Cardiomyopathy and Myocarditis

1963CHAPTER 259

and occasionally recent infections. Glucocorticoid therapy alone is

rarely effective, but in combination with other immunosuppression

therapies similar to those used for severe transplant rejection, it may

improve short-term outcomes in patients who are hemodynamically

stable at presentation. Most patients in cardiogenic shock from giant

cell myocarditis progress to urgent mechanical support or transplantation, which may be precluded by systemic infection from intensive immunosuppression. Although the severity of presentation and

myocardial histology are more fulminant than with sarcoidosis, the

occasional finding of giant cell myocarditis after a previous diagnosis

of sarcoidosis suggests that they may share the same disease spectrum.

Eosinophilic myocarditis can be an important manifestation of the

hypereosinophilic syndrome, which in Western countries is often considered idiopathic, although in Mediterranean and African countries,

it is associated with antecedent infection. It may also be seen with

systemic eosinophilic syndromes such as Churg-Strauss syndrome

or malignancies. Hypersensitivity myocarditis is often an unexpected

diagnosis, made when the biopsy reveals infiltration with lymphocytes

and mononuclear cells with a high proportion of eosinophils. Most

commonly, the reaction is attributed to antibiotics, particularly those

taken chronically, but thiazides, anticonvulsants, indomethacin, and

methyldopa have also been implicated. Occasional associations with

the smallpox vaccine (vaccinia) have been reported. Although the circulating eosinophil count may be slightly elevated in hypersensitivity

myocarditis, it is lower than in the hypereosinophilic syndrome. Highdose glucocorticoids and discontinuation of the trigger agent can be

curative for hypersensitivity myocarditis.

Myocarditis is often associated with systemic inflammatory diseases,

such as polymyositis and dermatomyositis, which affect skeletal and

cardiac muscle. Although noninfective inflammatory myocarditis is

sometimes included in the differential diagnosis, cardiac involvement

with connective tissue disease such as systemic lupus erythematosus

more often presents as pericarditis, vasculitis, pulmonary hypertension, and accelerated coronary artery disease.

The most dramatic form of noninfectious inflammatory myocarditis

is that seen with combined immune checkpoint inhibitors. Targeted

monoclonal antibody therapy to unblock the host immune response

has produced remarkable remission of melanoma, renal cell carcinoma,

refractory Hodgkin’s lymphoma, and other advanced tumors. Inhibitory receptors on T lymphocytes (such as CTLA4 and PD-1) and the

“programmed death” ligands, such as PD-L1, on target tissues interact

to turn off immune activation as part of normal autoregulation. Tumor

cells can upregulate these ligands to hide from immune recognition.

Antibodies to the inhibitory receptors or ligands can reawaken host

response, but also unleash immune attack against host tissues expressing PD-L1, which include myocytes and endothelial cells and multiple

organs, such as liver, pancreas, thyroid, skin, and skeletal muscle. The

frequency of myocarditis as reported is <0.5%, is higher with monoclonal therapy against PD-1 than against CTLA4, and is over tenfold

higher with combined used of two checkpoint inhibitors. Patients

can present with acute heart failure, often with bizarre electrocardiographic arrhythmias or conduction block and with evidence of skeletal

myositis. Echocardiography may suggest myocardial edema without

ventricular dilation, and initial ejection fraction may not be markedly

reduced. Troponin is often positive, B-type natriuretic peptide may be

elevated, and creatine phosphokinase may be high, particularly with

skeletal involvement. If performed, MRI shows widespread inflammation, and biopsy shows extensive lymphocytic infiltration with CD4+

and CD8+ T cells and CD68+ macrophages. The diagnosis should

be suspected immediately with acute cardiac presentation in patients

treated with checkpoint inhibitors, who may also present initially with

other acute organ system involvement, which warrants urgent multidisciplinary management usually in an intensive care unit. Initial therapy

involves high-dose glucocorticoids, which may be followed by other

immunosuppressive agents. Reported fatality in fulminant checkpoint

inhibition myocarditis has been ~50% and is higher after combined

checkpoint inhibition. Less commonly, cardiovascular involvement can

cause pericarditis or arteritis, particularly temporal arteritis.

■ PERIPARTUM CARDIOMYOPATHY

Peripartum cardiomyopathy (PPCM) develops during the last trimester

or within the first 6 months after pregnancy, affecting between 1:2000

and 1:4000 deliveries in the United Sates. Risk factors are increased

maternal age, increased parity, twin pregnancy, malnutrition, use of

tocolytic therapy for premature labor, and preeclampsia or toxemia of

pregnancy. Several of these risk factors contribute to antiangiogenic

signaling through secreted vascular endothelial growth factor (VEGF)

inhibitors, such as soluble FLT1 (sFLT1). Recent animal and human

studies have confirmed the role of decreased angiogenic reserve in the

pathogenesis of PPCM, which may be rescued by correcting the angiogenic imbalance. Another recently proposed mechanism invokes an

abnormal prolactin cleavage fragment, which is induced by oxidative

stress and also affects angiogenesis; this observation has led to preliminary investigation of bromocriptine as possible therapy.

However, other processes also contribute to PPCM. Heart failure

early after delivery was previously common in Nigeria, when the

custom for new mothers included salt ingestion while reclining on a

warm bed, which likely impaired mobilization of the excess circulating

volume after delivery. In the Western world, lymphocytic myocarditis

has sometimes been found on myocardial biopsy. This inflammation has been hypothesized to reflect increased susceptibility to viral

myocarditis or an autoimmune myocarditis due to cross-reactivity of

anti-uterine antibodies against cardiac muscle.

As the increased circulatory demand of pregnancy can aggravate

other cardiac disease that was clinically unrecognized, it is crucial to

the diagnosis of PPCM that there be no evidence for a preexisting cardiac disorder. By contrast, heart failure presenting earlier in pregnancy

has been termed pregnancy-associated cardiomyopathy (PACM).

Both PPCM and PACM have been found in some families with other

presentations of DCM. As in familial and sporadic DCM, truncating

mutations, predominantly in TTN, are present in 15% of patients with

PPCM and are associated with systolic dysfunction that persists. Pregnancy may represent another example of environmental triggers for

accelerated phenotypic expression of genetic cardiomyopathies.

■ TOXIC CARDIOMYOPATHY

Cardiotoxicity has been reported with multiple environmental and

pharmacologic agents. Often these associations are seen only with very

high levels of exposure or acute overdoses, in which acute electrocardiographic and hemodynamic abnormalities may reflect both direct

drug effect and systemic toxicity.

Alcohol is the most common toxin implicated in chronic DCM.

Excess consumption may contribute to >10% of cases of heart failure,

FIGURE 259-8 Sarcoidosis. Microscopic image of an endomyocardial biopsy

showing a noncaseating granuloma and associated interstitial fibrosis typical of

sarcoidosis. No microorganisms were present on special stains, and no foreign

material was identified. Hematoxylin and eosin–stained section, 200× original

magnification. (Image courtesy of Robert Padera, MD, PhD, Department of

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

1964 PART 6 Disorders of the Cardiovascular System

including exacerbation of heart failure with structural heart disease.

Alcoholic cardiomyopathy causes many more hospital admissions in

men than women, but prevalence is similar between men and women

with alcoholism, with left ventricular dysfunction detected in about a

third of asymptomatic patients. Estimates of the alcohol intake necessary to cause cardiomyopathy have been 4–5 ounces or 80–100 g

of pure ethanol daily for 5–10 years, about 1 L of wine, 8 beers, or

½ pint of hard liquor. Frequent binge drinking may also be sufficient.

Toxicity is attributed both to alcohol and to its primary metabolite,

acetaldehyde. Chronic heavy exposure may alter metabolism, protein

synthesis, substrate utilization, and oxidative stress. Polymorphisms

of the genes encoding alcohol dehydrogenase and the angiotensinconverting enzyme may influence the likelihood of alcoholic cardiomyopathy. Superimposed vitamin deficiencies and toxic alcohol additives

are rarely implicated currently. Mutations in TTN and other DCM

disease genes can be identified in ~10% of patients with presumed

alcohol cardiomyopathy.

Many patients with alcoholic cardiomyopathy are fully functional in

their daily lives without apparent stigmata of alcoholism. The cardiac

impairment in severe alcoholic cardiomyopathy is the sum of both

permanent damage and a substantial component that is reversible after

cessation of alcohol consumption. Atrial fibrillation occurs commonly

both early in the disease (“holiday heart”) and in advanced stages.

Medical therapy includes neurohormonal antagonists and diuretics

as needed for fluid management. Withdrawal should be supervised

to avoid exacerbations of heart failure or arrhythmias, and ongoing

support arranged. Even with severe disease, marked improvement can

occur within 3–6 months of abstinence, but the prognosis is grim if

alcohol consumption continues.

Cocaine, amphetamines, and related catecholaminergic stimulants

can produce chronic cardiomyopathy as well as acute ischemia, tachyarrhythmias, malignant hypertension, aortic dissection, and stroke.

Cardiac pathology reveals microinfarcts consistent with small vessel

ischemia, similar to those seen with pheochromocytoma, and thrombosis secondary to endothelial dysfunction in the case of cocaine.

Chemotherapy agents are the most common drugs implicated in

toxic cardiomyopathy. Judicious use balances risks of the malignancy

and the risks of cardiotoxicity presented not only by the drug regimens

but also by the patient’s cardiovascular profile and possibly genetic

factors influencing myocyte response to injury. Receipt of cardiotoxic

drugs or radiation may warrant designation as “stage B” heart failure,

with asymptomatic changes in cardiac structure and biomarkers. Once

symptoms are apparent, the prognosis with heart failure is worse than

for many types of cancer.

Anthracyclines (e.g., doxorubicin) cause characteristic histologic

changes of vacuolar degeneration and myofibrillar loss. Multiple mechanisms have been implicated, involving reactive oxygen species and

iron compounds, mitochondrial damage, transcription factors such as

hypoxia-induced factor, and, most recently, inhibition of topoisomerase

II involved in DNA repair. Risk for cardiotoxicity increases with older

age, preexisting cardiac disease, higher doses or combination therapies,

or left chest irradiation. Systolic dysfunction can occur acutely with

symptoms of heart failure noted soon after drug administration, but

more often is detected by surveillance echocardiography during the

first year after exposure. Doxorubicin cardiotoxicity generally does not

result in marked left ventricular dilation, such that stroke volume and

systemic perfusion can be severely reduced with only a modest reduction of ejection fraction. Therapy for reduced ejection fraction includes

β-adrenergic receptor blockade and inhibition of the renin-angiotensin

system, with conflicting data on whether these agents decrease toxicity

when given in parallel with chemotherapy. Once thought to have an

inexorable downward course, many patients with symptomatic heart

failure can improve to near-normal function with careful management,

including prevention of “second-hit” insults such as atrial fibrillation or

hypertension. The course differs for some children treated with these

agents before puberty, in whom inadequate growth of the heart may

lead to refractory heart failure as they reach their twenties.

Trastuzumab (Herceptin) is one of the humanized monoclonal antibodies that interfere with human epidermal growth receptor 2 (HER2),

which is crucial for growth of some tumors, such as breast cancer, and

for cardiac adaptation. Cardiotoxicity is highest when anthracyclines

are administered in conjunction with trastuzumab; however, less toxicity is seen now when these agents are combined compared with the

toxicity observed previously with paclitaxel for breast cancer. Although

more often reversible than anthracycline cardiotoxicity, trastuzumab

cardiomyopathy may persist in about a third of affected patients and

can progress to clinical heart failure and death. For cardiotoxicity

with anthracyclines or trastuzumab, therapy is recommended as for

other causes of reduced ejection fraction, but it is not clear whether

treatment enhances the spontaneous rate of improvement or whether

it decreases progression.

Cardiotoxicity with cyclophosphamide and ifosfamide generally

occurs acutely and with very high doses. 5-Fluorouracil, cisplatin,

and some other alkylating agents can cause recurrent coronary spasm

that occasionally leads to depressed contractility. Acute administration of interferon-α, interleukin 2, and other cytokine-based therapies can cause hypotension and arrhythmias. Clinical heart failure

occurring during their chronic administration usually resolves after

discontinuation.

VEGF, produced endogenously or by tumors, enhances angiogenesis

by activating the VEGF signaling pathways. Inhibitors of this pathway

and its receptors are potent against multiple cancers. Many smallmolecule tyrosine kinase inhibitors that affect VEGF are in use for different

malignancies. Although these agents are “targeted” at specific tumor

receptors or pathways, the biologic conservation of signaling pathways

means that some of these drugs also find targets in the cardiovascular

and other organ systems. Blood pressures increase in most patients

during therapy, attributed to an imbalance between endogenous vasodilators and vasoconstrictors and alteration of glomerular function.

Hypertension and proteinuria can develop with these agents, similar

to preeclampsia, and presentation is associated with increased risk

of future cardiac disease. Recognition of cardiotoxicity during therapy with these agents is complicated because they occasionally cause

peripheral fluid accumulation (ankle edema, periorbital swelling, pleural effusions) due to local factors rather than elevated central venous

pressures. Therapeutic approaches include withdrawal of the tyrosine

kinase inhibitor (when possible) and conventional treatment for heart

failure. Newer tyrosine kinase inhibitors effective against multiple

kinases may have more complex off-target effects.

The most dramatic toxicity of contemporary cancer therapy results

from combined immune checkpoint inhibitors, which block the natural counterregulatory T-cell suppression and unleash potentially fatal

inflammation directed toward multiple organs that can include the

heart and vessels. These are discussed in the previous section on noninfectious myocarditis (above).

Proteasome inhibitors used to treat multiple myeloma are associated

with an increased risk of hypertension, ischemic events, thromboembolism, and heart failure. The more potent agent, carfilzomib, appears

more cardiotoxic than bortezomib.

Other therapeutic drugs that can cause cardiotoxicity during

chronic use include tumor necrosis factor α antagonists for rheumatologic conditions, and carbamazepine, clozapine, and lithium for neurologic and psychiatric diagnoses. Antiretroviral therapies for HIV have

been implicated in cardiomyopathy. Chloroquine and hydroxychloroquine are widely used for systemic lupus erythematosus and rheumatoid arthritis and can decrease ejection fraction with either restrictive

or dilated phenotype, often in association with conduction block. The

presumed mechanism of toxicity is impaired lysosomal function, with

accumulation of inclusion bodies that can be seen on cardiac biopsy.

Toxic exposures can cause arrhythmias or respiratory injury acutely

during accidents. Chronic exposures implicated in cumulative cardiotoxicity include hydrocarbons, fluorocarbons, arsenicals, lead, and

mercury.

■ METABOLIC CAUSES OF CARDIOMYOPATHY

Endocrine disorders affect multiple organ systems, including the

heart. Hyperthyroidism and hypothyroidism do not often cause clinical

heart failure in an otherwise normal heart but commonly exacerbate

Cardiomyopathy and Myocarditis

1965CHAPTER 259

heart failure. Clinical signs of thyroid disease may be masked, so tests

of thyroid function are part of the routine evaluation of cardiomyopathy. Hyperthyroidism should always be considered with new-onset

atrial fibrillation or ventricular tachycardia or atrial fibrillation in

which the rapid ventricular response is difficult to control. The most

common current reason for thyroid abnormalities in the cardiac population is the treatment of tachyarrhythmias with amiodarone, a drug

with substantial iodine content. Hypothyroidism should be treated

with very slow escalation of thyroid supplements to avoid exacerbating

tachyarrhythmias and heart failure. Hyperthyroidism and heart failure

create a dangerous combination that merits very close supervision,

often hospitalization, during titration of antithyroid medications,

during which decompensation of heart failure may occur precipitously

and fatally.

Pheochromocytoma is rare but should be considered when a patient

has heart failure and very labile blood pressure and heart rate,

sometimes with episodic palpitations (Chap. 387). Patients with

pheochromocytoma often have postural hypotension. In addition to

α-adrenergic receptor antagonists, definitive therapy requires surgical

extirpation. Very high renin states, such as those caused by renal artery

stenosis, can lead to modest depression in ejection fraction with little

or no ventricular dilation and markedly labile symptoms with flash

pulmonary edema, related to sudden shifts in vascular tone and intravascular volume.

Controversies remain regarding whether diabetes and obesity are

sufficient to cause cardiomyopathy. Most heart failure in diabetes

results from epicardial coronary disease, with further increase in coronary artery risk due to accompanying hypertension and renal dysfunction. Cardiomyopathy may result in part from insulin resistance and

increased advanced-glycosylation end products, which impair both

systolic and diastolic function. However, much of the dysfunction can

be attributed to scattered focal ischemia resulting from distal coronary

artery tapering and limited microvascular perfusion even without

proximal focal stenoses. Diabetes is a typical factor in heart failure with

“preserved” ejection fraction, along with hypertension, advanced age,

and female gender.

The existence of a cardiomyopathy due to obesity is generally

accepted. In addition to cardiac involvement from associated diabetes,

hypertension, and vascular inflammation of the metabolic syndrome,

obesity alone is associated with impaired excretion of excess volume

load, which, over time, can lead to increased wall stress and secondary

adaptive neurohumoral responses. Fluid retention may be aggravated

by large fluid intake and the rapid clearance of natriuretic peptides by

adipose tissue. In the absence of another obvious cause of cardiomyopathy in an obese patient with systolic dysfunction without marked

ventricular dilation, effective weight reduction is often associated

with major improvement in ejection fraction and clinical function.

Improvement in cardiac function has been described after successful

bariatric surgery, although all major surgical therapy poses increased

risk for patients with heart failure. Postoperative malabsorption and

nutritional deficiencies, such as calcium and phosphate deficiencies,

may be particularly deleterious for patients with cardiomyopathy.

Nutritional deficiencies can occasionally cause DCM but are not

commonly implicated in developed countries. Beri-beri heart disease

due to thiamine deficiency can result from poor nutrition in undernourished populations and in patients deriving most of their calories

from alcohol and has been reported in teenagers subsisting only on

highly processed foods. This disease is initially a vasodilated state with

very-high-output heart failure that can later progress to a low-output

state; thiamine repletion can lead to prompt recovery of cardiovascular

function. Abnormalities in carnitine metabolism can cause dilated

or restrictive cardiomyopathies, usually in children. Deficiency of

trace elements such as selenium can cause cardiomyopathy (Keshan’s

disease).

Calcium is essential for excitation-contraction coupling. Chronic

deficiencies of calcium, such as can occur with hypoparathyroidism

(particularly postsurgical) or intestinal dysfunction (from diarrheal

syndromes and following extensive resection), can cause severe chronic

heart failure that responds over days or weeks to vigorous calcium

repletion. Phosphate is a component of high-energy compounds

needed for efficient energy transfer and multiple signaling pathways.

Hypophosphatemia can develop during starvation and early refeeding

following a prolonged fast and occasionally during hyperalimentation.

Hemochromatosis is variably classified as a metabolic or storage

disease (Chap. 414). It is included among the causes of restrictive cardiomyopathy, but the clinical presentation is often that of a DCM. The

autosomal recessive form is related to the HFE gene. With up to 10% of

the population heterozygous for one mutation, the clinical prevalence

might be as high as 1 in 500. The lower observed rates highlight the

limited penetrance of the disease, suggesting the role of additional

genetic and environmental factors such as alcoholism affecting clinical

expression. Cardiac siderosis can also be acquired from iron overload

due to hemoglobinopathies in patients treated with recurrent transfusions. Excess iron is deposited in the perinuclear compartment of cardiomyocytes, with resulting disruption of intracellular architecture and

mitochondrial function. Diagnosis is easily made from measurement

of serum iron and transferrin saturation, with a threshold of >60% for

men and >45–50% for women. MRI can help to quantitate iron stores

in the liver and heart, and endomyocardial biopsy tissue can be stained

for iron (Fig. 259-9), which is particularly important if the patient has

another cause for cardiomyopathy. If diagnosed early, hemochromatosis can often be managed by repeated phlebotomy to remove iron. For

more severe iron overload, iron chelation therapy with desferrioxamine

(deferoxamine) or deferasirox can help to improve cardiac function if

myocyte loss and replacement fibrosis are not too severe.

Inborn disorders of metabolism occasionally present with DCM,

although they are most often associated with restrictive cardiomyopathy (Table 259-4).

■ FAMILIAL DILATED CARDIOMYOPATHY

The genetic basis for cardiomyopathy is discussed above in the section,

“Genetic Etiologies of Cardiomyopathy.” The recognized frequency

of familial involvement in DCM has increased to >30%. Mutations in

TTN, encoding the giant sarcomeric protein titin, are the most common cause of DCM, accounting for up to 25% of familial disease. On

average, men with TTN mutations develop cardiomyopathy a decade

before women, without distinctive clinical features. Mutations in thick

and thin filament genes account for ~8% of DCM and may manifest in

early childhood.

The most recognizable familial cardiomyopathy syndromes with

extracardiac manifestations are the muscular dystrophies. Both Duchenne’s and the milder Becker’s dystrophies result from abnormalities in

the X-linked dystrophin gene of the sarcolemmal membrane. Skeletal

myopathy is present in multiple other genetic cardiomyopathies

(Table 259-3), some of which are associated with creatine kinase elevations.

FIGURE 259-9 Hemochromatosis. Microscopic image of an endomyocardial biopsy

showing extensive iron deposition within the cardiac myocytes with the Prussian

blue stain (400× original magnification). (Image courtesy of Robert Padera, MD, PhD,

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

1966 PART 6 Disorders of the Cardiovascular System

A B

LV

RV

FIGURE 259-10 Arrhythmogenic right ventricular cardiomyopathy. A. Cross-sectional slice of a pathology

specimen removed at transplantation, showing severe dilation and thinning of the right ventricle (RV) with

extensive fatty replacement of right ventricular myocardium. B. The remarkably thin right ventricular free

wall is revealed by transillumination. LV, left ventricle. (Images courtesy of Gayle Winters, MD, and Richard

Mitchell, MD, PhD, Division of Pathology, Brigham and Women’s Hospital, Boston.)

Patients and families with a history of arrhythmias and/or conduction system disease that precede or supersede cardiomyopathy may have

abnormalities of the nuclear membrane lamin

proteins, which are present in ~5% of patients

with DCM. While all DCMs carry a risk of sudden

death, a family history of cardiomyopathy with

sudden death raises suspicion for a particularly

arrhythmogenic mutation; affected family members may be considered for implantable defibrillators to prevent sudden death even without meeting

the reduced ejection fraction threshold.

A prominent family history of sudden death or

ventricular tachycardia before clinical cardiomyopathy suggests genetic defects in the desmosomal

proteins (Fig. 259-10). Originally described as

affecting the right ventricle (arrhythmogenic right

ventricular cardiomyopathy [ARVC]), this disorder

(arrhythmogenic cardiomyopathy) can affect either

or both ventricles. Patients often present first with

ventricular tachycardia. Genetic defects in proteins of the desmosomal

complex disrupt myocyte junctions and adhesions, leading to replacement of myocardium by deposits of fat. Thin ventricular walls may

be recognized on echocardiography but are better visualized on MRI.

Because desmosomes are also important for elasticity of hair and skin,

some of the defective desmosomal proteins are associated with striking

“woolly hair” and thickened skin on the palms and soles. Implantable

defibrillators are usually indicated to prevent sudden death. There is

variable progression to right, left, or biventricular failure.

Left ventricular noncompaction is a condition of unknown prevalence that is increasingly suspected with the refinement of imaging

techniques. The diagnostic criteria include the presence of multiple

trabeculations in the left ventricle distal to the papillary muscles, creating a “spongy” appearance of the apex, but are increasingly recognized

as nonspecific findings in other cardiac diseases. Noncompaction has

been associated with multiple genetic variants in the sarcomeric and

other genes, such as TAZ (encoding tafazzin). The diagnosis may be

made incidentally or in patients previously diagnosed with cardiomyopathy, in whom the criteria for noncompaction may appear and

disappear with changing left ventricular size and function. The three

cardinal clinical features of ventricular arrhythmias, embolic events,

and heart failure are largely restricted to noncompaction with concomitant systolic dysfunction. Treatment generally includes anticoagulation and early consideration for an implantable defibrillator, in

addition to neurohormonal antagonists as indicated by stage of disease.

Some families inherit a susceptibility to viral-induced myocarditis.

This propensity may relate to abnormalities in cell surface receptors,

such as the coxsackie-adenovirus receptor, that bind viral proteins.

Some may have partial homology with viral proteins such that an autoimmune response is triggered against the myocardium.

Prognosis and therapy of familial DCM are dictated primarily by the

stage of clinical disease and the risk for sudden death. In some cases, the

familial etiology facilitates prognostic decisions, particularly regarding the

likelihood of recovery after a new diagnosis, which is unlikely for familial

disease. The rate of progression of disease is to some extent heritable,

although marked variation can be seen. However, there have been cases

of remarkable clinical remission after acute presentation, likely after a

reversible “second hit,” such as prolonged tachycardia or viral myocarditis.

■ TAKOTSUBO CARDIOMYOPATHY

The apical ballooning syndrome, or acute stress-induced cardiomyopathy, occurs typically in older women after sudden intense emotional

or physical stress. The ventricle shows global ventricular dilation with

basal contraction, forming the shape of the narrow-necked jar (takotsubo)

used in Japan to trap octopuses. Originally described in Japan, it is well

recognized elsewhere during emergency cardiac catheterization and

intensive care unit admissions for noncardiac conditions. Presentations

include pulmonary edema, hypotension, and chest pain with ECG

changes mimicking an acute infarction. The left ventricular dysfunction

extends beyond a specific coronary artery distribution and generally

resolves within days to weeks. Animal models and ventricular biopsies suggest that this acute cardiomyopathy may result from intense

sympathetic activation with heterogeneity of myocardial autonomic

innervation, diffuse microvascular spasm, and/or direct catecholamine

toxicity. Cardiac MRI demonstrates diffuse myocardial edema without

necrosis. Coronary angiography may be required to rule out acute

coronary occlusion. No therapies have been proven beneficial, but

reasonable strategies include nitrates for pulmonary edema; intraaortic

balloon pump if needed for low output, provided transient left ventricular outflow tract obstruction is absent; combined alpha and beta

blockers rather than selective beta blockade if hemodynamically stable;

and magnesium for arrhythmias related to QT prolongation. The longterm prognosis is generally good, with the lowest mortality associated

with episodes triggered by emotional rather than physical triggers.

In-hospital complications and mortality are similar to acute myocardial

infarction. Recurrences have been described in up to 10% of patients.

■ IDIOPATHIC DCM

Idiopathic DCM is a diagnosis of exclusion, when all other known factors have been excluded. Approximately two-thirds of DCMs are still

labeled as idiopathic; however, a substantial proportion of these may

reflect unrecognized genetic disease. Continued reconsideration of

etiology during chronic heart failure management often reveals specific

causes later in a patient’s course.

OVERLAPPING TYPES OF

CARDIOMYOPATHY

The limitations of our phenotypic classification are revealed through

the multiple overlaps between the etiologies and presentations of the three

types. Cardiomyopathy with reduced systolic function but without

severe dilation can represent early DCM, “minimally dilated cardiomyopathy,” or restrictive diseases without marked increases in ventricular

wall thickness. For example, sarcoidosis and hemochromatosis can

present as dilated or restrictive disease. Early stages of amyloidosis

are often mistaken for hypertrophic cardiomyopathy. Progression of

hypertrophic cardiomyopathy into a “burned-out” phase occurs occasionally, with decreased contractility and modest ventricular dilation.

Overlaps are particularly common with the inherited metabolic disorders, which can present as any of the three major phenotypes (Fig. 259-4).

■ DISORDERS OF METABOLIC PATHWAYS

Multiple genetic disorders of metabolic pathways can cause myocardial

disease, due to infiltration of abnormal products or cells containing

them between the myocytes, and storage disease, due to their accumulation within cells (Tables 259-3 and 259-4). Hypertrophic cardiomyopathy may be mimicked by the myocardium thickened with

these abnormal products causing “pseudohypertrophy,” usually with

an abnormally short PR interval. The pseudohypertrophic phenotype

Cardiomyopathy and Myocarditis

1967CHAPTER 259

is most common, but restrictive cardiomyopathy and DCM may occur.

Most of these diseases are diagnosed during childhood.

Fabry’s disease results from a deficiency of the lysosomal enzyme

alpha-galactosidase A caused by one of more than 160 mutations in

GLA. This disorder of glycosphingolipid metabolism is an X-linked

disorder that may also cause clinical disease in female carriers. Glycolipid accumulation may be limited to the cardiac tissues but usually also

involves the skin, peripheral nerve, and kidney. Electron microscopy of

endomyocardial biopsy tissue shows diagnostic vesicles containing

concentric lamellar figures (Fig. 259-11). Diagnosis can be made

through assessment of enzyme activity and/or GLA sequencing and

is crucial because enzyme replacement can reduce abnormal deposits

and improve cardiac and clinical function. The magnitude of clinical

impact has not been well established for this therapy, which requires

frequent infusions of the enzyme at a cost of >$100,000 a year. The

oral chaperone therapy, migalastat, stabilizes mutant forms of alphagalactosidase, increases enzymatic activity, and was approved for use

in a subset of patients with Fabry’s disease bearing mutations amenable

to this therapy. Enzyme replacement can also improve the course of

Gaucher’s disease, in which cerebroside-rich cells accumulate in multiple organs due to a deficiency of beta-glucosidase. Cerebroside-rich

cells infiltrate the heart, which can also lead to a hemorrhagic pericardial effusion and valvular disease.

Glycogen storage diseases lead to accumulation of lysosomal storage products and intracellular glycogen accumulation, particularly

with glycogen storage disease type III, due to a defective debranching

enzyme. There are >10 types of mucopolysaccharidoses, in which autosomal recessive or X-linked deficiencies of lysosomal enzymes lead

to the accumulation of glycosaminoglycans in the skeleton, nervous

system, and occasionally the heart. With characteristic facies, short

stature, and frequent cognitive impairment, most individuals are diagnosed early in childhood and die before adulthood.

Carnitine is an essential cofactor in long-chain fatty acid metabolism. Multiple defects have been described that lead to carnitine

deficiency, causing intracellular lipid inclusions and restrictive cardiomyopathy or DCM, often presenting in children. Fatty acid oxidation

requires many metabolic steps with specific enzymes that can be

deficient, with complex interactions with carnitine. Depending on the

defect, cardiac and skeletal myopathy can be ameliorated with replacement of fatty acid intermediates and carnitine.

Two monogenic metabolic cardiomyopathies cause markedly

increased ventricular wall thickness without an increase of muscle

subunits or an increase in contractility. Mutations in the gamma-2

regulatory subunit of the adenosine monophosphate (AMP)-activated

protein kinase important for glucose metabolism (PRKAG2) have

been associated with a high prevalence of conduction abnormalities,

such as AV block and ventricular preexcitation. Several defects have

been reported in an X-linked lysosome-associated membrane protein

(LAMP2). This defect can be maternally transmitted or sporadic and

has occasionally been isolated to the heart, although it often leads to

a syndrome of skeletal myopathy, mental retardation, and hepatic dysfunction referred to as Danon’s disease. Extreme left ventricular hypertrophy appears early, often in childhood, and can progress rapidly to

end-stage heart failure with low ejection fraction. Electron microscopy

of these metabolic disorders shows that the myocytes are enlarged by

multiple intracellular vacuoles of metabolic by-products.

RESTRICTIVE CARDIOMYOPATHY

Restrictive cardiomyopathy is dominated by abnormal diastolic function, often with mildly decreased contractility and ejection fraction

(usually 30–50%). Both atria are enlarged, sometimes massively.

Modest left ventricular dilation can be present, usually with an enddiastolic dimension <6 cm. End-diastolic pressures are elevated in both

ventricles, with preservation of cardiac output until late in the disease.

Subtle exercise intolerance is usually the first symptom but is often

not recognized until after clinical presentation with congestive symptoms. The restrictive diseases often present with relatively more rightsided symptoms, such as edema, abdominal discomfort, and ascites,

although filling pressures are elevated in both ventricles. The cardiac

impulse is less displaced than in DCM and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than

a third heart sound in sinus rhythm, but atrial fibrillation is common.

Jugular venous pressures often show rapid Y descents and may increase

during inspiration (positive Kussmaul’s sign). Most restrictive cardiomyopathies are due to infiltration of abnormal substances between

myocytes, storage of abnormal metabolic products within myocytes, or

fibrotic injury (Table 259-5). The differential diagnosis should include

constrictive pericardial disease, which may also be dominated by rightsided heart failure.

■ INFILTRATIVE DISEASE

The most common restrictive cardiomyopathy is amyloidosis, in which

a common protein assembles into β-pleated sheets of amyloid fibrils

that infiltrate between cells of target organs (Figs. 259-12, 259-13, and

259-14). Almost all amyloid that affects the heart is caused by assembly

either of immunoglobulin light chains from clonal plasma cells (AL or

“primary” amyloid) or of transthyretin (ATTR), which is made in the

liver and can either be an inherited mutant protein (ATTRm) or the

normal protein (ATTRwt [wild-type], which accumulates with age,

leading to cardiac amyloid in half of people >90 years old, but clinically much more common in men than women). There are multiple

mutations in the transthyretin molecule, of which the most common is

V1221, which confers a 50% increased risk of heart failure in the 3-4%

of African Americans who are heterozygous, but it is often clinically

silent.

Right heart failure often dominates the clinical presentation of cardiac amyloidosis, although both ventricles are affected. Conduction

system disease and atrial fibrillation are common. Nephrotic syndrome

is common in AL amyloid, which may also cause angina as the amyloid encircles the coronary arteries. Because the ventricular cavity is

diminished by amyloid infiltration, cardiac output may be very low

with a modest ejection fraction reduction. Peripheral and autonomic

neuropathy are common in both AL amyloidosis and ATTRm amyloidosis. A history of carpal tunnel syndrome is common in ATTRm and

ATTRwt, often preceding cardiac symptoms by many years. ATTRwt

is also associated with spinal stenosis.

Amyloidosis should be suspected when ventricular myocardium

appears thick on imaging with low ECG voltage, but this mismatch is

more common with AL than TTR amyloidosis. Atrial enlargement is

prominent and diastolic dysfunction more severe than that of other

causes of hypertrophy. Longitudinal strain is frequently more preserved at the apex, creating a “bull’s-eye” pattern. MRI shows diffuse

late gadolinium enhancement. Technetium-pyrophosphate scanning

reliably highlights TTR amyloidosis but does not detect AL amyloid.

FIGURE 259-11 Fabry’s disease. Transmission electron micrograph of a right

ventricular endomyocardial biopsy specimen at high magnification showing the

characteristic concentric lamellar inclusions of glycosphingolipids accumulating

as a result of deficiency of the lysosomal enzyme alpha-galactosidase A. Image

taken at 15,000× original magnification. (Image courtesy of Robert Padera, MD, PhD,

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

1968 PART 6 Disorders of the Cardiovascular System

Endomyocardial biopsy is virtually 100% reliable for the diagnosis of

all amyloid due to the characteristic birefringence pattern of Congo

red staining of the amyloid fibrils under polarized light, but immunohistochemistry may be necessary to confirm the amyloid type, as

serum or urine electrophoresis may be misleading. Until recently, the

therapy of amyloidosis was limited to the treatment of congestion and

arrhythmias. There is no evidence for benefit from neurohormonal

antagonists, which may complicate the postural hypotension and fixed

low stroke volume of amyloid disease. However, specific therapies for

amyloidosis are changing the prognosis. Median survival with AL amyloidosis was previously 6–12 months but has markedly improved with

the use of the proteasome inhibitor bortezomib. If present, multiple

myeloma may be treated with conventional chemotherapy, if not limited by cardiac dysfunction. AL amyloid can sometimes be treated with

heart transplantation followed by delayed stem cell transplantation,

with some risk of recurrence of amyloid in the transplanted heart. The

course of TTR amyloidosis is measured in years even after the typical

delay in diagnosis and may be affected by new therapies. Stabilizers of

the normal transthyretin structure, tafamidis and diflusinal, have been

approved for therapy of the associated neuropathy and are now being

studied for effect on cardiac outcomes. Expression of transthyretin

can be decreased by patisiran, a small interfering RNA that decreases

message production, or inotersen, an antisense mRNA that enhances

mRNA degradation. Both have been approved as treatment for the

polyneuropathy of TTR amyloid, with possible benefit on long-term

outcomes. These therapies have not yet been approved for a cardiac

indication.

■ FIBROTIC RESTRICTIVE CARDIOMYOPATHY

Progressive fibrosis can cause restrictive myocardial disease without

ventricular dilation. Thoracic radiation, common for breast and lung

cancer or mediastinal lymphoma, can produce early or late restrictive

TABLE 259-5 Causes of Restrictive Cardiomyopathies

Infiltrative (Between Myocytes)

Amyloidosis

Primary (light chain amyloid)

Familial (abnormal transthyretin)a

Senile (normal transthyretin or atrial peptides)

Inherited metabolic defectsa

Storage (Within Myocytes)

Hemochromatosis (iron)a

Inherited metabolic defectsa

Fabry’s disease

Glycogen storage disease (II, III)

Fibrotic

Radiation

Scleroderma

Endomyocardial

Possibly related fibrotic diseases

Tropical endomyocardial fibrosis

Hypereosinophilic syndrome (Löffler’s endocarditis)

Carcinoid syndrome

Radiation

Drugs: e.g., serotonin, ergotamine

Overlap with Other Cardiomyopathies

Hypertrophic cardiomyopathy/”pseudohypertrophic”a

“Minimally dilated” cardiomyopathy

Early-stage dilated cardiomyopathy

Partial recovery from dilated cardiomyopathy

Sarcoidosis

Idiopathica

a

Can be familial.

FIGURE 259-12 Restrictive cardiomyopathy—amyloidosis. Gross specimen of a heart

with amyloidosis. The heart is firm and rubbery with a waxy cut surface. The atria are

markedly dilated, and the left atrial endocardium, normally smooth, has yellow-brown

amyloid deposits that give texture to the surface. (Image courtesy of Robert Padera,

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

LV

LA

Septum

RA

RV

Pacing

lead in

RV

Lateral

wall of

LV

Pericardial

effusion

FIGURE 259-13 Restrictive cardiomyopathy—amyloidosis. Echocardiogram showing

thickened walls of both ventricles without major chamber dilation. The atria are

markedly dilated, consistent with chronically elevated ventricular filling pressures. In

this example, there is a characteristic hyperrefractile “glittering” of the myocardium

typical of amyloid infiltration, which is a nonspecific finding with contemporary

echocardiography. The mitral and tricuspid valves are thickened. A pacing lead is

visible in the right ventricle (RV), and a pericardial effusion is evident. Note that

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

left ventricle (LV) is by convention on the top right in the echocardiographic image

and bottom right in the pathologic images. LA, left atrium; RA, right atrium. (Image

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

cardiomyopathy. Patients with radiation cardiomyopathy may present

with a possible diagnosis of constrictive pericarditis, as the two conditions often coexist. Careful hemodynamic evaluation and, often,

endomyocardial biopsy should be performed if considering pericardial

Cardiomyopathy and Myocarditis

1969CHAPTER 259

FIGURE 259-14 Amyloidosis—microscopic images of amyloid involving the myocardium. The left

panel (hematoxylin and eosin stain) shows glassy, gray-pink amorphous material infiltrating between

cardiomyocytes, which stain a darker pink. The right panel shows a sulfated blue stain that highlights the

amyloid green and stains the cardiac myocytes yellow. (The Congo red stain can also be used to highlight

amyloid; under polarized light, amyloid will have an apple-green birefringence when stained with Congo

red.) Images at 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of

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

LV Chamber

LV free

wall

IVS

RV Chamber

RV free

wall

Mitral valve Tricuspid valve

FIGURE 259-15 Hypertrophic cardiomyopathy. Gross specimen of a heart with

hypertrophic cardiomyopathy removed at the time of transplantation, showing

asymmetric septal hypertrophy (septum much thicker than left ventricular free wall)

with the septum bulging into the left ventricular outflow tract causing obstruction.

The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the

characteristic plaque of systolic anterior motion, manifest as endocardial fibrosis

on the interventricular septum in a mirror-image pattern to the valve leaflet. There is

patchy replacement fibrosis, and small thick-walled arterioles can be appreciated

grossly, especially in the interventricular septum. IVS, interventricular septum;

LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD,

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

stripping surgery, which is unlikely to be successful in the presence of

underlying restrictive cardiomyopathy. Scleroderma causes small vessel

spasm and ischemia that can lead to a small, stiff heart with reduced

ejection fraction without dilation. The pulmonary hypertension associated with scleroderma may lead to more clinical right heart failure

because of concomitant fibrotic disease of the right ventricle.

■ ENDOMYOCARDIAL DISEASE

The physiologic picture of elevated filling pressures with atrial enlargement and preserved ventricular contractility with normal or reduced

ventricular volumes can result from extensive fibrosis of the endocardium, without transmural myocardial disease. For patients who have

not lived in the equatorial regions, this picture is rare, and when seen is

often associated with a history of chronic hypereosinophilic syndrome

(Löffler’s endocarditis), which is more common in men than women.

In this disease, persistent hypereosinophilia of >1500 eosinophils/μL

for at least 6 months can cause an acute phase of eosinophilic injury in

the endocardium (see earlier discussion of eosinophilic myocarditis),

with systemic illness and injury to other organs. Hypereosinophilic

syndromes can occasionally be explained by allergic or parasitic disease, but are increasingly being recognized as due to myeloproliferative

variants. It is postulated to be followed by a period in which cardiac

inflammation is replaced by evidence of fibrosis with superimposed

thrombosis. In severe disease, the dense fibrotic layer can obliterate the

ventricular apices and extend to thicken and tether the AV valve leaflets. The clinical disease may present with heart failure, embolic events,

and atrial arrhythmias. While plausible, the sequence of transition

from eosinophilic myocarditis or Löffler’s endocarditis to endomyocardial fibrosis has not been clearly demonstrated.

In tropical countries, up to one-quarter of heart failure may be due

to endomyocardial fibrosis, affecting either or both ventricles. This

condition shares with the previous condition the partial obliteration

of the ventricular apex with fibrosis extending into the valvular inflow

tract and leaflets; however, it is not clear that the etiologies are the

same for all cases. Pericardial effusions frequently accompany endomyocardial fibrosis but are not common in Löffler’s endocarditis. For

endomyocardial fibrosis, there is no gender difference, but there is a

higher prevalence in African-American populations. While tropical

endomyocardial fibrosis could represent the end-stage of previous

hypereosinophilic disease triggered by endemic parasites, neither prior

parasitic infection nor hypereosinophilia is usually documented. Geographic nutritional deficiencies have also been proposed as an etiology.

Clonal proliferation with specific mutations may respond to monoclonal antibody therapy. Other treatment includes glucocorticoids

to suppress hypereosinophilia when present. Fluid retention may

become increasingly resistant to diuretic therapy. Anticoagulation is

recommended. Atrial fibrillation is associated with

worse symptoms and prognosis but may be difficult to suppress. Surgical resection of the apices

and replacement of the fibrotic valves can improve

symptoms, but surgical morbidity and mortality

and later recurrence rates are high.

The serotonin secreted by carcinoid tumors can

produce fibrous plaques in the endocardium and

right-sided cardiac valves, occasionally affecting

left-sided valves as well. Valvular lesions may

be stenotic or regurgitant. Systemic symptoms

include flushing and diarrhea. Liver disease from

hepatic metastases may play a role by limiting

hepatic function and thereby allowing more serotonin to reach the venous circulation.

HYPERTROPHIC

CARDIOMYOPATHY

Hypertrophic cardiomyopathy is defined as left

ventricular hypertrophy that develops in the

absence of causative hemodynamic factors, such

as hypertension, aortic valve disease, or systemic

infiltrative or storage diseases (Figs. 259-15 and 259-16). It has previously been termed hypertrophic obstructive cardiomyopathy (HOCM),

asymmetric septal hypertrophy (ASH), and idiopathic hypertrophic subaortic stenosis (IHSS). However, the accepted terminology is now hypertrophic cardiomyopathy with or without obstruction. Prevalence in North

America, Africa, and Asia is about 1:500. It is a leading cause of sudden

death in the young and is an important cause of heart failure. Although

pediatric presentation is associated with increased early morbidity and

mortality, the prognosis for patients diagnosed as adults is generally

favorable, although worse than for age-matched individuals without

hypertrophic cardiomyopathy.

A sarcomere mutation is present in ~50% of patients with hypertrophic cardiomyopathy and is more common in those with familial disease

and characteristic asymmetric septal hypertrophy. More than nine different genes with >1500 mutations have been implicated, although ~80% of

patients have a mutation in either MYH7 or MYBPC3 (Table 259-3).

1970 PART 6 Disorders of the Cardiovascular System

Hypertrophic cardiomyopathy is characterized by age-dependent

and incomplete penetrance. The defining phenotype of left ventricular

hypertrophy is rarely present at birth and usually develops later in life.

Women appear to have lower penetrance of sarcomere mutations and

an older age at hypertrophic cardiomyopathy diagnosis but subsequently increased rates of heart failure and mortality thereafter. Accordingly, screening of family members should begin in adolescence and

extend through adulthood. In MYBPC3 mutation carriers, the average

age of disease development is ~40 years, while 30% remain free from

hypertrophy after 70 years. Related individuals who carry the same

mutation may have a different extent and pattern of hypertrophy (e.g.,

asymmetric vs concentric), occurrence of outflow tract obstruction,

and associated clinical outcomes, although sudden death and progression to heart failure occur more commonly in families with that history.

At the level of the sarcomere, hypertrophic cardiomyopathy mutations lead to enhanced calcium sensitivity, maximal force generation,

and ATPase activity. Calcium handling is affected through modification of regulatory proteins. Sarcomere mutations lead to abnormal

energetics and impaired relaxation, both directly and as a result

of hypertrophy. Hypertrophic cardiomyopathy is characterized by

misalignment and disarray of the enlarged myofibrils and myocytes

(Fig. 259-17), which can also occur to a lesser extent in other cardiac

diseases. Although hypertrophy is the defining feature of hypertrophic

cardiomyopathy, fibrosis and microvascular disease are also present.

Interstitial fibrosis is detectable before overt hypertrophy develops

and likely results from early activation of profibrotic pathways. In the

majority of patients with overt cardiomyopathy, focal areas of replacement fibrosis can be readily detected with MRI. These areas of “scar”

may represent substrate for the development of ventricular arrhythmias. Increased thickness and decreased luminal area of the intramural

vessels in hypertrophied myocardium contribute to microvascular

ischemia and angina. Microinfarction of hypertrophied myocardium is

a hypothesized mechanism for replacement scar formation.

Macroscopically, hypertrophy is typically manifest as nonuniform

ventricular thickening (Fig. 259-15). The interventricular septum is the

typical location of maximal hypertrophy, although other patterns of hypertrophic remodeling include concentric and midventricular. Hypertrophy

confined to the ventricular apex (apical hypertrophic cardiomyopathy) is

less often familial and has a different genetic substrate, with sarcomere

mutations present in only ~15%. Left ventricular outflow tract obstruction represents the most common focus of diagnosis and intervention,

although diastolic dysfunction, myocardial fibrosis, and microvascular

ischemia also contribute to contractile dysfunction and elevated intracardiac pressures. Obstruction is present in ~30% of patients at rest and can

be provoked by exercise in another ~30%. Systolic obstruction is initiated

by drag forces, which push an anteriorly displaced and enlarged anterior

mitral leaflet into contact with the hypertrophied ventricular septum.

Mitral leaflet coaptation may ensue, leading to posteriorly directed mitral

regurgitation. In order to maintain stroke volume across outflow tract

obstruction, the ventricle generates higher pressures, leading to higher

wall stress and myocardial oxygen demand. Smaller chamber size and

increased contractility exacerbate the severity of obstruction. Conditions

of low preload, such as dehydration, and low afterload, such as arterial

vasodilation, may lead to transient hypotension and near-syncope. The

systolic ejection murmur of left ventricular outflow tract obstruction is

harsh and late peaking and can be enhanced by bedside maneuvers that

diminish ventricular volume and transiently worsen obstruction, such as

the Valsalva maneuver or standing from a squatting position.

DIAGNOSIS

The substantial variability of hypertrophic cardiomyopathy pathology

is reflected in the diversity of clinical presentations. Patients may be

diagnosed after undergoing evaluations triggered by the abnormal

physical findings (murmur) or by symptoms of exertional dyspnea,

angina, or syncope. Alternatively, diagnosis may follow evaluations

prompted by the detection of disease in family members. Cardiac

imaging (Fig. 259-16) is central to diagnosis, for which the physical

examination and ECG are insensitive. The identification of a disease-causing mutation in a proband can focus family evaluations on

mutation carriers, but this strategy requires a high degree of certainty

that the mutation is truly pathogenic and not a benign DNA variant.

Biopsy is not needed to diagnose hypertrophic cardiomyopathy but can

be used to exclude infiltrative and metabolic diseases. Rigorous athletic

training (athlete’s heart) may cause intermediate degrees of physiologic hypertrophy difficult to differentiate from mild hypertrophic

LV

LA

MV

Septum

FIGURE 259-16 Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic

cardiomyopathy shows asymmetric hypertrophy of the septum compared to the

lateral wall of the left ventricle (LV). The mitral valve (MV) is moving anteriorly

toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. 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. (Image courtesy of Justina Wu, MD, Brigham and

Women’s Hospital, Boston.)

FIGURE 259-17 Hypertrophic cardiomyopathy. Microscopic image of hypertrophic

cardiomyopathy showing the characteristic disarrayed myocyte architecture with

swirling and branching rather than the usual parallel arrangement of myocyte

fibers. Myocyte nuclei vary markedly in size and interstitial fibrosis is present.

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

Women’s Hospital, Boston.)

Cardiomyopathy and Myocarditis

1971CHAPTER 259

cardiomyopathy. Unlike hypertrophic cardiomyopathy, hypertrophy in

the athlete’s heart regresses with cessation of training and is accompanied by supernormal exercise capacity (VO2max >50 mL/kg per min),

mild ventricular dilation, and normal diastolic function.

TREATMENT

Hypertrophic Cardiomyopathy

Management focuses on treatment of symptoms and prevention

of sudden death and stroke (Fig. 259-18). Left ventricular outflow

tract obstruction can be controlled medically in the majority of

patients. β-Adrenergic blocking agents and L-type calcium channel

blockers (e.g., verapamil) are first-line agents that reduce the severity of obstruction by slowing heart rate, enhancing diastolic filling,

and decreasing contractility. Persistent symptoms of exertional dyspnea or chest pain can sometimes be controlled with the addition

of disopyramide, an antiarrhythmic agent with potent negative inotropic properties. Novel small-molecule inhibitors of actin-myosin

interactions are being developed for obstructive and nonobstructive

hypertrophic cardiomyopathy.

Patients with or without obstruction may develop heart failure

symptoms due to fluid retention and require diuretic therapies for

venous congestion. Severe medically refractory symptoms develop

in ~5% of patients, for whom surgical myectomy or alcohol septal

ablation may be effective. Developed over 60 years ago, surgical

myectomy effectively relieves outflow tract obstruction by excising

part of the septal myocardium involved in the dynamic obstruction.

In selected patients, perioperative mortality is extremely low with

excellent long-term survival free from recurrent obstruction and

symptoms. Mitral valve repair or replacement is usually unnecessary as associated eccentric mitral regurgitation resolves with

myectomy alone. Alcohol septal ablation in patients with suitable

coronary anatomy can relieve outflow tract obstruction via a controlled infarction of the proximal septum, which produces similar

periprocedural outcomes and gradient reduction as surgical myomectomy. Until long-term outcomes are demonstrated for septal

ablation procedures, they are relegated primarily to patients who

wish to avoid surgery or who have limiting comorbidities. Neither

procedure has been shown to improve outcomes other than symptoms. With both procedures, the most common complication is the

development of complete heart block necessitating permanent pacing. However, ventricular pacing as a primary therapy for outflow

tract obstruction is ineffective and not generally advised.

Patients with hypertrophic cardiomyopathy have an increased

risk of sudden cardiac death from ventricular tachyarrhythmias.

Vigorous physical activity and competitive sports have been historically prohibited; however, ongoing studies are reexamining the

relationship between exertion and ventricular arrhythmias in hypertrophic cardiomyopathy. Factors that increase the risk of sudden

death from a baseline of 0.5% per year are presented in Table 259-6.

As sudden death has not been reduced by medical or procedural

interventions, traditionally an implantable cardioverter-defibrillator

has been advised for patients with two or more risk factors and

advised on a selected basis for patient with one risk factor. Nevertheless, the positive predictive value of most risk factors is low, and many

patients receiving a defibrillator never receive an appropriate device

therapy. A complementary approach to sudden death risk stratification and discussion with patients is the application of an externally

validated risk score using major criteria from Table 259-6 and

Use diuretics with caution

to avoid hypovolemia,

particularly in presence of

outflow gradient

Evidence of

fluid retention?

Hypertrophic Cardiomyopathy

Septal ablation Mitral surgery

In all patients,

evaluate risk for

sudden death

Symptomatic?

If low, follow with

serial evaluation

Reevaluate cause

of symptoms

Rarely, consider

cardiac transplantation

Refractory

severe symptoms

Consider procedure

Evidence of severe

progressive LV dysfunction?

Titrate beta blocker

and/or calcium

channel blocker

If high,

consider ICD

No

Yes

Yes

No

No Yes

Yes

Persistent

symptoms

Outflow

gradient?

Try disopyramide

FIGURE 259-18 Treatment algorithm for hypertrophic cardiomyopathy depending on the presence and severity of symptoms and the presence of an intraventricular gradient

with obstruction to outflow. Note that all patients with hypertrophic cardiomyopathy should be evaluated for atrial fibrillation and risk of sudden death, whether or not they

require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.

1972 PART 6 Disorders of the Cardiovascular System

continuous variables such as outflow tract gradient and left atrial

size. Shared decision-making around implantable cardioverterdefibrillator implantation for primary prevention has emphasized

discussions of estimated risk levels rather than dichotomous yes-no

criteria. Long-term use of a defibrillator may be associated with

serious device-related complications, particularly in young active

patients. Refinement of sudden death risk through the application of

contemporary technologies such as cardiac MRI is ongoing.

Atrial fibrillation is common in patients with hypertrophic

cardiomyopathy and may lead to hemodynamic deterioration and

embolic stroke. Rapid ventricular response is poorly tolerated

and may worsen outflow tract obstruction. β-Adrenergic blocking agents and L-type calcium channel blockers slow AV nodal

conduction and improve symptoms; cardiac glycosides should be

avoided, as they may increase contractility and worsen obstruction.

Even with adequate rate control, symptoms exacerbated by atrial

fibrillation may persist due to loss of AV synchrony and may require

restoration of sinus rhythm. Disopyramide and amiodarone are

the preferred antiarrhythmic agents, with radiofrequency ablation

considered for medically refractory cases. Anticoagulation to prevent embolic stroke in atrial fibrillation is recommended.

PROGNOSIS

The general prognosis for hypertrophic cardiomyopathy is better than in

early studies of referral populations, but mortality remains higher than

in an age-matched population without cardiomyopathy. The sudden

death risk is <1% per year; however, up to 1 in 20 patients will progress to

overt systolic dysfunction with a reduced ejection fraction (<50%) with

or without dilated remodeling (i.e., “burned out” or end-stage hypertrophic cardiomyopathy). These patients may suffer from low cardiac

output and have an increased risk of death from progressive heart failure

and sudden death unless they undergo timely cardiac transplantation.

GLOBAL PERSPECTIVES

The worldwide prevalence of myocarditis and cardiomyopathy combined is estimated at 5.4 million people, compared to 26 million people

with heart failure. The estimated prevalence of myocarditis/cardiomyopathy has increased by >50% since 1990 due to the growing population, while the rate per 100,000 people has declined by >20% during

the same period to 68, with an estimated mortality of 4.8 per 100,000.

The highest age-standardized prevalence is reported in central Europe,

whereas the highest attributed mortality is in Eastern Europe; however,

comparison of myocardial diseases across eras and countries is complicated by differing ascertainment and techniques for cardiac diagnoses.

For comparison, the current mortality rates are similar to that of

rheumatic heart disease, which has declined overall by 26.5% and by

55% after adjustment for age. Deaths from Chagas’ cardiomyopathy

worldwide have declined from 12.7 thousand to 10.6 thousand, with a

reduction of 51.7% in the age-adjusted rates per 100,000 population to

0.2, attributable, in major part, to improved health conditions in rural

areas of South and Central America.

Health care for other diseases affects myocarditis and cardiomyopathy. Developed nations will see a higher prevalence of cardiomyopathy

due to chemotherapy. However, vaccination has reduced deaths from

diphtheria-associated myocarditis to <50 per 100 million population,

currently most common in Russia. World regions providing HAART for

HIV have decreased not only transmission but also the rate of associated

cardiomyopathy by several-fold. Increasing global availability of genetic

testing is expected to shift the apparent epidemiology of cardiomyopathy

away from acquired causes toward causative and facilitating genetic factors. For example, heart failure with preserved ejection fraction attributed to hypertension and diabetes is increasingly recognized to represent

amyloidosis from mutant transthyretin, with distinct, recognized mutations in Portugal, Japan, and the African-Caribbean population.

■ FURTHER READING

Bozkurt BJ et al: Current diagnostic and treatment strategies for

specific dilated cardiomyopathies: A scientific statement from the

American Heart Association. Circulation 134:e579, 2016.

Ho CY et al: Genotype and lifetime burden of disease in hypertrophic

cardiomyopathy insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 138:1387, 2018.

Hu JR et al: Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 115:854, 2019.

Kociol RD et al: Recognition and initial management of fulminant

myocarditis. Circulation 141:e69, 2020.

Maurer MS et al: Tafamidis treatment for patients with transthyretin

amyloid cardiomyopathy. N Engl J Med 379:1007, 2018.

Mazzarotto F et al: Reevaluating the genetic contribution of monogenic dilated cardiomyopathy. Circulation 141:387, 2020.

Morillo CA et al: Randomized trial of benznidazole for chronic

Chagas’ cardiomyopathy. N Engl J Med 373:1295, 2015.

Moslehi JJ: Cardiovascular toxic effects of targeted cancer therapies.

N Engl J Med 375:1457, 2016.

Page RL et al: Drugs that may cause or exacerbate heart failure: AHA

scientific statement. Circulation 134:e332, 2016.

Ware JS et al: Genetic etiology for alcohol-induced cardiac toxicity. J

Am Coll Cardiol 71:2293, 2018.

TABLE 259-6 Risk Stratification for Sudden Death in Hypertrophic

Cardiomyopathy

RISK FACTOR SCREENING TECHNIQUE

History of cardiac

arrest or spontaneous

sustained ventricular

tachycardiaa

History

Syncope Nonvagal, often with or

after exertion

History

Family history of sudden

cardiac death

Family history

Spontaneous

nonsustained ventricular

tachycardia

>3 beats at rate >120 Exercise or 24- to 48-h

ambulatory recording

LV thickness >30 mm Present in <10% of

patients

Echocardiography

Abnormal blood pressure

response to exerciseb

Systolic blood pressure

fall or failure to increase

at peak exercise

Maximal upright exercise

testing

Variables Utilized in the European Society of Calculator for Estimated Risk of

Sudden Death

LV outflow tract gradient Peak gradient measured

at rest or with the

Valsalva maneuver,

mmHg

Echocardiography

Left atrial diameter Diameter measured in

the parasternal long

axis, mm

Echocardiography

LV thickness Maximal wall thickness,

mm

Echocardiography

Age

Syncope, family history,

nonsustained ventricular

tachycardia

As above As above

Emerging Risk Factors

Late gadolinium

enhancement

As a percentage of

myocardial mass

Cardiac magnetic

resonance imaging

Left ventricular apical

aneurysm

Generally applicable

to patients with apical

hypertrophy

Echocardiography

with contrast, cardiac

magnetic resonance

imaging

a

Implantable cardioverter-defibrillator advised for patients with prior arrest or

sustained ventricular tachycardia regardless of other risk factors if life expectancy

is estimated to be >1 year. b

Prognostic value most applicable to patients <40 years

old. The European Society of Cardiology risk calculator can be found at https://

doc2do.com/hcm/webHCM.html and provides an estimated 5-year risk of cardiac

arrest. Patients with estimated risk of ≥6% are generally advised placement of an

implantable cardioverter-defibrillator; those with risk between 4 and 6% can be

considered for implant, and implant is not advised when risk is <4%. Emerging risk

factors merit further clinical validation.

Abbreviation: LV, left ventricle.

Cardiac Transplantation and Prolonged Assisted Circulation

1973CHAPTER 260

Advanced heart failure, a distinct syndrome, is characterized by

refractoriness to conventional therapy and represents a vexing clinical dilemma that is associated with an increased symptom burden,

frequent hospitalization, a poor quality of life, and high risk of death.

Such individuals do not tolerate neurohormonal antagonists at recommended doses, exhibit cardiorenal syndrome, maintain markedly

poor cardiac reserve on cardiopulmonary stress testing, and typically

display a low cardiac output state with elevated pulmonary pressures.

In general, therapeutic targets shift away from disease-modifying

neurohormonal therapy to surgical options that attend directly to

supporting the dysfunctional heart and address myocardial stress

and strain relationships. Most often, prolonged circulatory assistance

using mechanical ventricular assist devices or cardiac transplantation

is required to reliably improve quality of life and long-term survival.

CARDIAC TRANSPLANTATION

A decade after Norman Shumway had accomplished the technique of a

successful heart transplant in canines, Christiaan Barnard successfully

performed the first human-to-human transplant on December 3, 1967.

Now, >5 decades later, this surgery has become entrenched in the standard armamentarium for treating patients with advanced heart failure

who are otherwise healthy enough to receive such a life-altering treatment. Globally, >150,000 patients have undergone cardiac transplantation with a 1-year survival >80% and median survival of 12.5 years and

conditional survival of 14.8 years if the recipient survives the first year

after transplant. These gains have been ushered by advances in immunosuppression, identification and management of allograft rejection,

and a comprehensive appreciation for late complications including

accelerated coronary artery disease, malignancy, and renal failure.

■ CANDIDATES FOR CARDIAC TRANSPLANTATION

The demand for cardiac transplantation outstrips the availability of

organ donors. Hence, attention to the optimal utility, equitable allocation, and patient autonomy must dominate the decisions to identify and list candidates for transplantation. Simultaneously, attempts

at expanding the donor pool have surfaced. However, vigilance to

evaluating candidates most likely to have a successful outcome from

transplantation takes pre-eminence. In 2006, the International Society

for Heart and Lung Transplantation identified a set of criteria to guide

listing of patients. These criteria were updated in 2016 and include

additional attention to the growing epidemiology of candidates suffering from congenital heart disease, restrictive and infiltrative cardiomyopathy (such as amyloidosis), and chronic infections in recipients

(such as Chagas’ disease, tuberculosis and viral hepatitis). Selected

general principles for listing candidates for cardiac transplantation are

enumerated in Table 260-1.

■ PRINCIPLES OF DONOR RECOVERY AND

ALLOCATION

Although listing criteria for candidates are typically adjudicated at

a center level, organ allocation is handled by national regulatory

processes in most countries. The allocation of donor hearts is based

on (1) the urgency of the clinical situation, (2) the time spent on the

waiting list, and (3) the distance from the recipient center. Candidates

who are hospitalized in critical status and require extracorporeal

membrane oxygenation or temporary mechanical circulatory support

devices to support both ventricles are given the highest urgency status,

followed by those requiring daily invasive hemodynamic evaluation

and intravenous inotropic therapy to maintain stability, or those with

260 Cardiac Transplantation

and Prolonged Assisted

Circulation

Mandeep R. Mehra

complications of a durable left ventricular assist device. Others stable

at home while supported by a left ventricular assist device or those

able to ambulate and live at home receive a lower urgency status. The

geographical regional reach for allocation is based not only on territorial considerations but also on the time that a donor heart would be in

transit and therefore in out of body “ischemia time,” which is typically

limited to 4 h. The final key feature that is included in the allocation

offer relates to the ABO blood group. Donor organs are offered based

on these initial characteristics and then a more detailed donor assessment ensues, resulting in acceptance or decline for any given donor

heart. It is important to note that the time constraints imposed on the

retrieval process make it difficult to invoke HLA matching of the donor

and recipient. In cases where there is a high likelihood of sensitization in the recipient (preformed circulating antibodies against donor

antigens), a prospective or virtual cross match is entertained prior

to acceptance. Other clinical criteria that are employed in the decision on

accepting an offered donor include the donor-recipient size match, the

age of the donor (typically restricted to <55 years, but is often exceeded

due to organ shortages), and presence or absence of concomitant

pathology such as coronary artery disease, left ventricular hypertrophy,

or severe injury to the allograft manifest by excess leak of injury markers (troponins) or poor contractile performance. In many cases, the

prospective cardiac allograft can be reconditioned by use of hormonal

therapy (including thyroid hormone supplementation) and used for

transplantation even if the initial evaluation suggests poor function. In

efforts to enhance the donor pool, systems that allow ex vivo normothermic perfusion to evaluate and reanimate organs with a prolonged out

of body time are being developed. The classic heart donor is derived

from a donor with brain death; however, donors with circulatory death

are being increasingly evaluated as candidates for cardiac reanimation

using a variety of techniques including ex vivo reanimation and subsequent transplantation. Such donor organs obtained after circulatory

death are gaining more widespread acceptance, and early outcomes

suggest that their outcomes after transplantation are no different from

those of organs retrieved from brain death donors. In order to increase

TABLE 260-1 Principles for Listing Candidates for Cardiac

Transplantation

PRINCIPLE COMMENT

Advanced

Disease

Severity

Refractory heart failure with a VO2

 of <14 mL/kg per min (<12, if

on beta blockers) or percent predicted VO2

 <50%; combination

of intolerance to disease-modifying therapy, cardiorenal

syndrome, use of inotropic therapy to maintain stability, or need

for a left ventricular assist system.

Comorbidity Age is not an absolute contraindication, but frailty should

be considered a relative contraindication; a BMI >35 kg/m2

should require weight loss; cancer should be dealt with on

an individual basis (e.g., low-grade prostate cancer may not

be a contraindication); poorly controlled diabetes mellitus or

end-organ damage may be a contraindication; eGFR <30 mL/

min/1.73 m2

 is a relative contraindication, if persistent; severe

cerebrovascular disease or peripheral vascular disease

(which will limit rehabilitation or function) is also a relative

contraindication.

DonorRecipient

Matching

Sensitized individuals with circulating antibodies should have

a prospective or virtual cross match; pulmonary vascular

resistance with a transpulmonary gradient >15, PVR >3

Wood units, and absolute PA systolic pressure >50 mmHg

provided the systolic blood pressure is >85 mmHg is a relative

contraindication unless reactive to therapy.

Psychosocial

Issues

Tobacco use in any form limits posttransplant survival and

should be stopped for at least 6 months; substance abuse,

including marijuana, should be a contraindication if the

individual cannot demonstrate control and cessation; patients

with severe cognitive-behavioral disabilities or dementia

(inability to ever understand and cooperate with medical care)

have the potential for self-harm and should not receive a

transplant.

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate;

PA, pulmonary artery; PVR, pulmonary vascular resistance; VO2

, peak oxygen

consumption.

1974 PART 6 Disorders of the Cardiovascular System

the number of viable donors, organs from those infected with hepatitis

C virus are increasingly being utilized since curative antiviral therapy

can be used in the recipient shortly after transplantation.

■ SURGERY FOR CARDIAC TRANSPLANTATION

The most common contemporary operation is referred to as a “bi-caval”

orthotopic cardiac transplant that mimics the natural anatomic position. In this operation, the donor and recipient superior and inferior

venae cavae are connected as are the aortic and pulmonary great

vessels. The left atrium of the recipient retains its roof including the

draining pulmonary veins, and the donor left atrium is then sutured

to the retained atrial tissue. This technique maintains function of the

donor right atrium, important for governing early postoperative right

heart output, and may prevent atrial arrhythmias. The recipient is left

with a surgical denervation, and the allograft is not responsive to any

physiologic sympathetic or parasympathetic stimuli. Therefore, early

in the adaptive postoperative phase, high-dose catecholamines are

required to maintain adequate function. Due to denervation, bradycardia in a cardiac allograft cannot be treated with atropine and the

drug of choice is isoproterenol, or temporary electrical pacing is used.

Once the cardiac allograft adapts to its host circulation, the function is

usually adequate at rest and with exercise to provide normal physical

activity and quality of life.

■ CARDIAC ALLOGRAFT REJECTION AND

IMMUNOSUPPRESSION

The ability to perform endomyocardial biopsies and evaluate rejection

pathologically and the introduction of the immunosuppression agent

cyclosporine heralded cardiac transplantation as a viable clinical therapy.

Triple-drug immunosuppression, which includes a calcineurin inhibitor (cyclosporine or tacrolimus), corticosteroids, and antiproliferative

immunosuppression (azathioprine, mycophenolate mofetil, sirolimus,

or everolimus), is now the standard combination used. The combination immunosuppression strategy that is most commonly used and

that achieves the best standard outcomes includes tacrolimus, mycophenolate mofetil, and prednisone. In those at high risk for rejection

(multiparous women, sensitized individuals) or in situations where use

of calcineurin inhibitors needs to be delayed (renal dysfunction), induction therapy using monoclonal (basiliximab) or polyclonal antibodies

(antithymocyte globulin) to provide augmented immunosuppression

is used. Over several months, as surveillance endomyocardial biopsies

are regularly performed and clinical as well as subclinical pathologic

quiescence is established, gradual weaning of steroids is undertaken.

Table 260-2 describes the immunosuppression drugs in common use.

Acute cellular rejection (ACR) and antibody-mediated rejection

(AMR) are two separate forms of cardiac allograft rejection that are

TABLE 260-2 Immunoprophylaxis Drugs in Cardiac Transplantation

DRUG CLASS GENERIC DRUG CELLULAR TARGET MAJOR SIDE EFFECTS

Calcineurin

inhibitors

Cyclosporine Binds to cyclophilin, which then inhibits calcineurin Hypertension, dyslipidemia, gum hypertrophy,

hypertrichosis

Tacrolimus Binds to immunophilin FK506 binding protein, which inhibits calcineurin Hypertension, dyslipidemia, alopecia, diabetes

mellitus

Antithymocyte

globulin (ATG)

Rabbit ATG T-cell depletion in blood and peripheral lymphoid tissues through

complement-dependent lysis and T-cell activation and apoptosis

Cytokine release syndrome, leukopenia,

thrombocytopenia, serum sickness

Horse ATG Same as above Same as above

Interleukin-2

receptor antagonists

Basiliximab Inhibition of CD-25 of interleukin 2 receptor Well tolerated; rare hypersensitivity; increased

infection risk if used with calcineurin inhibitors

Antimetabolites Azathioprine Imidazolyl derivative and prodrug of 6-mercaptopurine (cell cycle

inhibitor)

Bone marrow suppression, pancreatitis, hepatitis

Mycophenolate

Mofetil

Inhibits inosine monophosphate dehydrogenase, which controls

guanine monophosphate in the de novo pathway of purine synthesis

(inhibits T- and B-cell proliferation)

Leukopenia, gastrointestinal toxicity

Proliferation signal

inhibitors

Sirolimus Binds with FKBP12 and complex inhibits the mechanistic target of

rapamycin (mTOR)

Delayed wound healing, nonspecific

pneumonia, pericardial effusion, hyperlipidemia

(hypertriglyceridemia)

Everolimus Binds to FKBP12, which inhibits mTORC1 (and not mTORC2) Dyslipidemia, stomatitis, pericardial effusions, and

pancytopenia

recognized and can sometimes coexist. ACR occurs early after transplantation and then tends to decline in incidence after 6 months.

This occurs due to a T cell–mediated assault on the donor allograft

tissue and histologically is characterized by lymphocytic infiltrates in

the myocardium. In mild cases, these infiltrates are localized to the

perivenular regions, and in severe cases, they progress diffusely into the

cardiac interstitium. In late stages of severe ACR, most often associated

with hemodynamic compromise, multiclonal cells such as macrophages, neutrophils, and eosinophils are observed with intramyocardial

hemorrhage, myocyte injury, and myocyte necrosis. Subclinical ACR

is typically treated with high doses of corticosteroid pulses, although

some centers choose to simply observe mild forms of infiltration since

it is known that many of these patients may recover spontaneously

over time. If hemodynamic compromise occurs, rescue polyclonal

antibodies are used in tandem with corticosteroids. Conversely, AMR

is immunologically described as a noncellular antibody-driven phenomenon associated with a pattern of immunopathologic findings of

immunoglobulin deposition and complement fixation on immunofluorescence, along with histopathologic findings of endothelial swelling

and interstitial edema and cardiac allograft arteriolar vasculitis. AMR

is characterized by the emergence of circulating donor-specific antibodies that are thought to fix complement and bind to the allograft.

Commonly, AMR leads to allograft dysfunction, increases the risk

for development of cardiac allograft vasculopathy, and is associated

with worsened cardiac allograft survival compared with ACR. In this

form of rejection, therapy is directed toward suppression and removal

of circulating antibodies using plasmapheresis and drugs such as

rituximab (chimeric monoclonal antibody directed against the CD20

antigen) or, in refractory cases, bortezomib (a proteasome inhibitor)

or eculizumab (a terminal complement inhibitor). The treatment with

immunosuppression requires prophylaxis for opportunistic infections

and ongoing surveillance and expertise in recognizing the more common clinical presentations of infections caused by cytomegalovirus

(CMV), Aspergillus, and other opportunistic agents such as Nocardia

and toxoplasmosis.

■ LATE COMPLICATIONS AFTER CARDIAC

TRANSPLANTATION

The long-term consequences of exposure to chronic immunosuppression result in a variety of nonimmunologic cardiometabolic effects

such as hypertension, hyperlipidemia, and hyperglycemia, as well as

systemic disorders of bone loss and renal dysfunction. One aggressive

complication that limits late survival of cardiac allografts includes the

development of an accelerated form of coronary artery disease, referred

to as cardiac allograft vasculopathy (CAV). This is characterized by a

Cardiac Transplantation and Prolonged Assisted Circulation

1975CHAPTER 260

proliferative thickening of the vascular intima of the vasculature that

is initiated as a diffuse endothelialitis in the setting of the confluence

of the consequences of brain death, ischemia reperfusion injury during

the transplant process, and early immunologic insults. Chronically, the

metabolic consequences of hypertension, hyperlipidemia, and disordered glucose regulation result in worsening of vascular lesions that

are diffuse and noted throughout the coronary tree. Early diagnosis

and preventative therapy are critical since it is commonly silent in its

development. Intravascular ultrasound is more sensitive than routine coronary angiography for the diagnosis of CAV. A standardized

grading scheme for CAV was proposed by the International Society

for Heart and Lung Transplantation in 2010. CAV is graded as absent

(CAV0), mild (CAV1), moderate (CAV2), or severe (CAV3) based on

extent of angiographic disease and presence of allograft dysfunction

by echocardiography or restrictive cardiac physiology. The grade of

CAV correlates with patient prognosis. Angiographic CAV is present

in ~30% of patients by 5 years after transplant and ~50% of patients

by 10 years after transplant. Use of statins may help prevent CAV

development after heart transplantation. Antihypertensive agents and

anti-CMV therapy have demonstrated some benefits in reducing CAV

with varying degrees of supportive evidence. Antiproliferative immunosuppressive therapy such as mycophenolate mofetil and sirolimus or

everolimus prevents vascular intimal thickening compared with azathioprine-based regimens. Options for medical treatment of established

CAV remain limited. Revascularization using percutaneous coronary

intervention or coronary artery bypass grafting may be employed

in selected cases with focal lesions but does not improve survival in

patients with CAV. However, retransplantation is the only definitive

form of therapy for advanced CAV (Fig. 260-1).

Another concern in cardiac transplantation is the development of

malignancy with a greater frequency than in the normal population,

suggesting that immunosuppression plays a sentinel role in its generation. Posttransplant lymphoproliferative disorders, typically driven

by Epstein-Barr virus, occur most frequently and require a reduction

in immunosuppression, administration of antiviral agents, and traditional chemo- and radiotherapy. Specific antilymphocyte (targeted

against CD20) therapy has also shown promise. Solid cancers most

often manifest as skin malignancies (both basal cell and squamous cell

carcinomas), and regular use of sunscreen is advised. Future research

is required to define strategies for immune modulation, immune suppression, and malignancy prevention; however, the impact of decreasing immunosuppression in the treatment of these cancers is unclear.

PROLONGED ASSISTED CIRCULATION

The quest for a prolonged and durable implantable mechanical circulatory support device has led to the development of continuous flow

left ventricular assist systems (LVAS). Initially designed for short-term

support as a bridge to recovery or to cardiac transplantation, the most

frequent use today entails permanent support for lifetime therapy

(“destination therapy”). The decision to implant LVAS dichotomously

as either a bridge to transplantation or for destination therapy is not

always clear, and in several instances, these devices are used as a

“bridge to decision” (in those with potentially reversible underlying

relative contraindications such as renal insufficiency or pulmonary

hypertension, who may become future candidates for transplantation).

■ LEFT VENTRICULAR ASSIST SYSTEMS AND

CLINICAL TRIALS

A pivotal trial, REMATCH, published in 2001, was the first study to

reliably demonstrate that survival of patients with transplant-ineligible,

refractory, predominantly inotropic therapy–supported heart failure

is improved by implantation of an LVAS. This study used an early

generation pulsatile flow device and demonstrated a 48% reduction in

risk of death. However, the LVAS used was of limited durability, and

meaningful “out of hospital” survival was prolonged by a median of

only 5 months. Furthermore, complications of strokes, multisystem

organ failure, and infections reduced enthusiasm for widespread adoption. Over time, continuous flow systems that had small turbo-pumps

with minimal moving parts and no valves were introduced, leading to

greater durability and more generalized worldwide adoption.

A landmark trial compared the older bulky pulsatile LVAS studied

in the REMATCH trial with a newer generation axial continuous flow

LVAS, the HeartMate II, and demonstrated a marked improvement

in short- and long-term survival, along with an improvement in

functional capacity and meaningful quality-of-life enhancement. A

centrifugal continuous flow LVAS, the HeartWare HVAD, was also

Severe, diffuse, mid to distal luminal loss

Angiogram Pathology

Severe fibrotic intimal proliferation leading to luminal loss

IMMUNOLOGIC

FACTORS

IMMUNE ACTIVATION–

RELATED

INFLAMMATION

NONIMMUNOLOGIC

FACTORS

VASCULOPATHY

IVUS

FIGURE 260-1 Cardiac allograft vasculopathy is initiated and propagated by the combined influence of immunologic and nonimmunologic insults on the allograft vasculature.

An inflammatory milieu determines the development of diffuse, aggressive luminal blockages that in early forms exhibit intimal thickening and fibrosis. IVUS, intravascular

ultrasound (can be used to diagnose early forms of intimal thickening).

1976 PART 6 Disorders of the Cardiovascular System

introduced and demonstrated noninferiority to the HeartMate II pump.

A newer centrifugal device with a fully magnetically levitated system, the HeartMate 3 LVAS, is now the most commonly used pump.

Unlike the HeartMate II LVAS, which requires an abdominal pump

pocket, this smaller device is fully implanted in the thoracic cavity

(Fig. 260-2). This LVAS has been shown to nearly eliminate the complication of pump thrombosis and markedly reduce stroke rates, as

well as decrease bleeding complications. Real-world experience from

registry analyses has pointed to a median survival of >50% at 4 years

with currently available LVAS; however, long-term durability beyond

5–10 years remains a question. The patients for whom LVAS should

ideally be employed include those with severe persistent systolic heart

failure symptoms who have failed to respond to optimal medical management. Commonly, these patients have marked functional limitation

indicated by a peak oxygen consumption of <12 mL/kg per min, or the

patient is bound to continuous intravenous inotropic therapy owing to

symptomatic hypotension or demonstrates worsening renal function

or persistent refractory congestion. Currently, the role of LVAS in “less

sick” patients (those with moderate symptoms) is less well supported

since sufficient equipoise does not exist due to the adverse risk-benefit

ratio from device-related complications and because it needs to be tethered to an external driveline that connects to a power source.

■ MANAGEMENT OF LVAS AND THEIR

COMPLICATIONS

Continuous flow LVAS rely on pressure gradients between the left

ventricular cavity and the aorta. As such, forward flow is critically

dependent on management of systemic blood pressure. Due to the low

pulsatile nature of the blood flow, blood pressure is measured by using a

Doppler ultrasound (which measures mean or opening blood pressure,

which is less than the systolic blood pressure) since a peripheral pulse is

usually not detectable. The ideal mean arterial blood pressure should be

kept to ≤90 mmHg and antihypertensive drug therapy prescribed using

renin-angiotensin-aldosterone system drugs or other vasodilators. The

blood flow path through current devices results in increased shear

stress which may manifest in the form of low-grade hemolysis and the

development of an acquired von Willebrand disease due to loss of highmolecular-weight multimers of von Willebrand Factor. This hematologic aberration has been associated with a risk of gastrointestinal

bleeding, particularly resulting from arteriovenous malformations

in the intestines. Therefore, a common complication encountered in

patients is that of an anemia, often due to iron deficiency.

The unsupported right ventricle often demonstrates worsening

function and results in congestion requiring diuretic therapy. While

unloading of the left ventricle decreases right-sided afterload, increased

device flow results in a greater right heart preload, and effects of the

LVAS on the septum reduce right ventricular contractile efficiency,

leading to development of right ventricular dilatation and maladaptation between the right ventricle and pulmonary circuit. Cardiac

arrhythmias are common in patients supported with LVAS and often

require antiarrhythmic therapy since such events can trigger low flow

through the device.

Hemocompatibility-related adverse outcomes include neurologic

events (ischemic and hemorrhagic strokes), device-related thrombosis

leading to pump malfunction, and nonsurgical bleeding complications

(Fig. 260-3). Antiplatelet therapy using aspirin in doses of 81–325 mg

daily along with warfarin targeted to an international normalized ratio

of 2–3 is used with current LVAS to avoid the morbidity of hemocompatibility-related adverse events. On one hand, this therapy protects

against thrombotic complications, whereas on the other hand, it predisposes the patient to bleeding complications. Strokes occur with a

frequency ranging from 10% with the HeartMate 3 LVAS to as high

as 29% with the HeartWare HVAD device by 2 years of treatment.

Optimal control of blood pressure is associated with improved rates of

strokes with some devices such as the HeartWare HVAD pump; however, this complication is an important reason for lack of adoption of

device therapy in the less sick population. Another cause of morbidity

is pump thrombosis requiring reoperation for device malfunction.

This complication with the older devices was noted in 6–12% of LVAS

implants, occurs early (in the first 6 months), and is more commonly

encountered with the HeartMate II device than with the HeartWare

HVAD pump. The subclinical phase of LVAS thrombosis is characterized by increasing hemolysis and elevation in the device power.

Progressively, inability to “unload” the left ventricle is manifest leading

to decompensated heart failure and possibly hemodynamic compromise. Lactate dehydrogenase is an excellent (although nonspecific)

biomarker of hemolysis and hence impending or established pump

thrombosis. Patients who have suspected left ventricular assist device

LOW PULSE PRESSURE

Axial Flow Centrifugal Flow

Magnetically Levitated

Intrathoracic

Wide Blood Paths

Intrinsic Pulse @30 beats/min

HeartMate II HeartMate 3

Mechanical Bearing

Intrathoracic and Abdominal

Restrictive Blood Paths

No Intrinsic Pulse

Better device durability

Absence of pump thrombosis, fewer strokes, and less bleeding

Current New

CLINICAL IMPROVEMENT

FIGURE 260-2 Continuous flow left ventricular assist systems (LVAS) and their types and mechanisms. The mechanical bearing, axial flow HeartMate II pump is prone to

thrombosis, while the frictionless, magnetically levitated, centrifugal flow HeartMate 3 does not induce hemolysis or pump thrombosis.

Cardiac Transplantation and Prolonged Assisted Circulation

1977CHAPTER 260

(LVAD) thrombosis and do not undergo LVAD exchange or cardiac

transplantation have a 6-month mortality rate of 48%, inferring that

medical therapy for ventricular assist device thrombosis may be inadequate (or cause harm in the case of thrombolytic use). Reoperation

(pump exchange) carries a modest 6.5% perioperative mortality risk

and a 65% 2-year survival following exchange.

Infection is common, most often involving the driveline (the conduit connecting the device to the external controller and batteries) and

occurs in 1 in 5 patients following LVAS implant. Such an infection is

treated with local internal exploration and requires long-term suppressive antibiotics unless the patient undergoes cardiac transplantation

or the device is exchanged. Infection and its inflammatory sequelae

predispose to thrombosis and heighten the risk of neurologic complications, leading to a worsening milieu in hemocompatibility.

■ NOVEL DEVICES

The HeartMate 3 is a centrifugal, continuous flow pump that is placed

in the thorax and is engineered to be a more hemocompatible LVAS.

This device is constructed with a fully magnetically levitated motor,

offers wider blood flow paths, and exhibits a fixed intrinsic pulse (by

the motor ramping its speed up and down at 2-s intervals). These

features have been shown to reduce rates of hemolysis and decrease

the shearing of high-molecular-weight multimers of von Willebrand

factor. This pump has been tested in the MOMENTUM 3 trial, which

reported its final results in 1028 patients randomly allocated to either

the HeartMate 3 pump or the HeartMate II LVAS. The fully magnetically levitated HeartMate 3 pump was associated with less frequent

need for pump replacement than the HeartMate II device and was

superior with respect to survival free of disabling stroke or reoperation

to replace or remove a malfunctioning device. The need for pump

replacement and occurrence of stroke of any severity, major bleeding,

or gastrointestinal hemorrhage were lower in the centrifugal-flow

pump group than in the axial-flow pump group. Experience beyond

5 years with this LVAS will be important in discerning whether these

findings result in improved long-term survival.

■ TOTAL ARTIFICIAL HEART

Not all patients are candidates for an LVAS, particularly those with

severe right-sided heart failure or conditions that do not allow placement of an LVAS (restrictive cardiomyopathy, massive anterior myocardial infarction, complex congenital heart disease). In such patients,

either a biventricular assist device approach or a total artificial heart

pump can be considered. The SynCardia total artificial heart is a

pulsatile, implantable pump that consists of two polyurethane ventricles

with pneumatically driven diaphragms and four tilting disc valves. This

requires excision of the native ventricles and thus cannot be employed

as a myocardial recovery strategy. There are specific clinical issues that

are unique to the total artificial heart management. This device operates

on a steep physiologic curve and has little adaptability to tolerate either

systemic blood pressure changes or large shifts in blood volume. As

the ventricles are excised, most patients exhibit a sharp decline in renal

function due to the loss of natriuretic peptide expression by the myocardium. Severe hemolysis is common due to the presence of four mechanical valves, and aberrant erythropoiesis is noted, leading to a severe

anemia. Newer artificial hearts using biocompatible surfaces are under

development, as well as those that use continuous flow technology.

■ GLOBAL CONSIDERATIONS

While LVAS are available worldwide, their use and indications vary

from country to country. In the United States, payers used to require

discrete discrimination of indication into either a bridge to transplant

or destination therapy, whereas in most European countries, this

artificial segregation was not used. Cost-effectiveness studies suggest

improvement with the newer devices, yet some countries only allow

use of this technology as a bridge to transplantation (United Kingdom)

while awaiting more definitive long-term studies for lifetime use. The

use of LVAS in moderately symptomatic ambulatory patients with

chronic systolic heart failure is still discouraged throughout the world,

awaiting the availability of hemocompatible devices that can be fully

internalized without the need for an external driveline. Globally, the

rates of myocardial recovery allowing for decommissioning or removal

of devices remain low.

■ FURTHER READING

Aslam S et al: Utilization of hepatitis C virus-infected organ donors

in cardiothoracic transplantation: An ISHLT expert consensus statement. J Heart Lung Transplant 39:418, 2020.

Berry GJ et al: The 2013 International Society for Heart and Lung

Transplantation Working Formulation for the standardization of

nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 32:1147, 2013.

Mehra MR: Contemporary concepts in prevention and treatment of

cardiac allograft vasculopathy. Am J Transplant 6:1248, 2006.

Mehra MR et al: International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac

allograft vasculopathy-2010. J Heart Lung Transplant 29:717, 2010.

02

03

01

HEMOCOMPATIBILITY-RELATED ADVERSE EVENTS

PUMP

THROMBOSIS

01

GASTROINTESTINAL

BLEEDING

02 CEREBROVASCULAR

DISEASE

03

PUMP THROMBOSIS results in need for reoperation and

occurs with a high rate with the HeartMate II (10–14%) and

HeartWare HVAD (6–8%) LVAS; no hemolysis and near

elimination of pump thrombosis with the HeartMate 3 LVAS

GASTROINTESTINAL BLEEDING is associated with

diminished pulsatility, defects in von Willebrand factor,

development of AV malformations, and antiplatelet and

anticoagulation intensity

CEREBROVASCULAR DISEASE includes strokes

(ischemic and bleeds), TIA, and seizures; occurrence

correlated with blood pressure control and antiplatelet

therapy for some devices

FIGURE 260-3 Hemocompatibility-related adverse events with left ventricular assist systems (LVAS) are often interrelated and typically result in cerebrovascular,

gastrointestinal, or pump malfunction events. AV, atrioventricular; TIA, transient ischemic attack.

1978 PART 6 Disorders of the Cardiovascular System

Mehra MR et al: The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update.

J Heart Lung Transplant 35:1, 2016.

Mehra MR et al: A fully magnetically levitated left ventricular assist

device: Final report. N Engl J Med 380:1618, 2019.

Messer S et al: Outcome after heart transplantation from donation

after circulatory-determined death donors. J Heart Lung Transplant

36:1311, 2017.

Nair N et al: Long-term immunosuppression and malignancy in thoracic transplantation: Where is the balance? J Heart Lung Transplant

33:461, 2014.

Rogers JG et al: Intrapericardial left ventricular assist device for

advanced heart failure. N Engl J Med 376:451, 2017.

Stewart GC, Mehra MR: A history of devices as an alternative to

heart transplantation. Heart Fail Clin 10:S1, 2014.

GLOBAL BURDEN OF VALVULAR

HEART DISEASE

Primary valvular heart disease ranks well below coronary heart disease, stroke, hypertension, obesity, and diabetes as a major threat to

the public health. Nevertheless, it can cause significant morbidity and

lead to premature death. Rheumatic fever (Chap. 359) is the dominant

cause of valvular heart disease in low- and middle-income countries.

Its prevalence has been estimated to range from as low as 1 per 100,000

school-age children in Costa Rica to as high as 150 per 100,000 in

China (Fig. 261-1). Rheumatic heart disease accounts for 12–65% of

hospital admissions related to cardiovascular disease and 2–10% of

hospital discharges in some endemic countries. Prevalence and mortality rates vary among communities even within the same country as

a function of overcrowding and the availability of medical resources

and population-wide programs for detection and treatment of group A

streptococcal pharyngitis. In economically deprived areas, tropical and

subtropical climates (particularly on the Indian subcontinent and in

261 Aortic Stenosis

Patrick T. O’Gara, Joseph Loscalzo

Southeast Asia), Central America, and the Middle East, rheumatic valvular disease progresses more rapidly than in more developed nations

and frequently causes serious symptoms in patients aged <20 years. This

accelerated natural history may be due to repeated infections with more

virulent strains of rheumatogenic streptococci. Approximately 30–35

million people live with rheumatic heart disease worldwide, an estimated prevalence characterized by 300,000 new cases and 233,000 case

fatalities per year, with the highest prevalence and age-adjusted mortality rates in sub-Saharan Africa, South Asia, and Oceania. The major

drivers of untreated streptococcal pharyngitis in these endemic areas

include reduced access to high-quality health care and social determinants of health. In the United States, rheumatic heart disease accounted

for 3320 deaths in 2017. Although globally the age standardized mortality rate from rheumatic heart disease declined by nearly 50% between

1990 and 2015, the prevalence of heart failure attributable to rheumatic

heart disease increased by nearly 90% over the same time interval.

Although there have been recent reports of isolated outbreaks of

streptococcal infection in North America, valve disease in high-income

countries is dominated by degenerative or inflammatory processes

that lead to valve thickening, fibrosis, calcification, and dysfunction.

The prevalence of valvular heart disease increases significantly with

age. The prevalence of undiagnosed moderate or severe valvular heart

disease is ~6% in individuals aged >65 years. Significant left-sided

valve disease may affect as many as 12–13% of adults aged >75 years

(Fig. 261-2). Severe aortic stenosis (AS) is estimated to affect 3.5%

of the population aged >75 years. A Swedish epidemiologic study

estimated the incidence of newly diagnosed valvular heart disease at

64 per 100,000 person-years. AS and mitral regurgitation contributed

approximately one-half and one-quarter, respectively, of the valvular

heart disease diagnoses in this study.

The incidence of infective endocarditis (Chap. 128) has increased

with the aging of the population, the more widespread prevalence

of vascular grafts and intracardiac devices, the emergence of more

virulent multidrug-resistant microorganisms, the growing epidemic

of diabetes mellitus, and the opioid crisis. The more restricted use of

antibiotic prophylaxis since 2007 has not been convincingly associated

with an increase in incidence rates for infective endocarditis cases

attributable to oropharyngeal pathogens. Infective endocarditis has

become a relatively more frequent cause of acute valvular regurgitation. Valve surgery during the acute phase of infective endocarditis is

performed in ~50% of hospitalized patients. Duration of intravenous

antibiotic use may be shortened in selective cases.

Change in agestandardized prevalence

(1990–2013)

>20% decrease

<50,000

<100,000

<500,000

<1,000,000

<2,500,000

<5,000,000

<8,000,000

<8,000,000

>20% increase

No data available

<5% decrease

<5% increase

11–20% decrease

5–10% decrease

5–10% increase

5–20% increase

Number of prevalent

case (2013)

FIGURE 261-1 The global burden of rheumatic heart disease. This world map provides a snapshot of both the change in prevalence of rheumatic heart disease cases

between 1990 and 2013 (upper right legend) and the estimated number of rheumatic heart disease cases per country (lower right legend). Regions in which the disease is

highly prevalent include sub-Saharan Africa, India, China, and Southeast Asia. (Reproduced with permission from JR Carapetis et al: Acute rheumatic fever and rheumatic

heart disease. Nat Rev Dis Primers 2:15084, 2016.)