiology (post–myocardial infarction or ischemic

cardiomyopathy) are the two single most important risk markers for

stratification of need and benefit. Currently, patients with NYHA class

II or III symptoms of HF and an LVEF <35%, irrespective of etiology

of HF, are appropriate candidates for ICD prophylactic therapy. In

patients with a myocardial infarction and optimal medical therapy with

residual LVEF ≤30% (even when asymptomatic), placement of an ICD

is appropriate. A recent Danish trial suggested that prophylactic ICD

implantation in patients with symptomatic systolic HF not caused by

coronary artery disease was not associated with a significantly lower

long-term rate of death from any cause than was usual clinical care. In

this trial, benefits were noted in those aged <60 years. In patients with a

terminal illness and a predicted life span of <6 months or in those with

NYHA class IV symptoms who are refractory to medications and who

are not candidates for transplant, the risks of multiple ICD shocks must

be carefully weighed against the survival benefits. If a patient meets

the QRS criteria for CRT, combined CRT with ICD is often employed

(Table 258-3).

SURGICAL THERAPY IN HEART FAILURE

Coronary artery bypass grafting (CABG) is considered in patients

with ischemic cardiomyopathy with multivessel coronary artery

disease. The recognition that hibernating myocardium, defined as

myocardial tissue with abnormal function but maintained cellular

function, could recover after revascularization led to the notion

that revascularization with CABG would be useful in those with

living myocardium. Revascularization is most robustly supported

in individuals with ongoing angina and left ventricular failure.

1952 PART 6 Disorders of the Cardiovascular System

Revascularizing those with left ventricular failure in the absence of

angina remains controversial. The Surgical Treatment for Ischemic

Heart Failure (STICH) trial in patients with an EF of ≤35% and

coronary artery disease amenable to CABG demonstrated no significant initial benefit compared to medical therapy. However, patients

assigned to CABG had lower rates of death from cardiovascular

causes and of death from any cause or hospitalization for cardiovascular causes over 10 years than among those who received medical

therapy alone. An ancillary study of this trial also determined that

the detection of hibernation (viability) pre-revascularization did not

materially influence the efficacy of this approach, nor did it help

to define a population unlikely to benefit if hibernation was not

detected.

Surgical ventricular restoration (SVR), a technique characterized by infarct exclusion to remodel the left ventricle by reshaping it

surgically in patients with ischemic cardiomyopathy and dominant

anterior left ventricular dysfunction, has been proposed. However,

in a 1000-patient trial in patients with HFrEF who underwent CABG

alone or CABG plus SVR, the addition of SVR to CABG had no disease-modifying effect. However, left ventricular aneurysm surgery is

still advocated in those with refractory HF, ventricular arrhythmias,

or thromboembolism arising from an akinetic aneurysmal segment of

the ventricle. Other remodeling procedures, such as use of an external

mesh-like net attached around the heart to limit further enlargement,

have not been shown to provide hard clinical benefits, although favorable cardiac remodeling was noted.

Functional (or secondary) mitral regurgitation (MR) occurs with

varying degrees in patients with HFrEF and dilated ventricles, and

its severity is correlated inversely with prognosis. Annular dilatation

and leaflet noncoaptation related to distorted papillary muscle geometry in the context of ventricular remodeling is typically responsible,

although in patients with ischemic heart disease and prior myocardial

infarction, leaflet tethering and displacement may contribute. The

primary approach to management of functional MR is optimization

of guideline-directed medical therapy, followed by CRT in eligible

patients, but relief may be incomplete for many patients with advanced

HF. In these patients with HF and severe left ventricular dysfunction who are not candidates for surgical coronary revascularization,

surgical mitral valve repair (MVR) to remedy functional MR carries

significant risk and remains controversial. The development of percutaneous approaches to edge-to-edge MVR has provided a less invasive

approach that enables reduction in functional MR at lower risk than

conventional surgery. Recently, two large randomized trials of transcatheter MVR using this approach have been conducted in patients

with symptomatic HFrEF and moderate-severe functional MR. In the

Cardiovascular Outcomes Assessment of the MitraClip Percutaneous

Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) study, patients allocated to MVR versus standard HF

therapy experienced a marked reduction in both HF hospitalizations

and mortality at 2 years, supporting the efficacy of this approach. In the

second trial, Percutaneous Repair with the MitraClip Device for Severe

Functional/Secondary Mitral Regurgitation (MITRA-FR), which

employed a similar design, the rates of death or HF hospitalization

did not differ between the percutaneous MVR and medical therapy

groups. The precise reason for discrepant results between these studies

remains unclear but may be related to differences in background utilization of guideline-directed medical therapy, procedural success rates,

and patient selection (particularly whether or not the severity of MR

is proportionate or disproportionate to the degree of left ventricular

cavity dilation). Because mortality rates at 2 years remain high even

with percutaneous MVR, patients with advanced symptoms of HF in

whom MR severity is driven principally by end-stage left ventricular

remodeling should also be considered for advanced therapies such as

mechanical circulatory support.

CELLULAR AND GENE-BASED THERAPY

The cardiomyocyte possesses regenerative capacity, and such renewal

is accelerated under conditions of stress and injury, such as an ischemic event or HF. Investigations that use either bone marrow–derived

precursor cells or autologous cardiac-derived cells have gained traction

but have not generally improved clinical outcomes in a convincing

manner. More promising, however, are cardiac-derived stem cells. Two

preliminary pilot trials delivering cells via an intracoronary approach

have been reported. In one, autologous c-kit–positive cells isolated

from the atria obtained from patients undergoing CABG were cultured

and reinfused. In another, cardiosphere-derived cells grown from endomyocardial biopsy specimens were used. These small trials demonstrated improvements in left ventricular function but require far more

work to usher in a clinical therapeutic success. Efforts to utilize mesenchymal stem cells to facilitate left ventricular recovery and weaning

from mechanical circulatory support in patients with left ventricular

assist devices have also been disappointing. The appropriate route of

administration, the quantity of cells to achieve a minimal therapeutic

threshold, the constitution of these cells (single source or mixed), the

mechanism by which benefit accrues, and short- and long-term safety

remain to be elucidated.

Targeting molecular aberrations using gene transfer therapy, mostly

with an adenoviral vector, has been tested in HFrEF. A cellular target

includes calcium cycling proteins such as inhibitors of phospholamban

such as SERCA2a, which is deficient in patients with HFrEF. Primarily

responsible for reincorporating calcium into the sarcoplasmic reticulum during diastole, this target was tested in the CUPID (Efficacy and

Safety Study of Genetically Targeted Enzyme Replacement Therapy for

Advanced Heart Failure) trial. This study used coronary arterial infusion of adeno-associated virus type 1 carrying the gene for SERCA2a

and initially demonstrated that natriuretic peptides were decreased,

reverse remodeling was noted, and symptomatic improvements were

forthcoming. However, a confirmatory trial failed to meet its primary

efficacy endpoint.

More advanced therapies for late-stage HF such as left ventricular

assist devices and cardiac transplantation are covered in detail in

Chap. 260.

DISEASE MANAGEMENT AND

SUPPORTIVE CARE

Despite stellar outcomes with medical therapy, admission rates following HF hospitalization remain high, with nearly half of all patients

readmitted to hospital within 6 months of discharge. Recurrent HF and

related cardiovascular conditions account for only half of readmissions

in patients with HF, whereas other comorbidity-related conditions

account for the rest. The key to achieving enhanced outcomes must

begin with the attention to transitional care at the index hospitalization

with facilitated discharge through comprehensive discharge planning,

TABLE 258-3 Principles of ICD Implantation for Primary Prevention

of Sudden Death

PRINCIPLE COMMENT

Arrhythmia–sudden

death mismatch

Sudden death in heart failure patients is generally due

to progressive LVD, not a focal arrhythmia substrate

(except in patients with post-MI HF)

Diminishing returns

with advanced disease

Intervention at early stages of HF most successful

since sudden death diminishes as cause of death with

advanced HF

Timing of benefits LVEF should be evaluated on optimal medical therapy

or after revascularization before ICD therapy is

employed; no benefit to ICD implant within 40 days of

an MI (unless for secondary prevention)

Estimation of benefits

and prognosis

Patients and clinicians often overestimate benefits of

ICDs; an ICD discharge is not equivalent to an episode

of sudden death (some ventricular arrhythmias

terminate spontaneously); appropriate ICD discharges

are associated with a worse near-term prognosis

Abbreviations: HF, heart failure; ICD, implantable cardioverter-defibrillator; LVD,

left ventricular disease; LVEF, left ventricular ejection fraction; MI, myocardial

infarction.

Heart Failure: Management

1953CHAPTER 258

patient and caregiver education, appropriate use of visiting nurses,

and planned follow-up. Early postdischarge follow-up, whether by

telephone or clinic-based, may be critical to ensuring stability because

most HF-related readmissions tend to occur within the first 2 weeks

after discharge. Although routinely advocated, intensive surveillance

of weight and vital signs with use of telemonitoring has not decreased

hospitalizations. Serial measurement of intrathoracic impedance has

been utilized to identify early signals of worsening congestion to guide

preemptive management to obviate the need for hospitalization. However, when systematically studied in randomized trials, this approach

has not been proven to improve outcomes in comparison with routine

HF care and may even enhance the rate of hospitalization due to the

high frequency of impedance threshold crossings and device alerts.

Implantable hemodynamic monitoring systems that directly measure

pulmonary artery pressure tend to provide signals for early decompensation, and in patients with HF and moderately advanced symptoms

across the full spectrum of EF, such systems have been shown to provide information that can allow implementation of therapy to avoid

hospitalizations by as much as 39% (in the CardioMEMS Heart Sensor

Allows Monitoring of Pressure to Improve Outcomes in NYHA Class

III Heart Failure Patients [CHAMPION] trial). Whether this reduction in hospital admissions translates into a long-term reduction in

mortality remains to be determined by ongoing trials (Hemodynamic

Guided Management of Heart Failure [GUIDE-HF]; clinicaltrials.

gov identifier: NCT03387813). Alternate approaches to longitudinal

HF monitoring that leverage multiparameter signals derived from

implantable cardiac rhythm devices such as pacemakers and defibrillators to provide a global index of congestion are also being explored

as adjuncts to longitudinal HF management (Multiple Cardiac Sensors

for the Management of Heart Failure [MANAGE-HF]; clinicaltrials.

gov identifier: NCT03237858).

Once HF becomes advanced, regularly scheduled review of the

disease course and options with the patient and family is recommended, including discussions surrounding end-of-life preferences

when patients are comfortable in an outpatient setting. As the disease

state advances further, integrating care with social workers, pharmacists, and community-based nursing may be critical in improving

patient satisfaction with the therapy, enhancing QOL, and avoiding HF

hospitalizations. Equally important is attention to seasonal influenza

vaccinations and periodic pneumococcal vaccines that may obviate

non-HF hospitalizations in these ill patients. When nearing end of life,

facilitating a shift in priorities to outpatient and hospice palliation is

key, as are discussions around advanced therapeutics and continued

use of ICD prophylaxis, which may worsen QOL and prolong death.

Small randomized trials have suggested that systematic integration of

palliative care considerations in high-risk HF patients by a specialized

team has been demonstrated to improve QOL, anxiety, depression, and

spiritual well-being and to facilitate goal-concordant care.

GLOBAL CONSIDERATIONS

Substantial differences exist in the practice of HF therapeutics and

outcomes by geographic location. The penetrance of CRT and ICD

is higher in the United States than in Europe. Conversely, therapy

unavailable in the United States, such as levosimendan, is designated

as useful in Europe. Variation in the benefits of beta blockers based

on world region remains an area of controversy. In oral pharmacologic

therapy trials of HFrEF, patients from southwest Europe have a lower

incidence of ischemic cardiomyopathy and those in North America

tend to have more diabetes and prior coronary revascularization. There

is also regional variation in medication use even after accounting for

indication. In trials of HF, disparate effects are noted across populations. As a recent example, in TOPCAT, the drug spironolactone

was effective when used in the U.S. population, whereas patients

recruited from Russia and contiguous territories showed no difference.

Whether this represents population differences or trial conduct disparity remains to be investigated. ADHF patients in Eastern Europe

tend to be younger, with higher EFs and lower natriuretic peptide

levels. Patients from South America tend to have the lowest rates of

comorbidities, revascularization, and device use. In contrast, patients

from North America have the highest comorbidity burden with high

revascularization and device use rates. Given geographic differences

in baseline characteristics and clinical outcomes, the generalizability

of therapeutic outcomes in patients in the United States and Western

Europe may require verification.

■ FURTHER READING

Borlaug BA: The pathophysiology of heart failure with preserved

ejection fraction. Nat Rev Cardiol 11:507, 2014.

Braunwald E: Heart failure. JACC Heart Fail 1:1, 2013.

Braunwald E: The war against heart failure: The Lancet lecture. Lancet 385:812, 2015.

Hein AM et al: Medical management of heart failure with reduced

ejection fraction in patients with advanced renal disease. JACC Heart

Fail 7:371, 2019.

Hollenberg SM et al: 2019 ACC Expert Consensus Decision Pathway

on Risk Assessment, Management, and Clinical Trajectory of Patients

Hospitalized with Heart Failure: A Report of the American College

of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol

74:1966, 2019.

Hussein AA, Wilkoff BL: Cardiac implantable electronic device therapy in heart failure. Circ Res 124:1584, 2019.

Kusumoto FM et al: HRS/ACC/AHA expert consensus statement on

the use of implantable cardioverter-defibrillator therapy in patients

who are not included or not well represented in clinical trials. Circulation 130:94, 2014.

Lam CS et al: Heart failure with preserved ejection fraction: From

mechanisms to therapies. Eur Heart J 39:2780, 2018.

Maddox TM et al: 2021 Update to the 2017 ACC Expert Consensus

Decision Pathway for Optimization of Heart Failure Treatment:

Answers to 10 Pivotal Issues About Heart Failure with Reduced

Ejection Fraction: A Report of the American College of Cardiology

Solution Set Oversight Committee. J Am Coll Cardiol 77:772, 2021.

McMurray JJ et al: PARADIGM-HF Investigators and Committees.

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

N Engl J Med 371:993, 2014.

McMurray JJV et al: Dapagliflozin in patients with heart failure and

reduced ejection fraction. N Engl J Med 381:1995, 2019.

Obadia JF et al: Percutaneous mitral valve repair or medical therapy

for secondary mitral regurgitation. N Engl J Med 379:2297, 2018.

Packer M, Grayburn PA: Neurohormonal and transcatheter repair

strategies for proportionate and disproportionate functional mitral

regurgitation in heart failure. JACC Heart Fail 7:518, 2019.

Packer M et al: Cardiovascular and renal outcomes with empagliflozin

in heart failure. N Engl J Med 383:1413, 2020.

Parikh KS et al: Heart failure with preserved ejection fraction expert

panel report: Current controversies and implications for clinical trials. JACC Heart Fail 6:619, 2018.

Pfeffer MA et al: Heart failure with preserved ejection fraction in

perspective. Circ Res 124:1598, 2019.

Solomon SD et al: Angiotensin-neprilysin inhibition in heart failure

with preserved ejection fraction. N Engl J Med 381:1609, 2019.

Stone GW et al: Transcatheter mitral valve repair in patients with

heart failure. N Engl J Med 379:2307, 2018.

Teerlink JR et al: Cardiac myosin activation with omectamtiv mecarbil in

systolic heart failure. N Engl J Med 384:105, 2021.

Velazquez EJ et al: STICHES Investigators. Coronary-artery bypass

surgery in patients with ischemic cardiomyopathy. N Engl J Med

374:1511, 2016.

1954 PART 6 Disorders of the Cardiovascular System

■ DEFINITION AND CLASSIFICATION

Cardiomyopathy is disease of the heart muscle. It is estimated that

cardiomyopathy accounts for 5–10% of the heart failure in the

5–6 million patients carrying that diagnosis in the United States. This

term is intended to exclude cardiac dysfunction that results from other

structural heart disease, such as coronary artery disease, primary valve

disease, or severe hypertension; however, in general usage, the phrase

ischemic cardiomyopathy is sometimes applied to describe diffuse

dysfunction attributed to multivessel coronary artery disease, and

nonischemic cardiomyopathy is used to describe cardiomyopathy from

other causes. As of 2013, cardiomyopathies are defined as “disorders

characterized by morphologically and functionally abnormal myocardium in the absence of any other disease that is sufficient, by itself,

to cause the observed phenotype.” It was further specified that many

cardiomyopathies will be attributable to genetic disease.1

The traditional classification of cardiomyopathies into a triad of

dilated, restrictive, and hypertrophic was based initially on autopsy

specimens and later on echocardiographic findings. Dilated and

hypertrophic cardiomyopathies can be distinguished on the basis of

left ventricular wall thickness and cavity dimension; however, restrictive cardiomyopathy can have variably increased wall thickness and

chamber dimensions that range from reduced to slightly increased,

with prominent atrial enlargement. Restrictive cardiomyopathy is now

defined more on the basis of abnormal diastolic function, which is also

present but initially less prominent in dilated and hypertrophic cardiomyopathy. Restrictive cardiomyopathy can overlap in presentation,

gross morphology, and etiology with both hypertrophic and dilated

cardiomyopathies (Table 259-1).

Expanding information renders this classification triad based on

phenotype increasingly inadequate to define disease or therapy. While

dilated cardiomyopathy is associated with low left ventricular ejection

fraction and hypertrophic cardiomyopathy with normal or high ejection fraction, efforts to define intermediate phenotypes based on arbitrary thresholds for mid-range ejection fraction are confounded by the

increasing prevalence of patients whose low ejection has improved with

contemporary therapies. Identification of more genetic determinants

of cardiomyopathy has suggested a four-way classification scheme

of etiology as primary (affecting primarily the heart) and secondary

to other systemic disease. The primary causes are then divided into

genetic, mixed genetic and acquired, and acquired. In practice, however, genetic information is rarely available at initial presentation, the

phenotypic expression of a given mutation varies widely, and acquired

cardiomyopathies may also be influenced by genetic predisposition,

which can be monogenic or polygenic, to establish a “two-hit” etiology. Identification of genetic causes of cardiomyopathy will become

increasingly relevant as classification moves beyond morphology to

identify specific molecular targets for intervention.

GENERAL PRESENTATION

The early symptoms of cardiomyopathy often reflect exertional intolerance with breathlessness or fatigue. As filling pressures become elevated at rest, shortness of breath may occur during routine activity or

when lying down at night. Although often considered the hallmark of

congestion, peripheral edema may be absent despite severe fluid retention, particularly in younger patients in whom abdominal discomfort

from hepato-splanchnic congestion and ascites may dominate. Patients

259 Cardiomyopathy and

Myocarditis

Neal K. Lakdawala, Lynne Warner Stevenson,

Joseph Loscalzo

may also present initially with atypical chest pain, with palpitations or

syncope related to associated rhythm disorders, or with an embolism

from an intracardiac thrombus. Acute cardiogenic shock is the primary

presentation for fulminant myocarditis, which can occur in otherwise

healthy young adults and require rapid diagnosis and aggressive support, after which cardiac function may improve to near-normal levels.

The nonspecific term congestive heart failure describes only the

resulting syndrome of fluid retention, which is common to all three

structural phenotypes of cardiomyopathy and also to other cardiac

structural diseases, such as mitral valve disease, that are associated with

elevated intracardiac filling pressures. Initial evaluation begins with

a detailed clinical history and examination seeking clues to cardiac,

extracardiac, and genetic causes of heart disease (Tables 259-1 and

259-2). Echocardiography remains the initial imaging modality, with

increasing use of MRI to provide further information on myocardial

tissue characterization and evidence of focal and diffuse inflammation

and abnormal interstitium.

■ GENETIC CAUSES OF CARDIOMYOPATHY

Estimates for the prevalence of a genetic etiology for cardiomyopathy continue to rise, with increasing availability of genetic

testing and attention to the family history. Well-recognized in

hypertrophic cardiomyopathy, heritability is also present in at least 30%

of dilated cardiomyopathy (DCM) without other clear etiology. Careful

family history should elicit information about not only known cardiomyopathy and heart failure, but also family members who have had

sudden death, often incorrectly attributed to “a massive heart attack,”

who have had atrial fibrillation or pacemaker implantation by middle

age, or who have muscular dystrophy.

Most familial cardiomyopathies are inherited in an autosomal

dominant pattern, with occasional autosomal recessive, matrilineal

(mitochondrial), and X-linked inheritance (Table 259-3). Missense

mutations with amino acid substitutions and truncating variants are

the most common genetic abnormalities in cardiomyopathy. Expressed

mutant proteins may interfere with function of the normal allele

through a dominant negative mechanism. Mutations introducing a

premature stop codon (nonsense) or shift in the reading frame (frameshift) may create a truncated or unstable protein, the lack of which

causes cardiomyopathy (haploinsufficiency). Deletions or duplications

of an entire exon or gene are uncommon causes of cardiomyopathy,

except for the dystrophinopathies.

Many different genes have been implicated in human cardiomyopathy (locus heterogeneity), and many mutations within those genes

have been associated with disease (allelic heterogeneity). Although

most identified mutations are “private” to individual families, several

specific mutations are found repeatedly, either due to a founder effect

or recurrent mutations at a common residue.

Genetic cardiomyopathy is characterized by age-dependent and

incomplete penetrance. The defining phenotype of cardiomyopathy is

rarely present at birth and, in some individuals, may never manifest.

Related individuals who carry the same mutation may differ in the

severity and rate of progression of cardiac dysfunction and associated

rhythm disorders, indicating the important role of other genetic,

epigenetic, and environmental modifiers in disease expression. Sex

appears to play a role, as penetrance and clinical severity may be

greater in men for most cardiomyopathies. Clinical disease expression

is generally more severe in the ~1% of individuals who harbor two or

more mutations linked to cardiomyopathy. However, the clinical course

of a patient usually cannot be predicted based on which mutation is

present; thus, current therapy is based on the phenotype rather than

the genetic defect. Currently, the greatest utility of genetic testing for

cardiomyopathy is to inform family evaluations. However, genetic testing occasionally enables the detection of a disease for which specific

therapy is indicated, such as the replacements for defective metabolic

enzymes in Fabry’s disease and Gaucher’s disease.

■ GENES AND PATHWAYS IN CARDIOMYOPATHY

Mutations in sarcomeric genes, encoding the thick and thin myofilament proteins, are the best characterized. While the majority are 1

From E Arbustini et al: J Am Coll Cardiol 62:2046, 2013.

Cardiomyopathy and Myocarditis

1955CHAPTER 259

associated with hypertrophic cardiomyopathy, sarcomeric mutations

are also implicated in DCM, and some in left ventricular noncompaction. The most commonly recognized genetic causes of DCM are

truncating mutations of the giant protein titin, encoded by TTN, which

maintains sarcomere structure and acts as a key signaling molecule.

As cytoskeletal proteins play crucial roles in the structure, connection, and stability of the myocyte, multiple defects in these proteins can

lead to cardiomyopathy, usually with a dilated phenotype (Fig. 259-1).

For example, desmin forms intermediate filaments that connect the

nuclear and plasma membranes, Z-lines, and the intercalated disks

between muscle cells. Desmin mutations impair the transmission of

force and signaling for both cardiac and skeletal muscle and may cause

combined cardiac (restrictive > dilated) and skeletal myopathy.

Defects in the sarcolemmal membrane proteins are associated with

DCM. The best known is dystrophin, encoded by the X chromosome

gene DMD, abnormalities of which cause Duchenne’s and Becker’s

muscle dystrophy. (Interestingly, abnormal dystrophin can be acquired

when the coxsackie virus cleaves dystrophin during viral myocarditis.)

This protein provides a network that supports the sarcolemma and also

connects to the sarcomere. The progressive functional defect in both

cardiac and skeletal muscle reflects vulnerability to mechanical stress.

Dystrophin is associated at the membrane with a complex of other proteins, such as metavinculin, abnormalities of which also cause DCM.

Defects in the sarcolemmal channel proteins (channelopathies) are generally associated with primary arrhythmias, but mutations in SCN5A,

the α subunit of the Nav 1.5 ion channel protein, distinct from those

that cause the Brugada or long QT syndromes, have been implicated in

DCM with conduction disease.

Nuclear membrane protein defects in cardiac and skeletal muscle

occur in either autosomal (lamin A/C) or X-linked (emerin) patterns.

These defects are associated with a high prevalence of atrial and ventricular arrhythmias and conduction system disease, which can occur

in some family members without or before detectable cardiomyopathy.

Intercalated disks contribute to intracellular connections, allowing

mechanical and electrical coupling between cells and also connections

to desmin filaments within the cell. Mutations in proteins of the desmosomal complex compromise attachment of the myocytes, which can

become disconnected and die via activation of Wnt/β-catenin and proinflammatory signaling pathways, to be replaced by fat and fibrous tissue.

These areas are highly arrhythmogenic and may dilate to form aneurysms. Although more often noted in the right ventricle (arrhythmogenic right ventricular cardiomyopathy), this condition can affect both

ventricles and has also been termed “arrhythmogenic cardiomyopathy.”

As many signaling pathways are conserved over multiple systems,

we anticipate discovering extracardiac manifestations of abnormal

TABLE 259-1 Typical Presentation with Symptomatic Cardiomyopathy

DILATED RESTRICTIVE HYPERTROPHIC

Ejection fraction (normal >55%) Usually <30% when symptoms severe Usually >40–50% >60%

Left ventricular diastolic

dimension (normal <55 mm)

≥60 mm if chronic <60 mm (may be decreased) Often decreased

Left ventricular wall thickness Normal or decreased Normal or increased Markedly increased

Atrial size Increased, left before right Increased; may be massive and involve both

atria equally

Increased; related to

elevated filling pressures

Valvular regurgitation Related to annular and ventricular dilation; mitral

appears earlier during decompensation; tricuspid

regurgitation with right ventricular dysfunction

Related to endocardial involvement; frequent

mitral and tricuspid regurgitation, rarely severe

Related to valve-septum

interaction; mitral

regurgitation

Common first symptoms Exertional intolerance Exertional intolerance, fluid retention early, may

have dominant right-sided symptoms

Exertional intolerance; may

have chest pain

Congestive symptomsa Left before right, except right prominent in young

adults

Right often dominates Left-sided congestion at rest

may develop late

Arrhythmias Ventricular tachyarrhythmia; conduction block

in Chagas’ disease, and some genetic etiologies.

Atrial fibrillation

Conduction disease is common in amyloidosis, in

which ventricular arrhythmias are uncommon.

Atrial fibrillation is very common

Ventricular tachyarrhythmias;

atrial fibrillation

a

Left-sided symptoms of pulmonary congestion: dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea. Right-sided symptoms of systemic venous congestion:

hepatic and abdominal distention, discomfort on bending, peripheral edema. It should be noted that overlaps exist between these phenotypes, such that nondilated

cardiomyopathy may have aspects of both dilated and restrictive cardiomyopathy, while restrictive cardiomyopathy with small internal ventricular dimensions may be

difficult to distinguish from hypertrophic cardiomyopathy.

TABLE 259-2 Initial Evaluation of Cardiomyopathy

Clinical Evaluation

Thorough history and physical examination to identify cardiac and noncardiac

disordersa

Detailed family history of heart failure, cardiomyopathy, skeletal myopathy,

conduction disorders, tachyarrhythmias, and sudden death

History of alcohol, illicit drugs, chemotherapy, or radiation therapya

Assessment of ability to perform routine and desired activitiesa

Assessment of volume status, orthostatic blood pressure, body mass indexa

Laboratory Evaluation

Electrocardiograma

Chest radiographa

Two-dimensional and Doppler echocardiograma

Magnetic resonance imaging for evidence of myocardial inflammation and fibrosis

Chemistry:

Serum sodium,a

 potassium,a

 calcium,a

 magnesiuma

Fasting glucose (glycohemoglobin in diabetes mellitus)

Creatinine,a

 blood urea nitrogena

Albumin,a

 total protein,a

 liver function testsa

Lipid profile

Thyroid-stimulating hormonea

Serum iron, transferrin saturation

Urinalysis

Creatine kinase isoforms

Cardiac troponin levels

Hematology:

Hemoglobin/hematocrita

White blood cell count with differential,a

 including eosinophils

Erythrocyte sedimentation rate

Initial Evaluation When Specific Diagnoses Are Suspected

DNA sequencing for genetic disease, panel selection based on phenotype

Titers for infection in the setting of clinical suspicion:

Acute viral (coxsackie, echovirus, influenza)

Human immunodeficiency virus

Chagas’ (Trypanosoma cruzi), Lyme (Borrelia burgdorferi), toxoplasmosis

Catheterization with coronary angiography in patients with angina who are

candidates for interventiona

Serologies for active rheumatologic disease

Endomyocardial biopsy including sample for electron microscopy when

suspecting specific diagnosis with therapeutic implications

a

Level I recommendations from American College of Cardiology/American Heart

Association Practice Guidelines for Chronic Heart Failure in the Adult.

1956 PART 6 Disorders of the Cardiovascular System

TABLE 259-3 Selected Genetic Defects Associated with Cardiomyopathy

GENE PRODUCT INHERITANCE CARDIAC PHENOTYPE

ISOLATED CARDIAC

PHENOTYPEa EXTRACARDIAC MANIFESTATIONS

Sarcomere ACTC1 (cardiac actin) AD HCM, DCM Yes

MYH7 (β myosin heavy chain) AD HCM, DCM, LVNC Yes Skeletal myopathy

MYBPC3 (myosin binding protein C) AD HCM Yes

TNNT2 (cardiac troponin T) AD HCM, DCM, LVNC Yes

TNNI3 (cardiac troponin I) AD, AR HCM, DCM, RCM Yes

TTN (Titin) AD DCM Yes

TPM1 (α-tropomyosin) AD HCM, DCM Yes

TNNC1 (cardiac troponin C) AD DCM Yes

MYL2 (myosin regulatory light chain) AD HCM Yes Skeletal myopathy

MYL3 (myosin essential light chain) AD HCM Yes

Z-Disk and

Cytoskeleton

DES (desmin) AD RCM, DCM Yes Skeletal myopathy

FLNC (filamin C) AD DCM Yes Skeletal myopathy

NEXN (nexilin) AD DCM Yes

VCL (vinculin) AD DCM Yes

Nuclear

Membrane

LMNA (lamin A/C) AD, AR CDDC Yes Skeletal myopathy

EMD (emerin) X-linked CDDC No Skeletal myopathy, contractures

ExcitationContraction

Coupling

PLN (phospholamban) AD DCM, ARVC Yes

SCN5A (NAV 1.5) AD CDDC Yes Note other mutations associated

with Brugada syndrome

RYR2 (cardiac ryanodine receptor) AD ARVC Yes

CASQ2 (calsequestrin 2) AR ARVC Yes

Cellular

Metabolism

PRKAG2 (γ-subunit of AMP kinase) AD HCM+ Yes

LAMP2 (lysosomal associated

membrane protein)

X-linked HCM+ Nob Danon’s disease: skeletal myopathy,

cognitive impairment

TAZ (tafazzin) X-linked DCM, LVNC No Barth’s syndrome: skeletal

myopathy, cognitive impairment,

neutropenia

FXN (frataxin) AR HCM No Friedreich’s ataxia: ataxia, diabetes

mellitus type 2

TMEM43 (transmembrane protein 43) AD ARVC Yes

GLA (α-galactosidase-A) X-linked HCM+ No Fabry’s disease: renal failure,

angiokeratomas and painful

neuropathy

Mitochondria Mitochondrial DNA Maternal

transmission

DCM, HCM No MELAS, MERRF, Kearns-Sayre

syndrome, ocular myopathy

Sarcolemmal

Membrane

DMD (dystrophin) X-linked DCM Nob Duchenne’s and Becker’s muscular

dystrophy

DMPK (dystrophica myotonica

protein kinase)

AD DCM No Myotonic dystrophy type 1

Desmosome DSP (desmoplakin) JUP (Plakoglobin) AD, AR ARVC, DCM Yes Carvajal syndrome (AR), Naxos

syndrome (AR), “woolly hair” and

hyperkeratosis of palms and soles

DSG2 (desmoglein 2), DSC2

(desmocollin 2), PKP2 (plakophilin 2)

AD ARVC Yes

Other Examples RBM20 (RNA binding motif 20) AD DCM Yes

PSEN1 (presenilin-1,2) AD DCM Yes Dementia

BAG3 (BCL2-associated athanogene

3)

AD DCM Yes

ALPK3 (α-kinase 3) AR HCM Yes

a

Indicates that the usual clinical presentation is of isolated cardiomyopathy; however, occasionally present extracardiac manifestations are also provided. b

Indicates that

isolated cardiac phenotype can occur in women with the X-linked defects.

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ARVC, arrhythmogenic right ventricular cardiomyopathy; CDDC, conduction disease with dilated

cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HCM+, HCM with preexcitation; LVNC, left ventricular noncompaction; MELAS,

(mitochondrial) myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome; MERRF, myoclonic epilepsy with ragged red fibers; RCM, restrictive

cardiomyopathy.

Cardiomyopathy and Myocarditis

1957CHAPTER 259

proteins initially considered restricted to the heart. In contrast, the

monogenic disorders of metabolism that affect the heart are already

clearly recognized to affect multiple organ systems. Currently, it is most

important to diagnose defective enzymes for which specific therapy

can now ameliorate the course of disease, such as with alpha-galactosidase A deficiency (Fabry’s disease). Abnormalities of mitochondrial

DNA (maternally transmitted) impair energy production with multiple clinical manifestations, including impaired cognitive function

and skeletal myopathy. The phenotypic expression is highly variable

depending on the distribution of the maternal mitochondria during

embryonic development. Heritable systemic diseases, such as familial

amyloidosis and hemochromatosis, can affect the heart without mutation of genes expressed in the heart.

For any patient with suspected or proven genetic disease, family

members should be considered and evaluated in a longitudinal fashion.

Screening generally includes both an echocardiogram and electrocardiogram (ECG). The indications and implications for confirmatory

specific genetic testing vary depending on the specific mutation. The

profound questions raised by families about diseases shared and passed

down merit serious and sensitive discussion, ideally provided by a

trained genetic counselor.

DILATED CARDIOMYOPATHY

An enlarged left ventricle with reduced systolic function as measured

by left ventricular ejection fraction characterizes DCM (Figs. 259-2,

259-3, and 259-4). Systolic failure is more prominent than diastolic

dysfunction. Although the syndrome of DCM has many disparate

etiologies (Table 259-4), these often evolve to common pathways

of secondary response and disease progression (convergent phenotype). When myocardial injury is acquired, some myocytes may die

initially, whereas others survive only to have later programmed cell

death (apoptosis), and remaining myocytes hypertrophy in response

to increased wall stress. Local and circulating factors stimulate deleterious secondary responses that contribute to progression of disease.

Dynamic remodeling of the interstitial scaffolding affects diastolic

function and the amount of ventricular dilation. Mitral regurgitation

commonly develops as the valvular apparatus is distorted and is usually

substantial by the time heart failure is severe. Many cases that present

“acutely” have progressed silently through these stages over months

to years. Dilation and decreased function of the right ventricle may

result directly from the initial injury, but more often develops later

in response to elevated afterload presented by secondary pulmonary

hypertension and in relation to mechanical interactions with the failing

left ventricle.

Regardless of the nature and degree of direct cell injury and loss, the

resulting impairment often reflects secondary responses that may be

modifiable or reversible. About a third of patients with new-onset cardiomyopathy demonstrate substantial spontaneous recovery. Chronic

DCM may also improve in some patients without underlying structural

heart disease to near-normal ejection fractions during recommended

therapy with neurohormonal modulation, cardiac resynchronization therapy for left bundle branch block, and diuretics as needed to

FIGURE 259-1 Drawing of myocyte indicating multiple sites of abnormal gene products associated with cardiomyopathy. Major functional groups include the sarcomeric

proteins (actin, myosin, tropomyosin, and the associated regulatory proteins), the dystrophin complex stabilizing and connecting the cell membrane to intracellular

structures, the desmosome complexes associated with cell-cell connections and stability, and multiple cytoskeletal proteins that integrate and stabilize the myocyte. ATP,

adenosine triphosphate. (Figure adapted from Jeffrey A. Towbin, MD, University of Tennessee Health Science Center.)

1958 PART 6 Disorders of the Cardiovascular System

FIGURE 259-2 Dilated cardiomyopathy. This gross specimen of a heart removed at

the time of transplantation shows massive left ventricular dilation and moderate

right ventricular dilation. Although the left ventricular wall in particular appears

thinned, there is significant hypertrophy of this heart, which weighs >800 g (upper

limit of normal = 360 g). A defibrillator lead is seen traversing the tricuspid valve into

the right ventricular apex. (Image courtesy of Robert Padera, MD, PhD, Department

of Pathology, Brigham and Women’s Hospital, Boston.)

LV

LA

RV

RA

FIGURE 259-3 Dilated cardiomyopathy. This echocardiogram of a young man with

dilated cardiomyopathy shows massive global dilation and thinning of the walls of

the left ventricle (LV). The left atrium (LA) is also enlarged compared to normal. Note

that the echocardiographic and pathologic images are vertically opposite, such that

the LV is by convention on the top right in the echocardiographic image and bottom

right in the pathologic images. RA, right atrium; RV, right ventricle. (Image courtesy

of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)

FIGURE 259-4 Dilated cardiomyopathy. Microscopic specimen of a dilated

cardiomyopathy showing the nonspecific changes of interstitial fibrosis and

myocyte hypertrophy characterized by increased myocyte size and enlarged,

irregular nuclei. Hematoxylin and eosin–stained section, 100× original magnification.

(Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and

Women’s Hospital, Boston.)

maintain fluid balance. In many patients, these therapies can stabilize

cardiac and clinical function and extend survival (Chap. 252). Further

aspects of diagnosis and therapy specific to etiologies of DCM are

discussed below.

■ MYOCARDITIS

Myocarditis (inflammation of the heart) is most often attributable to

infective agents but can also arise from other causes of inflammation.

Infectious myocarditis cannot be assumed from a presentation of

decreased systolic function in the setting of an acute infection, as any

severe condition causing systemic cytokine release can depress cardiac

function transiently, as seen frequently in medical intensive care units.

Myocardial inflammation without obvious infection is seen in sarcoidosis and giant cell myocarditis, with checkpoint inhibitor therapy, in

eosinophilic myocarditis, or in association with autoimmune diseases

such as polymyositis and systemic lupus erythematosus. Fulminant

myocarditis can result from viral infection, checkpoint inhibitor therapy, giant cell myocarditis, or necrotizing eosinophilic myocarditis,

and is often complicated by recurrent arrhythmias. Early recognition

of fulminant myocarditis is crucial as recovery to near-normal cardiac

function can occur during aggressive circulatory support.

■ INFECTIVE MYOCARDITIS

Infections can injure the myocardium through direct invasion, disruption of normal cellular processes, production of cardiotoxic substances,

or stimulation of chronic inflammation with or without persistent

infection. Myocarditis has been reported with almost all types of

infective agents but is most commonly associated with viruses and the

protozoan Trypanosoma cruzi. The pathogenesis of viral myocarditis

has been extensively studied in murine models as divided into three

phases. For the direct viral invasion phase, viruses gain entry through

the respiratory or gastrointestinal tract and infect organs possessing

specific receptors, such as the coxsackie-adenovirus receptors on the

heart, which are prominent around intercalated disks and the atrioventricular (AV) node. Viral infection and replication can cause myocardial injury and lysis. For example, the enteroviral protease 2A degrades

the myocyte structural protein dystrophin and interacts with other host

proteins to induce apoptosis, inhibit the host serum response factor,

and interfere with autophagy of protein aggregates.

The second phase is the nonspecific (innate) host response to infection, which is heavily dependent on Toll-like receptors that recognize

common antigenic patterns. Cytokine release is rapid, followed by triggered activation and expansion of specific T- and B-cell populations.

This initial response appears to be crucial, as early immunosuppression

in animal models can increase viral replication and worsen cardiac

Cardiomyopathy and Myocarditis

1959CHAPTER 259

injury. However, successful recovery from viral infection depends not

only on the efficacy of the immune response to limit viral infection,

but also on timely downregulation to prevent ongoing autoimmune

injury to the host.

The secondary acquired (adaptive) immune response is specifically

addressed against the viral proteins and can include both T-cell infiltration and antibodies to viral proteins. If unchecked, the acquired

immune response can perpetuate secondary cardiac damage. Ongoing

cytokine release activates matrix metalloproteinases that can disrupt

the collagen and elastin scaffolding of the heart, potentiating ventricular dilation. Stimulation of profibrotic factors leads to pathologic

interstitial fibrosis. Some antibodies triggered through co-stimulation

or molecular mimicry also recognize targets within the host myocyte,

such as the β-adrenergic receptor, α-myosin, and troponin, but it

remains unclear as to whether or not these antibodies contribute to

cardiac dysfunction in humans or merely serve as markers of cardiac

injury.

It is not known how long the viruses persist in the human heart,

whether late persistence of the viral genome continues to be deleterious, or how often a dormant virus can be reactivated. Genomes of

common viruses are often present in patients with clinical diagnoses of

myocarditis or DCM, but there is little information on how often these

are present in patients without cardiac disease (see below). Further

information is needed to understand the relative timing and contribution of infection, immune responses, and secondary adaptations in the

progression of heart failure after viral myocarditis (Fig. 259-5).

Clinical Presentation of Viral Myocarditis Acute viral myocarditis

often presents with symptoms and signs of heart failure, but may

present with chest pain and ECG changes suggestive of pericarditis or

acute myocardial infarction, and occasionally with atrial or ventricular

tachyarrhythmias. The typical patient with presumed viral myocarditis

is a young to middle-aged adult who develops progressive dyspnea and

weakness within a few days to weeks after a viral syndrome that was

accompanied by fever and myalgias. Subacute presentation may occur

within a few weeks or months of a viral infection. As viral infections

are common and the resulting cytokine activation can depress cardiac

function, it is often difficult to determine whether viral infection caused

myocarditis or unmasked a previously unrecognized cardiomyopathy.

A small number of patients present with fulminant myocarditis,

with rapid progression within hours from a severe febrile respiratory

syndrome to cardiogenic shock that may involve multiple organ systems, leading to renal failure, hepatic failure, and coagulopathy. These

patients are typically young adults who have recently been dismissed

from urgent care settings with antibiotics for bronchitis, only to return

within a few days in rapidly progressive cardiogenic shock. Recognition of patients with this fulminant presentation is potentially life-saving

as more than half can survive with aggressive support, which may

include high-dose intravenous catecholamine therapy and sometimes

temporary mechanical circulatory support. The ejection fraction function of these patients often recovers to near-normal, although residual

diastolic dysfunction may limit vigorous exercise for some survivors.

Chronic viral myocarditis is often invoked, but rarely proven, as a

diagnosis when no other cause of DCM can be identified. Many cases

attributed to previous viral infection will later be recognized as due

to genetic causes or consumption of excess alcohol or illicit stimulant

drugs. The proportion of chronic DCM due to viral infection remains

a subject of controversy.

Laboratory Evaluation for Myocarditis The initial evaluation

for suspected myocarditis includes an ECG, an echocardiogram, and

serum levels of troponin and creatine phosphokinase, of which both

cardiac and skeletal muscle fractions may be elevated. Magnetic resonance imaging is increasingly used for the diagnosis of myocarditis,

which is supported but not proven by evidence of increased tissue

edema and gadolinium enhancement (Fig. 259-6), particularly in the

mid-wall (as distinct from usual coronary artery territories).

Endomyocardial biopsy is indicated when a new presentation of

heart failure is accompanied by conduction blocks or ventricular

tachyarrhythmias, which suggest possible etiologies of noninfectious

TABLE 259-4 Major Causes of Dilated Cardiomyopathy (with Common

Examples)

Inflammatory Myocarditis

Infective

Viral (coxsackie,a

 adenovirus,a

 HIV, hepatitis C)

Parasitic (T. cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis)

Bacterial (diphtheria)

Spirochetal (Borrelia burgdorferi—Lyme disease)

Rickettsial (Q fever)

Fungal (with systemic infection)

Noninfective

Granulomatous inflammatory disease

 Sarcoidosis

 Giant cell myocarditis

Eosinophilic myocarditis

Polymyositis, dermatomyositis

Collagen vascular disease

Checkpoint inhibitor chemotherapy

Transplant rejection

Toxic

Alcohol

Catecholamines: amphetamines, cocaine

Chemotherapeutic agents (anthracyclines, trastuzumab)

Interferon

Other therapeutic agents (hydroxychloroquine, chloroquine)

Drugs of misuse (emetine, anabolic steroids)

Heavy metals: lead, mercury

Occupational exposure: hydrocarbons, arsenicals

Metabolica

Nutritional deficiencies: thiamine, selenium, carnitine

Electrolyte deficiencies: calcium, phosphate, magnesium

Endocrinopathy

Thyroid disease

Pheochromocytoma

Diabetes

Obesity

Hemochromatosis

Inherited Metabolic Pathway Defectsa

Familiala

 (See Table 259-3)

Skeletal and cardiac myopathy

Dystrophin-related dystrophy (Duchenne’s, Becker’s)

Mitochondrial myopathies (e.g., Kearns-Sayre syndrome)

Hemochromatosis

Associated with other systemic diseases

Susceptibility to immune-mediated myocarditis

Overlap with Nondilated Cardiomyopathy

“Minimally dilated cardiomyopathy”

Hemochromatosisa

Amyloidosisa

Hypertrophic cardiomyopathya

 (“burned-out”)

“Idiopathic”a

Miscellaneous (Shared Elements of Above Etiologies)

Arrhythmogenic ventricular cardiomyopathy

Peripartum cardiomyopathy

Left ventricular noncompactiona

Tachycardia-related cardiomyopathy

Supraventricular arrhythmias with uncontrolled rate

 Very frequent nonsustained ventricular tachycardia or high premature

ventricular complex burden

a

Some specific cases can be linked now to specific genetic mutation in a familial

cardiomyopathy; others with similar phenotypes that appear to be acquired or

idiopathic may represent genetic factors not yet identified.

1960 PART 6 Disorders of the Cardiovascular System

FIGURE 259-6 Magnetic resonance image of myocarditis showing the typical midwall location (arrow) for late gadolinium enhancement from cardiac inflammation

and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD,

Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.)

Ab anti-myocyte surface proteins

Ab anti-myocyte cellular proteins

Ab anti-pathogen

Natural killer T cells

Specific T cell respones

Ab anti-pathogen

Cytokines

Entry into myocytes

Chronic dilated

cardiomyopathy

Persistent or latent

infection Delayed apoptosis

Myocyte lysis

Viral replication

and protein expression Viremia

Infection Immune Responses

Chronic

Dilated cardiomyopathy

Macrophages

Alterations in

extracellular matrix

FIGURE 259-5 Schematic diagram demonstrating the possible progression from infection through direct,

secondary, and autoimmune responses to dilated cardiomyopathy. Most of the supporting evidence for this

sequence is derived from animal models. It is not known to what degree persistent infection and/or ongoing

immune responses contribute to ongoing myocardial injury in the chronic phase.

FIGURE 259-7 Acute myocarditis. Microscopic image of an endomyocardial biopsy

showing massive infiltration with mononuclear cells and occasional eosinophils

associated with clear myocyte damage. The myocyte nuclei are enlarged and

reactive. Such extensive involvement of the myocardium would lead to extensive

replacement fibrosis even if the inflammatory response could be suppressed.

Hematoxylin and eosin–stained section, 200× original magnification. (Image

courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and

Women’s Hospital, Boston.)

inflammatory causes that warrant aggressive immunosuppression,

such as sarcoidosis or giant cell myocarditis. The indications, yield,

and benefit of endomyocardial biopsy for evaluation of myocarditis or

new-onset cardiomyopathy are not well established. When biopsy is

performed, the key Dallas criteria for myocarditis include lymphocytic

infiltrate with evidence of myocyte necrosis (Fig. 259-7) and are negative in 80–90% of patients with clinical myocarditis. Negative Dallas

criteria can reflect sampling error or early resolution of lymphocytic

infiltrates, but may also be influenced by the insensitivity of the test

when inflammation results from cytokines and antibody-mediated

injury. Routine histologic examination of endomyocardial biopsy

rarely reveals a specific infective etiology, such as toxoplasmosis or

cytomegalovirus subsets. Immunohistochemistry of myocardial biopsy

samples is commonly used to identify active lymphocyte subtypes and

may also detect upregulation of HLA antigens and the presence of

complement components attributed to inflammation, but the specificity and significance of these findings are uncertain.

An increase in circulating viral titers

between acute and convalescent blood samples

supports a diagnosis of acute viral myocarditis with potential spontaneous improvement.

Respiratory virus panels can detect adenovirus,

influenza, and coronavirus. There is no established role for measuring circulating anti-heart

antibodies, which may be the result, rather than

a cause, of myocardial injury and have also been

found in patients with coronary artery disease

and genetic cardiomyopathy.

Patients with recent or ongoing viral syndromes have been classified into three levels of

myocarditis diagnosis. (1) Possible subclinical

acute myocarditis is diagnosed when a typical

viral syndrome occurs without cardiac symptoms, but with elevated biomarkers of cardiac

injury, ECG suggestive of acute injury, and/

or reduced left ventricular ejection fraction or

regional wall motion abnormality. (2) Probable

acute myocarditis is diagnosed when the above

criteria are met and accompanied by cardiac

symptoms, such as shortness of breath or chest

pain, which can result from pericarditis or

myocarditis. When clinical findings of pericarditis are accompanied by elevated troponin

or CK-MB or abnormal cardiac wall motion,

the terms perimyocarditis or myopericarditis

are sometimes used. (3) Definite myocarditis

is diagnosed when there is histologic or immunohistologic evidence

of inflammation on endomyocardial biopsy (see below) and does not

require any other laboratory or clinical criteria. Magnetic resonance

imaging is increasingly employed early in the evaluation for possible

myocarditis. With the original 2009 Lake Louise criteria for myocarditis, a positive study required any two of three findings: abnormal

T2-weighted imaging or early or late gadolinium enhancement.

Revised criteria for specificity require both a T2-weighted criterion

indicating edema and one T1-based criterion consistent with inflammatory injury, although more liberal diagnostic criteria allowing for

the presence of either one yields higher sensitivity. The presence of

pericardial effusion supports the diagnosis of inflammation, although

it is not specific.

Cardiomyopathy and Myocarditis

1961CHAPTER 259

■ SPECIFIC VIRUSES IMPLICATED IN MYOCARDITIS

In humans, viruses are rarely proven to be the direct cause of clinical

myocarditis. First implicated was the picornavirus family of RNA

viruses, principally the enteroviruses, coxsackie virus, echovirus, and

poliovirus. Influenza, another RNA virus, is implicated with varying

frequency every winter and spring as epitopes change. Of the DNA

viruses, adenovirus, vaccinia, and the herpesviruses (varicella-zoster

virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus

6 [HHV6]) are well recognized to cause myocarditis but also occur

commonly in the healthy population. Polymerase chain reaction (PCR)

detects viral genomes in the majority of patients with DCM, but also

in normal “control” hearts. Most often detected are parvovirus B19 and

HHV6, which may affect the cardiovascular system, in part, through

infection of vascular endothelial cells. However, their contribution to

chronic cardiomyopathy is uncertain, as serologic evidence of exposure

is present in many children and most adults.

Human immunodeficiency virus (HIV) was associated with an

incidence of DCM of 1–2%. However, with the advent of highly active

antiretroviral therapy (HAART), HIV has been associated with a significantly lower incidence of cardiac disease. Cardiomyopathy in HIV

may also result from cardiac involvement with other associated viruses,

such as cytomegalovirus and hepatitis C. Antiviral drugs to treat

chronic HIV can cause cardiomyopathy, both directly and through

drug hypersensitivity. The clinical picture may be complicated by

pericardial effusions and pulmonary hypertension. There is a high frequency of lymphocytic myocarditis found at autopsy, and viral particles

have been demonstrated in the myocardium in some cases, consistent

with direct causation.

Hepatitis C has been repeatedly implicated in cardiomyopathy,

particularly in Germany and Asia. Cardiac dysfunction may improve

after interferon therapy. As this cytokine itself often depresses cardiac

function transiently, careful coordination of its administration and

ongoing clinical evaluation are critical. The cardiac effects of curative

treatments for hepatitis C on cardiac function have not yet been well

studied but do not appear to have limited the successful transplantation

of hepatitis C–positive donors. Involvement of the heart with hepatitis

B is uncommon but can be seen when associated with systemic vasculitis (polyarteritis nodosa).

Additional viruses implicated specifically in myocarditis include

mumps, respiratory syncytial virus, the arboviruses (dengue fever and

yellow fever), and arenaviruses (Lassa fever). For any serious infection,

the systemic inflammatory response can cause nonspecific depression

of cardiac function, which is generally reversible if the patient survives.

This nonspecific inflammatory response is likely responsible for most

of the cardiac findings with SARS-CoV-2, for which clinical information is accumulating rapidly. There is some evidence for direct cardiomyocyte invasion by the virus, consistent with an early model of acute

myocarditis in rabbits caused by rabbit coronavirus. Some patients do

present with ECG changes mimicking acute myocardial infarction.

The endothelium is also a distinct cellular target of SARS-CoV-2, and

the resulting vasoconstrictive and prothrombotic endotheliopathy may

contribute to myocardial ischemia (and stroke). The dominant injury

is to the lungs, where adult respiratory distress syndrome can develop,

particularly in older patients and those with underlying comorbidities.

When heart failure develops later in the course, it is usually in the setting of refractory respiratory failure and other organ failure from which

survival is unlikely.

■ THERAPY OF VIRAL MYOCARDITIS

There is currently no specific therapy recommended during any

stage of viral myocarditis. During acute infection, therapy with

anti-inflammatory or immunosuppressive medications is avoided, as

their use has been shown to increase viral replication and myocardial

injury in animal models. Therapy with specific antiviral agents (such

as oseltamivir) has not been studied in specific relation to cardiac

involvement. There is ongoing investigation into the impact of antiviral

therapy to treat chronic viral persistence identified from endomyocardial biopsy. Large trials of immunosuppressive therapy for Dallas

criteria–positive myocarditis have been negative. There are some initial

encouraging results and ongoing investigations with immunosuppressive therapy for immune-mediated myocarditis defined by immunohistologic criteria on biopsy or circulating antimyocardial antibodies

in the absence of myocardial viral genomes. However, neither antiviral

nor anti-inflammatory therapies are currently recommended. Until we

have a better understanding of the phases of viral myocarditis and the

effects of targeted therapies, treatment will continue to be guided by

general recommendations for DCM.

■ OTHER INFECTIOUS CAUSES

Parasitic Myocarditis Chagas’ disease is the third most common

parasitic infection in the world and the most common infective cause

of cardiomyopathy. The protozoan T. cruzi is transmitted by the bite

of the reduviid bug, endemic in the rural areas of South and Central

America. Transmission can also occur through blood transfusion,

organ donation, from mother to fetus, and occasionally orally. While

programs to eradicate the insect vector have decreased the prevalence

from about 16 million to <10 million in South America, cases are

increasingly recognized in Western developed countries (see Global

Perspectives below).

Multiple pathogenic mechanisms are implicated. The parasite

itself can cause myocyte lysis and primary neuronal damage. Specific

immune responses may recognize the parasites or related antigens and

lead to chronic immune activation in the absence of detectable parasites. Molecular techniques have revealed persistent parasite DNA fragments in infected individuals. Further evidence for persistent infection

is the eruption of parasitic skin lesions during immunosuppression

after cardiac transplantation. As with viral myocarditis, the relative

roles of persistent infection and of secondary autoimmune injury have

not been resolved (Fig. 259-5). An additional factor in the progression

of Chagas’ disease is the autonomic dysfunction and microvascular

damage that may contribute to cardiac and gastrointestinal disease.

The acute phase of Chagas’ disease with parasitemia is usually

unrecognized, but in fewer than 5% of cases, it presents clinically

within a few weeks of infection with nonspecific symptoms or occasionally with acute myocarditis and meningoencephalitis. In the

absence of antiparasitic therapy, the silent stage progresses slowly for

>10–30 years in almost half of patients to manifest chronically in the

cardiac and gastrointestinal systems. Features typical of Chagas’ disease

are conduction system abnormalities, particularly sinus node and AV

node dysfunction and right bundle branch block. Atrial fibrillation and

ventricular tachyarrhythmias also occur. Small ventricular aneurysms

are common, particularly at the ventricular apex. These dilated ventricles are particularly thrombogenic, giving rise to pulmonary and systemic emboli. Xenodiagnosis, detection of the parasite itself, is rarely

performed. The serologic tests for specific IgG antibodies against the

trypanosome lack sufficient specificity and sensitivity, requiring two

separate positive tests to make a diagnosis.

Treatment of the advanced stages focuses on clinical manifestations

of the disease and includes heart failure medications, pacemakerdefibrillators, and anticoagulation. The most common antiparasitic

therapies are benznidazole and nifurtimox, which have been effective

in children with chronic T. cruzi infection. Both drugs are associated

with multiple severe reactions, including dermatitis, gastrointestinal

distress, and neuropathy. Moreover, in a large trial of adults with established Chagas’ cardiomyopathy, benznidazole did not prevent disease

progression, leaving the role of antiparasitic therapy unclear. Survival

is <30% at 5 years after the onset of overt clinical heart failure. Patients

without major extracardiac disease have occasionally undergone transplantation, after which they require surveillance testing and recurrent

antiparasitic therapy to suppress reactivation of infection.

African trypanosomiasis infection results from the tsetse fly bite

and can occur in travelers exposed during trips to Africa. The West

African form is caused by Trypanosoma brucei gambiense and progresses silently over years. The East African form caused by T. brucei

rhodesiense can progress rapidly through perivascular infiltration to

myocarditis and heart failure, with frequent arrhythmias. The diagnosis is made by identification of trypanosomes in blood, lymph nodes,

1962 PART 6 Disorders of the Cardiovascular System

or other affected sites. Antiparasitic therapy has limited efficacy and is

determined by the specific type and the stage of infection. Toxoplasmosis

is contracted through ingestion of undercooked infected beef or pork,

transmission from feline feces, organ transplantation, transfusion, or

maternal-fetal transmission. Immunocompromised hosts are most

likely to experience reactivation of latent infection from cysts, found

in up to 40% of autopsies of patients dying from HIV infection. Toxoplasmosis may present with encephalitis or chorioretinitis and, in the

heart, can cause myocarditis, pericardial effusion, constrictive pericarditis, and heart failure. The diagnosis in an immunocompetent patient

is made when the IgM is positive and the IgG becomes positive later.

Active toxoplasmosis may be suspected in an immunocompromised

patient with myocarditis and a positive IgG titer for toxoplasmosis, particularly when avidity testing identifies high specificity of the antibody.

Fortuitous sampling occasionally reveals the cysts in the myocardium.

Combination therapy can include pyrimethamine and sulfadiazine or

clindamycin.

Trichinellosis is caused by Trichinella spiralis larva ingested with

undercooked meat. Larvae migrating into skeletal muscles cause myalgias, weakness, and fever. Periorbital and facial edema, and conjunctival and retinal hemorrhage may also be seen. Although the larva may

occasionally invade the myocardium, clinical heart failure is rare and,

when observed, attributed to the eosinophilic inflammatory response.

The diagnosis is made from the specific serum antibody and is further

supported by the presence of eosinophilia. Treatment includes antihelminthic drugs (albendazole, mebendazole) and glucocorticoids if

inflammation is severe.

Cardiac involvement with echinococcus is rare, but cysts can form

and rupture in the myocardium and pericardium.

Bacterial Infections Most bacterial infections can involve the

heart occasionally through direct invasion and abscess formation,

but do so rarely. More commonly, systemic inflammatory responses

depress contractility in severe infection and sepsis. Diphtheria specifically affects the heart in almost one-half of cases, and cardiac involvement is the most common cause of death in patients with this infection.

The prevalence of vaccines has shifted the incidence of diphtheria from

children worldwide to countries without routine immunization and to

older populations who have lost their immunity. The bacillus releases

a toxin that impairs protein synthesis and may particularly affect the

conduction system. The specific antitoxin should be administered as

soon as possible, with higher priority than antibiotic therapy. Clostridial toxin causes myocardial damage, and gas bubbles can be detected

in the myocardium, with occasional abscess formation in the myocardium and pericardium. Streptococcal infection with β-hemolytic

streptococci is most commonly associated with acute rheumatic fever

and is characterized by inflammation and fibrosis of cardiac valves and

systemic connective tissue, but it can also lead to a myocarditis with

focal or diffuse infiltrates of mononuclear cells. Other systemic bacterial infections that can involve the heart include brucellosis, legionella,

meningococcus, mycoplasma, psittacosis, and salmonellosis, for which

specific treatment is directed at the systemic infection.

Tuberculosis can involve the myocardium directly as well as through

tuberculous pericarditis, but rarely does so when the disease is treated

with antibiotics. Whipple’s disease is caused by Tropheryma whipplei.

The usual manifestations are in the gastrointestinal tract, but pericarditis, coronary arteritis, valvular lesions, and occasionally clinical heart

failure may also occur. Multidrug antituberculous regimens are effective, but the disease tends to relapse even with appropriate treatment.

Tick-Borne Infections Spirochetal myocarditis has been diagnosed from myocardial biopsies containing Borrelia burgdorferi, which

causes Lyme disease. Lyme carditis most often presents with arthritis

and conduction system disease that resolves within 1–2 weeks of antibiotic treatment and is only rarely implicated in chronic heart failure.

Other tick-borne illnesses associated with febrile illnesses and myocarditis include Rocky Mountain spotted fever, Q fever, and ehrlichiosis,

all of which are treated with doxycycline alone or in combination with

other agents.

■ NONINFECTIVE MYOCARDITIS

Myocardial inflammation can occur in the absence of infectious causes.

The paradigm of noninfective inflammatory myocarditis is cardiac

transplant rejection, from which we have learned that myocardial

depression can develop and reverse quickly, that noncellular mediators

such as antibodies and cytokines play a major role in addition to lymphocytes, and that myocardial antigens are exposed by prior physical

injury and viral infection.

The most commonly diagnosed noninfective inflammatory process

affecting the myocardium is granulomatous myocarditis, including

both sarcoidosis and giant cell myocarditis. Sarcoidosis, as discussed

in Chap. 367, is a multisystem disease most commonly affecting the

lungs. Although classically presenting with higher prevalence in young

African-American men, the epidemiology appears to be changing, with

increasing recognition of sarcoidosis in Caucasian patients in nonurban areas. Patients with pulmonary sarcoid are at high risk for cardiac

involvement, but cardiac sarcoidosis also occurs without clinical lung

disease. Regional clustering of the disease supports the suspicion that

the granulomatous reaction is triggered by infectious or environmental

allergens not yet identified.

The sites and density of cardiac granulomata, the time course,

and the degree of extracardiac involvement are remarkably variable.

Patients may present with rapid-onset heart failure and ventricular

tachyarrhythmias, conduction block, chest pain syndromes, or minor

cardiac findings in the setting of ocular involvement, an infiltrative

skin rash, or a nonspecific febrile illness. They may also present less

acutely after months to years of fluctuating cardiac symptoms. When

ventricular tachycardia or conduction block dominates the initial presentation of heart failure without coronary artery disease, suspicion

should be high for these granulomatous myocarditides.

Depending on the time course, the ventricles may appear restrictive

or dilated. There may be a right ventricular predominance of both

dilation and ventricular arrhythmias, sometimes initially attributed to

arrhythmogenic right ventricular cardiomyopathy, with which sarcoidosis shares multiple features.

Small ventricular aneurysms are common in the heart with sarcoid.

Computed tomography of the chest often reveals pulmonary lymphadenopathy even in the absence of clinical lung disease. Metabolic

imaging (positron emission tomography [PET]) of the whole chest

can highlight active sarcoid lesions that are avid for glucose. Magnetic

resonance imaging (MRI) of the heart can identify myocardial scar in a

pattern not compatible with myocardial infarction, and this distinctive

type of late gadolinium enhancement is associated, as in other cardiac

disease, with increased risk of ventricular arrhythmias. To rule out

chronic infections, such as tuberculosis or histoplasmosis, as the cause

of adenopathy, the diagnosis often requires pathologic confirmation.

Biopsy of enlarged mediastinal nodes may provide the highest yield.

The scattered granulomata of sarcoidosis are commonly missed on

cardiac biopsy (Fig. 259-8).

Immunosuppressive treatment for sarcoidosis is initiated with highdose glucocorticoids, often supplemented with methotrexate, and is generally more effective in suppressing arrhythmias than improving severely

impaired systolic function. Patients with sarcoid lesions that persist

or recur during tapering of corticosteroids are considered candidates

for other immunosuppressive therapies. Pacemakers and implantable

defibrillators are generally indicated to prevent life-threatening heart

block or ventricular tachycardia, respectively. Because the inflammation often resolves into extensive fibrosis that impairs cardiac function

and provides pathways for reentrant arrhythmias, the prognosis for

improvement is best when the density of granulomata is limited and

the ejection fraction is not severely reduced.

Giant cell myocarditis is less common than sarcoidosis, but accounts

for 10–20% of biopsy-positive cases of myocarditis. Giant cell myocarditis typically presents with rapidly progressive heart failure and

tachyarrhythmias in patients generally older than those with acute viral

myocarditis. Diffuse granulomatous lesions are surrounded by extensive inflammatory infiltrate unlikely to be missed on endomyocardial

biopsy, often with eosinophilic infiltration. Associated conditions are

thymomas, thyroiditis, pernicious anemia, other autoimmune diseases,