B P6 C52 The Dilated, Restrictive, and Infiltrative Cardiomyopathies Flashcards
_____ is characterized by an enlarged left ventricle with systolic dysfunction that is not caused by ischemic or valvular heart disease.
DCM
Due to the prevalence of ischemic cardiomyopathy, the most common clinical and clinical research approach is to sort DCM into _____
Ischemic or nonischemic categories
Electrocardiography in DCM frequently reveals _____
LV hypertrophy
Nonspecific ST-T wave changes
Bundle branch block
Conduction system disease in DCM has specific gene associations (e.g., _____ cardiomyopathy)
LMNA
In advanced cases of DCM with extensive fibrosis, _____ limb leads may be seen.
Low-voltage
Echocardiography in patients with DCM reveals LV _____ that may also show biventricular dysfunction in at least one third of cases, all of which can range from mild to severe.
Systolic dysfunction
In DCM, most commonly, _____ LV hypokinesis is present, but regional wall motion abnormalities may also be seen, particularly septal dyskinesis in those with left bundle branch block
Global
Echo in DCM: A _____ pattern is most commonly seen in patients with volume overload in “decompensated” heart failure and often improves with initiation of diuretic or vasodilator therapy.
Restrictive
Coronary angiography in DCM should be considered in all patients who have risk factors for CAD, most importantly cigarette smoking or a prominent family history of early-onset CAD observed in familial hypercholesterolemia, or in those who are of an age where CAD is commonly observed regardless of added risk factors, conventionally above ___ years in males and above ___ years in females.
Males > 40 years
Females > 45 years
Cardiac magnetic resonance imaging (CMR) in DCM has become foundational for the evaluation of a patient who presents with a recently diagnosed cardiomyopathy. A pattern of _____ suggests a nonischemic cause.
Nontransmural delayed gadolinium enhancement in a noncoronary distribution in a dilated left ventricle
In a significant proportion of patients with DCM, no obvious cause can be found even with a comprehensive clinical evaluation; these patients are assigned a diagnosis of _____
Idiopathic DCM
Patients with DCM typically have an _____ phase for many years before symptomatic heart failure, an arrhythmia, or an embolic event develops later in the course of the disease
Asymptomatic
Truncating variants in the giant scaffolding protein _____ have been shown to be the most common, associated with 10% to 20% of cases of DCM depending upon cohort studied
The only general variation in phenotype commonly recognized is “DCM with prominent conduction system disease,” which has been observed in _____ DCM and some cases of sodium channel (SCN5A) or desmin (DES) DCM
Titin (TTN)
Lamin A/C (LMNA)
Most cases of familial DCM are transmitted via _____ inheritance, with the offspring of a mutation carrier having a 50% chance of inheriting the rare variant
Autosomal dominant
Therapy for DCM is similar to that for all types of _____
HFrEF
_____ is now considered a genetically determined cardiomyopathy that has been historically characterized by lethal arrhythmias in relatively young adults and with fibrofatty replacement of the myocardium, especially of the right ventricle.
ARVC
A recognized misnomer in the ARVC term is that biventricular involvement occurs in up to ___% of cases and a small proportion of cases affect predominantly the left ventricle
50% Biventricular
ARVC is classically conceptualized as having three stages: _____
(1) an early subclinical phase in which imaging studies are negative but during which sudden cardiac death can still occur;
(2) a phase in which (usually) RV abnormalities are obvious without any clinical manifestation of RV dysfunction but with the development of a symptomatic ventricular arrhythmia
(3) progressive fibrofatty replacement and infiltration of the myocardium leading to severe RV dilation and aneurysm formation and associated right-sided heart failure. LV dilation and failure may also arise at this stage or may occur later (sometimes referred to as phase 4)
_____ is a key facilitator of arrhythmias at all stages of ARVC
Exercise
The electrical manifestations of ARVC reflect the pathologic disturbance. In the early stage,_____ may lead to a fatal arrhythmia. As the disease progresses, _____ results in inhomogeneous activation and a further delay in conduction
Early: slow conduction and electrical uncoupling
Progression: fibrofatty infiltration
The predominant site of cardiac involvement in ARVC, known as the triangle of dysplasia, was believed to involve the _____. However, recent data suggest that the RV apex is only involved in advanced disease and that an area involving the _____ and ______ may be most commonly involved
RV outflow tract
Area below the tricuspid valve
RV apex
Basal inferior and anterior RV
Posterolateral LV
Patients with ARVC exhibit a typical monomorphic ventricular tachycardia (VT) characterized by _____. A classic “epsilon wave” in the right precordial leads is a specific but insensitive finding
LBBB morphology with a superior axis
Typical T wave inversions extending to V3 or beyond
The classic hallmark of ARVC, fibrofatty replacement, is now understood to be related to aberrant Wnt signaling of _____ proteins, as well as direct plakoglobin signaling, which transforms myocytes into adipocytes with disease progression.
Desmosomal
Diagnostic Terminology for Revised Criteria of ARVC
Definite:
2 Major
1 Major + 2 minor* (IE criteria -1)
4 mino*
Borderline:
1 major + 1 minor
3 minor
Possible:
1 Major
2 minor
Major criteria in the diagnosis of ARVC
I. Global and/or regional dysfunction and structural alterations
By two-dimensional echocardiography:
- Regional RV akinesia, dyskinesia, or aneurysm and one of the following (end diastole):
– RVOT PLAX>/= 32 mm (19 mm/m2)
– RVOT PSAX>/= 36 mm (21 mm/m2)
OR
- Fractional area change <33%
By MRI:
- Regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and one of the following:
–Ratio of RVEDV to BSA 110 mL/m2 (male) or >/=100 mL/m2 (female) or RVEF </= 40%
By RV angiography:
Regional RV akinesia, dyskinesia, or aneurysm
II. Tissue Characterization of Wall
Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of RV free wall myocardium in at least one sample, with or without fatty replacement of tissue seen on endomyocardial biopsy
III. Repolarization Abnormalities
Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in absence of complete right bundle branch block QRS >/= 120 msec)
IV. Depolarization/Conduction Abnormalities
Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of T wave) in right precordial leads (V1–V3)
When a genetic cause can be identified, rare variants in the genes encoding _____ account for most genetic causes of ARVC
Plakophilin 2 (PKP2)
Desmoglein 2 (DSG2)
Desmoplakin (DSP)
The autosomal recessive syndromic _____, so named because it was discovered on the Greek island of Naxos, is manifested as ARVC cosegregating with palmoplantar keratoderma and wooly hair
Naxos disease
ARVC
Plakoglobin
A second autosomal recessive syndromic disease, _____, resembles Naxos disease in that individuals have palmoplantar keratoderma and wooly hair, but individuals with Carvajal syndrome manifest DCM, not ARVC. Carvajal syndrome is caused by a frameshift rare variant in DSP, which encodes desmoplakin.
Carvajal syndrome
DCM
Desmoplakin
The differential diagnosis of ARVC in the early stages (before the onset of visible structural abnormalities) includes _____ VTs.
Idiopathic and RVOT VT
The morphology of the classic ARVC-related VT differs from these entities, and in the presence of _____ during sinus rhythm, ARVC should be the initial diagnosis. Cardiac sarcoidosis may occasionally mimic ARVC morphologically and be indistinguishable, even with multiple imaging modalities.
Precordial T wave inversion during sinus rhythm
Cardiac biopsy in patients with sarcoidosis often fails to show the pathognomonic granulomas but may reveal extensive _____, which may also be confused with ARVC.
Fibrosis
Intense physical exertion is associated with an earlier onset of symptoms and an increased risk of sustained VT, and therefore patients with a diagnosis of ARVC are advised not to participate in _____.
Athletic activity
The classic monomorphic VT in ARVC with predominant RV involvement is generally well tolerated, even at a rapid rate, possibly because of _____ LV function in most patients.
Preserved LV function
Antiarrhythmic drugs may suppress a symptomatic arrhythmia but have not been shown to prevent sudden death. ____ agents may suppress catecholamine-triggered arrhythmia and slow progression of ventricular dysfunction and have been recommended as potentially valuable in all patients with ARVC.
Beta blockers
An _____ is recommended in patients with aborted sudden death, synope, or decreased LV function and may be considered in other patients with ARVCb
ICD
Catheter ablation has not been shown to reduce sudden death in ARVC but is valuable in a patient with an ICD and frequent arrhythmias or in occasional patients with very well-tolerated single-morphology VT.
Ablation appears to be most successful when lesions are made in both the _____t; it should be performed only at centers experienced in the technique, either as a combined procedure or with epicardial ablation reserved for recurrence after endocardial ablation
Epicardial and endocardial surfaces of the heart
Because a history of _____ among carriers of a pathogenic ARVC desmosome rare variant is associated with an earlier onset of symptoms and a higher prevalence of VT or ventricular fibrillation, there is a task force recommendation that persons with definite or suspected ARVC should not compete in most competitive sports.
Vigorous sustained exercise
Class I indication for ICD implantation in ARVC
High Risk:
Aborted SCD due to VF
Sustained VT
Severe dysfunction of RV, LV, or both
Echocardiographic Diagnostic Criteria for Left Ventricular Noncompaction
Chin et al. (California criteria)*
- LVNC is defined by an X/Y ratio </= 0.5
- These criteria evaluate trabeculae at the LV apex on the parasternal short axis and apical views and by using the LV free wall thickness at end- diastole
Jenni et al. (Zurich criteria)†
- Bilayered myocardium consisting of a thin C layer and a much thicker NC layer with deep endomyocardial recesses: NC/C >2
- Predominant location of the pathology is midlateral, midinferior, and at the apex
- Evidence of intertrabecular recesses filled with blood from the LV cavity
- Acquisition of image views: short axis with measurement of the NC/C ratio performed at end-systole
MRI Diagnostic Criteria for LVNC
Petersen et al.
Ratio between NC and C layers >2.3 at end-diastole
Jacquier et al.
Trabeculated LV mass >20% of global LV mass (measurements made at end-diastole)
The “purest” form of tachycardia-induced cardiomyopathy is probably that caused by _____, often in a child or young patient with systolic dysfunction
Incessant or extremely frequent atrial tachycardia or permanent reciprocating junctional tachycardia
The _____ of the arrhythmia, more than the heart rate, is probably a critical factor in tachycardia-induced cardiomyopathy.
Duration
Most patients with PVC-associated tachycardia-induced cardiomyopathy have more than _____ PVCs over a 24-hour period, but the condition has also been described with a lesser frequency of arrhythmia.
> 20,000/24H
Most cases of tachycardia-induced cardiomyopathy improve within _____months after correction of the arrhythmia, but occasionally patients have been seen with late improvement, up to 1 year
3-6 months
Because the rapid, irregular ventricular response to atrial fibrillation is associated with marked beat-to-beat variation in the ejection fraction, the most accurate way to determine whether an improvement in systolic function has really occurred is to evaluate the ejection fraction_____ and then compare it with a reevaluation 3 to 6 months later.
Early after restoration of sinus rhythm
_____ has been defined as DCM that occurs in a temporal relationship to pregnancy
Peripartum cardiomyopathy (PPCM)
Definitive evidence of this was recently shown, where 172 women with PPCM underwent sequencing for DCM genes, with _____ identified in 26 of the 172 (15%)
TTN truncating variants (TTNtvs)
The U.S. incidence is estimated to be between 1 in 1000 and 1 in 4000 live births, with a major risk factor that of _____ ancestry; significantly higher incidence has been reported in countries with predominant African ancestry. _____ are also risk factors.
African ancestry
Preeclampsia
Older age
Multiple-fetus pregnancies
In patients with PPCM, symptoms and signs of heart failure develop during late pregnancy or after delivery, similar to those of any patient with heart failure caused by LV systolic dysfunction. Most diagnoses are made in the _____ months following delivery; prepartum diagnoses are most commonly made in the _____ month of pregnancy.
4 months after delivery
Last month of pregnancy
In approximately _____% of patients with PPCM who are given standard medical therapy, the LV ejection fraction returns to normal, although the patients may still be at risk for recurrent PPCM. The remainder are often stabilized with medical therapy; however, a proportion of patients may experience progressive heart failure.
50%
However, if heart failure occurs during pregnancy, ACE inhibitors or angiotensin-receptor blockers are contraindicated because of the risk for fetotoxic effects. Diuretics should be used with caution, and _____ should be used rather than carvedilol. Eplerenone should be avoided, but _____ can be used cautiously later in pregnancy
Metoprolol
Spironolactone
Takotsubo cardiomyopathy (TC) (referred to as Takotsubo syndrome [TTS] in Europe) or stress-induced cardiomyopathy, is an acute, reversible condition first recognized in the 1990s
_____ was the predominant symptom in 76%, dyspnea in 47%, and syncope in 7.7% in TTS.
Chest pain
A preceding physical trigger occurred in 36% and an emotional trigger in 28%, and troponin values were elevated in 87%, with ST elevation shown on the ECG in almost _____ of the patients with TC.
1/2
While men can be affected, women are ____-fold more likely to show TC overall, and women older than 55 years are five times more likely to experience TC compared to those less than 55 years. Of those younger than 50 years, men were more commonly affected with more antecedent neurologic or psychiatric disorders compared to older individuals
10 fold
A complete explanation for the pathophysiology of TC remains elusive, but _____ appears central, with an identifying emotional or physiologic stimulus preceding onset in most cases
Activation of the sympathetic nervous system
The LV contractile abnormalities in TC are prominent, and although they involve the _____ in more than 80% of patients, regional wall motion abnormalities may be limited to the midventricular wall or other LV walls in a minority of patient
LV apex (resulting in the synonym of “apical ballooning syndrome”)
In TC, compensatory hyperdynamic contraction of the _____ segments with associated _____ may result in acute LV outflow tract obstruction because of systolic anterior motion of the mitral valve with an associated outflow tract gradient and hypotension.
Basal LV segments + apical LV dyskinesis
Malignant ventricular arrhythmia, particularly _____ associated with Takotsubo-related QT prolongation, may occur, as (rarely) may complete heart block
Torsades de pointes
International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)
- Patients show transient left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or midventricular, basal, or focal wall motion abnormalities. Right ventricular involvement can be present. Besides these regional wall motion patterns, transitions between all types can exist. The regional wall motion abnormality usually extends beyond a single epicardial vascular distribution; however, rare cases can exist where the regional wall motion abnormality is present in the subtended myocardial territory of a single coronary artery (focal TTS).
- An emotional, physical, or combined trigger can precede the takotsubo syndrome event, but this is not obligatory.
- Neurologic disorders (e.g., subarachnoid hemorrhage, stroke/transient ischemic attack, or seizures) as well as pheochromocytoma may serve as triggers for takotsubo syndrome.
- New electrocardiogram (ECG) abnormalities are present (ST-segment elevation, ST-segment depression, T wave inversion, and QTc prolongation); however, rare cases exist without any ECG changes.
- Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain natriuretic peptide is common.
- Significant coronary artery disease is not a contradiction in takotsubo syndrome.
- Patients have no evidence of infectious myocarditis.**
- Postmenopausal women are predominantly affected.
*Wall motion abnormalities may remain for a prolonged period of time or documentation of recovery may not be possible. For example, death before evidence of recovery is captured.
**Cardiac magnetic resonance imaging is recommended to exclude infectious myocarditis and diagnosis confirmation of takotsubo syndrome.
An InterTAK Clinical Score to Differentiate Takotsubo Syndrome from Acute Coronary Syndrome
Female sex 25 points
Emotional stress 24 points
Physical stress 13 points
No ST-segment depression (except aVR) (12 points)
Psychiatric disorders 11 points
Neurologic disorders 9 points
QTc prolongation 6 points
</=70 points, low/intermediate probability of TTS
>70 points, high probability
Classification of TC has been recommended into lower- risk and higher-risk categories, with the latter based on an _____.
LV ejection fraction of < 45%
Hypotension
Outflow tract gradient of > 40 mm Hg
Presence of an arrhythmia
Use of an _____ or both, is recommended in the higher-risk groups of TC
ACE inhibitor or a beta blocker
In patients with hypotension associated with TC, pressors should be used with caution because _____ may be precipitated
LV outflow tract obstruction
In most cases of TC resolution is complete or nearly complete within _____, although the major adverse events, including cardiogenic shock or death, mandate observation of the acute phase of TC in an intensive care unit (ICU) setting
Days to weeks
Major adverse events in TC occur in approximately 5% of individuals, with _____ most at risk.The recurrence risk has been estimated at 5%, usually within the first year
Younger males
in patients with TC, the use of _____ long term have been shown to reduce recurrence. In contrast, prophylactic use of _____ has not been shown to reduce recurrence, even though attempting to minimize a catecholamine-induced trigger provides a rationale for their use.
ACE inhibitors: Reduces recurrence
Beta blockers: Does not reduce recurrence
The _____ are a heterogeneous group of diseases characterized by a nondilated left ventricle, often with a normal or near-normal LV ejection fraction
RCMs
The predominant manifestation is _____ as a result of myocardial disease, and although severe hypertensive disease, aortic stenosis, and some cases of HCM may feature restrictive pathophysiology, these conditions are not classified as RCMs.
Diastolic dysfunction
_____ has increased the diagnostic yield and thus reduced the need for endomyocardial biopsy. When a cause cannot be identified, the condition is known as idiopathic RCM
CMR imaging with T1, T2, and extracellular volume mapping
Symptoms of idiopathic RCM are nonspecific and reflect the presence of heart failure. _____ is an initial complaint in most patients; edema occurs in approximately half; and palpitations, fatigue, and orthopnea are reported by 22% to 33%
Dyspnea
Physical examination in RCM is usually consistent with _____, with jugular venous distention noted in most patients but ascites and significant edema being found in advanced cases
Biventricular heart failure
Echocardiography in RCM reveals a typical pattern of _____.
Biatrial enlargement and nondilated ventricles with a normal or near normal LV ejection fraction and LV wall thickness
Cardiac catheterization in RCM, _____ often seen; unlike in constrictive pericarditis, however, equalization of diastolic pressures is uncommon. Careful evaluation of simultaneously recorded LV and RV pressures during respiration demonstrates _____ in systolic pressures in RCM, rather than a discordance (inspiratory increase in RV systolic pressure with a simultaneous decrease in LV pressure) seen in constrictive pericarditis
RV and LV filling pressures are elevated with a dip-and-plateau tracing
Concordant changes
Endomyocardial biopsy in RCM demonstrates nonspecific findings such as _____.
Myocyte hypertrophy
Interstitial fibrosis
Endocardial fibrosis
Treatment of idiopathic RCM is generally limited to medical treatment emphasizing judicious use of _____, but in selected advanced cases, cardiac transplantation has been performed with similar outcomes as in those with nonrestrictive cardiomyopathy
Diuretics
_____ is a multisystem disorder of unknown cause characterized histologically by noncaseating granulomas.
Sarcoidosis
Cardiac involvement in sarcoidosis takes the form of _____.
Ventricular dysfunction
Heart block
Ventricular arrhythmias
_____, presumably from heart block or a ventricular arrhythmia, may be the first manifestation either of sarcoidosis itself or of heart disease in a patient with known pulmonary or systemic sarcoid.
Sudden death
The prevalence of cardiac involvement in patients with pulmonary sarcoidosis was previously thought to be no more than 5%, but autopsy studies indicate a much higher prevalence, and recent cardiac imaging studies have demonstrated abnormalities in at least ___% of patients with pulmonary sarcoidosis
25%
The pathology of sarcoid heart disease raises puzzling questions about the cause of the systolic dysfunction, which can be severe. _____, the hallmark of the disease, are patchily distributed even in severe disease and thus may not alone account for the severe systolic dysfunction
Noncaseating granulomas
The _____ render cardiac biopsy a low-yield procedure for detecting diagnostic histology in cardiac sarcoidosis, and finding granulomas may be difficult even at autopsy, because end- stage disease is characterized predominantly by fibrosis.
(1) Patchy nature of granulomatous infiltration
(2) Sometimes extensive fibrosis
_____ function can be impaired in patients with severe pulmonary sarcoidosis and pulmonary hypertension, even in the absence of direct sarcoid involvement of the heart.
RV
The most common noncardiac site of sarcoid involvement is the _____, with approximately half of patients having overt parenchymal disease and the remainder having isolated bilateral hilar lymphadenopathy.
Lungs
In patients with established extracardiac sarcoid, _____ dysfunction is most commonly due to associated cardiac sarcoidosis.
LV systolic dysfunction
The most common clinical feature of cardiac sarcoidosis is _____.
Biventricular heart failure
Sarcoid granulomas have a predilection for the _____, and high-degree atrioventricular (AV) block may occur, either as an initial manifestation of cardiac sarcoidosis or later in the disease
Cardiac conduction system
A rare manifestation of cardiac sarcoidosis is acute sarcoid myocarditis, characterized by _____.It may be difficult to distinguish this from giant cell myocarditis unless systemic features of sarcoid are also present.
High-degree AV block
Malignant ventricular arrhythmia
Heart failure
CMR with gadolinium enhancement in cardiac sarcoidosis is a sensitive test for detecting cardiac abnormalities. Delayed gadolinium enhancement may be:
(1) Found in either a coronary or non- coronary distribution
(2) Usually nontransmural
(3) Hredilection for the basal and/or midventricular septum
In the acute stage of cardiac sarcoidosis, T2-weighted imaging may show myocardial edema, which is characterized by _____ on T2-weighted and early gadolinium-enhanced images
Focal areas of thickening and increased signal intensity
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning is complementary to CMR in patients with sarcoidosis; it reveals _____, permits serial evaluation of response to therapy, and is becoming an important tool for the diagnosis and management of cardiac disease
Areas of inflammation in active disease
Steroids are frequently effective in noncardiac sarcoidosis,and nonrandomized data suggest a benefit in patients with cardiac sarcoid complicated by heart failure, particularly early in the disease when irre- versible fibrosis has not yet developed. Prednisone is generally initiated in doses between _____ and tapered gradually over a period of several months with careful monitoring. _____ is often used as a second agent if steroid therapy is unsuccessful, and several recent case reports have shown promising responses to anti-tumor necrosis factor (anti-TNF) monoclonal antibodies.
Prednisone: 1 mg/kg and 40 mg daily
Methotrexate
On the assumption that high-degree AV block in systemic sarcoidosis is a marker of associated myocardial sarcoidosis, use of a _____ has been recommended for any patient with sarcoidosis who requires pacing
Pacemaker-ICD
Initial tests in a patient presenting with: Unexplained sustained 2nd-degree or 3rd-degree AV block in young adults (<55 yr) and/orsSustained monomorphic VT idiopathic dilated cardiomyopathy
High resolution CT chest
Advanced cardiac imaging utilizing CMR or FDG-PET† (consider availability and expertise)
Tests following biopsy proven extracardiac sarcoidosis
12 lead ECG
Holter
2DED
Class I recommendations from Heart Rhythm Society Recommendations for Management of Arrhythmia in Cardiac Sarcoidosis
Diagnosis and screening:
(1) It is recommended that patients with biopsy-proven extracardiac sarcoidosis should be asked about unexplained syncope/presyncope/significant palpitations.
(2) It is recommended that patients with biopsy-proven extracardiac sarcoidosis should be screened for cardiac involvement with a 12-lead electrocardiogram.
Implantable Cardioverter-Defibrillator Implantation:
(1) Spontaneous sustained ventricular arrhythmias, including prior cardiac arrest
(2) LVEF </= 35% despite optimal medical therapy and a period of immunosuppression (if there is active inflammation)
Fabry disease is caused by progressive lysosomal accumulation of _____, primarily globotriaosylceramide; it results from deficiency of the enzyme _____, which is encoded by GLA on the X chromosome.
Accumulation of: Neutral glycosphingolipids
Deficiency of: alpha-galactosidase A
Gaucher disease is an autosomal recessive glycogen storage disease that results from deficient _____ enzyme activity caused by homozygous or compound heterozygous rare variants in GBA
Deficiency of: beta-glucocerebrosidase
_____ is a disease caused by iron overload in which iron infiltrates major organs, especially the liver, heart, thyroid, gonads, skin, and pancreatic islet cells, to give the characteristic clinical findings of advanced disease that include cirrhosis, cardiomyopathy, diabetes, and endocrine disease.
Hemochromatosis
_____ is an autosomal recessive disease that in almost all cases results from the homozygous rare variant Cys282Tyr, although 3% to 8% of cases are compound heterozygotes for Cys282Tyr and His63Asp
HFE (hemochromatosis gene)-associated hereditary hemochromatosis
Screening tests include _____, with the accepted level being 200 ng/mL in women and 300 ng/ mL in men or 45% in women and 50% in men. If both tests are negative, iron overload is effectively excluded.
Serum ferritn
Women: 200 ng/mL
Men: 300 ng/mL
AND
Percent transferrin saturation
Women: 45%
Men: 50%
With elevated transferrin saturation, molecular genetic testing for _____ is indicated.
HFE
With elevated transferrin saturation and ferritin levels higher than 1000, _____ is indicated.
(1) Iron removal, usually by phlebotomy
(2) Evaluation of liver and cardiac function
A definitive tissue-based diagnosis of iron overload causing cardiac dysfunction can also be made by _____, which may be particularly useful if other testing is inconclusive or the degree of cardiovascular involvement by hemochromatosis is confounded by other cardiovascular disease (e.g., coronary disease).
Endomyocardial biopsy
Definitive treatment is centered on _____ in HFE-associated hereditary hemochromatosis, and as iron stores are depleted, cardiac function will improve in most cases, sometimes to a dramatic degree. Cardiac transplantation can be avoided in most patients with timely diagnosis and phlebotomy.
Iron removal, usually by phlebotomy
_____,a disease first described in Uganda in 1948 (initially termed tropical endocar- dial disease or endocardial fibroelastosis [EFE]),may well be the most common cause of RCM worldwide
Endomyocardial fibrosis (EMF)
Carcinoid heart disease is a rare condition that occurs as part of carcinoid syndrome, a systemic disorder mediated by elevated circulating levels of vasoactive substances, including _____ produced by a rare metastatic neuroendocrine malignancy, carcinoid.
Serotonin (5-hydroxytryptamine [5-HT])
5-hydroxytryptophan
Histamine
Bradykinin
Tachykinins
Prostaglandins
Carcinoid syndrome is characterized by a triad of symptoms—_____—that occur in association with hepatic metastases
Flushing
Diarrhea
Bronchospasm
The metastases in Carcinoid Heart Disease produce high levels of these vasoactive substances, particularly 5-HT, which reaches the systemic circulation via the hepatic vein. High levels in the right side of the heart cause progressive _____
Fibrotic endocardial plaque
Inactivation in the _____to hydroxyindoleacetic acid (5-HIAA) generally protects the left-sided heart structures
in carcinoid heart disease, but these structures may become involved if levels are very high or if a patent foramen ovale allows right- to-left shunting.
Lung
The characteristic pathologic features of carcinoid heart disease are:
(1) Right-sided valve thickening and retraction resulting from myofibroblast proliferation along with
(2) deposition of collagen and smooth muscle cell
Tricuspid annular and subvalvar involvement and pulmonary root constriction also occur, thereby adding to the valvular dysfunction. Very rarely the heart is involved directly by carcinoid metastases.
Elevation of urinary _____ levels is highly specific and moderately sensitive for the diagnosis of carcinoid syndrome, and the echocardiographic and CMR features of _____ are highly suggestive of carcinoid heart disease
Urine: 5-HIAA
Echo/CMR: thickened immobile tricuspid and pulmonary valves with combined stenosis and regurgitant lesions
Untreated patients with carcinoid syndrome have a median survival time of 3 to 4 years, and the presence of carcinoid heart disease shortens this to less than ___ year.
<1 year
Therapy in carcinoid heart disease is not generally curative and includes debulking the hepatic metastases by embolization or partial hepatic resection and by the use of _____, a somatostatin analogue that binds to somatostatin receptors on the surface of carcinoid tumor cells and inhibits the secretion of vasoactive substances
Ocreotide
Valve replacement in carcinoid heart disease can be performed successfully but carries unique challenges, such as the development of an acute carcinoid crisis characterized by _____.
Acute carcinoid crisis:
Profound hypotension
Severe flushing bronchoconstriction
Arrhythmia
_____ occurs within the spectrum of the hypereosinophilic conditions in which increased numbers of eosinophils invade and damage tissues in a variety of organs, including the endocardium and myocardium, by releasing highly active biologic substances.
Löffler endocarditis
Hypereosinophilia has been defined as either a chronic absolute eosinophil count higher than _____ cells/mL for at least _____ month, although hypereosinophilia persisting for 6 months or longer is common, or pathologic evidence of hypereosinophilic tissue invasion.
> 1500 cells/mL at least 1 month
Regardless of cause, eosinophilic-mediated cardiac disease has been categorized into three stages: _____
Acute, intermediate, and fibrotic
Identify the stage of Eosinophilic-mediated cardiac disease:
Usually characterized by few or no signs or symptoms, eosinophils invade the myocardium, degranulate, and aided by lymphocytes, cause intense myocardial inflammation and eventually myocardial necrosis. Even though findings on echocardiography may be normal during this phase, contrast-enhanced CMR can detect disease, and myocardial biomarkers may be elevated to variable degrees
Acute stage
Identify the stage of Eosinophilic-mediated cardiac disease:
In the second stage, thrombus favoring the apices covers the affected endocardium. Symptoms include chest pain or dyspnea. Other evidence of disease includes mitral or tricuspid valvular regurgitation, cardiomegaly, and heart failure. Embolism of endocardial thrombus to the brain or other organs is common and may be the initial feature of the disease.The ECG may show T wave inversions, and imaging studies will reveal mural thrombus in affected areas, at times so extensive that large portions of the myocardial chamber are obliterated with clot
Intermediate stage
Identify the stage of Eosinophilic-mediated cardiac disease:
This phase progresses with diffuse scarring that results in endocardial fibrosis and RCM.The scar process commonly involves the mitral and tricuspid subvalvular structures; it impairs their mobility and leads to valvular regurgitation. Valve leaflet scarring can also occur
Fibrotic stage
If eosinophilic endocarditis can be identified in the first stage, therapy is focused on treatment of the underlying condition. Corticosteroids and cytolytic therapies have been used with some response. The fibrotic stage needs to be addressed _____to mitigate the restrictive nature of the endocardial fibrosis.
Surgically by valve release, repair, or replacement and by resection of the endocardial scar
EMF, an unusual disease in North America but common in Africa, is characterized by fibrosis of the _____ causing an RCM
LV and RV apical endocardium
Environmental exposure to _____, a rare element present in affected areas, has also been considered to be a cause of EMF
Cerium
Cardiovascular imaging in EMF shows:
(1) Restrictive filling
(2) Apical fibrosis that commonly involves the mitral and tricuspid subvalvular apparatus
(3) Atrial enlargement
