Chapter 24. Restrictive Cardiomyopathy

• Predominant biventricular diastolic dysfunction with lesser impairment of systolic performance.
• Symptomatic presentation:
  • Chronic biventricular “backward failure” manifest as dyspnea and peripheral edema (often hepatomegaly and ascites).
  • Reduced preload limits cardiac output (fatigue).
• Echocardiography: small stiff ventricles, preserved systolic function (until late stages), dilated atria and diastolic dysfunction by Doppler.
• Many disorders manifest restrictive “physiology” and must be excluded (eg, hypertrophic cardiomyopathy and constrictive pericarditis).
• Cardiac magnetic resonance imaging powerful: delineates myocardial infiltration, inflammation, and fibrosis and assesses pericardium, thereby helping establish underlying disorder.
• Tissue biopsy may be necessary for definitive diagnosis in some disorders (eg, amyloidosis).

Restrictive cardiomyopathies (RCM) are indolent disabling diseases resulting from pathophysiologic processes that induce predominant diastolic chamber dysfunction with lesser impairment of systolic performance. RCM is characterized by small stiff ventricles with progressive impairment of diastolic filling, leading to the hemodynamic conundrum of low preload but high filling pressures (Figure 24–1). This pattern of diastolic dysfunction leads to dilated atria and elevated mean atrial pressures, resulting clinically in biventricular “backward failure” manifest as pulmonary venous congestion (dyspnea) as well as systemic venous pressure elevation (peripheral edema). Systolic function is preserved in most cases, depending on the underlying cause (at least in the presenting stages of most of the underlying diseases). However, despite intact systolic function, the restrictive constraints on true ventricular preload limit stroke volume, thereby resulting in low cardiac output (fatigue) and ultimately hypoperfusion.

The abnormal diastolic properties of the ventricle are typically attributable to abnormalities of the myocardium (infiltration, inflammation, or fibrosis) or the endomyocardial surface (inflammation and scarring). The RCM classification (Figure 24–2) may be most easily considered based on underlying pathophysiologic process as infiltrative (eg, amyloidosis), storage (eg, hemochromatosis), inflammatory (eg, hypereosinophilic syndrome), noninfiltrative (eg, diabetic), or idiopathic. Identification of specific infiltrative processes may have prognostic and therapeutic implications. Of note, secondary restrictive physiology can develop at a late stage in hypertrophic, dilated, valvular, hypertensive, and ischemic heart disease.

The vast majority of the underlying disease processes are slowly progressive, but by the time patients develop cardiac symptoms, the disease is advanced pathologically and heart failure progresses rapidly over a short period of time, and the majority die within a few years following diagnosis.

An appreciation of the physiology of the venous circulations and the dynamic effects of intrathoracic pressure (ITP) and respiratory motion on cardiovascular physiology is critical to understanding the hemodynamic pathophysiology of RCM and differentiating it from other conditions, particularly constrictive pericarditis (CP). Under physiologic conditions, venous return to both atria is biphasic, with a systolic peak determined by atrial relaxation (“X” descent of the atrial and jugular venous pressure [JVP] waveforms) and a diastolic peak determined by tricuspid valve (TV) resistance and right ventricular (RV) compliance (“Y” descent). Respiratory oscillations exert complex effects on cardiac filling and dynamics, with disparate effects on the right and left heart attributable to differences in their anatomic relationships to the respective venous return systems relative to the intrapleural space. Normally, inspiration induces decrements in ITP (–25 to –30 mm Hg), which are transmitted through the pericardium to the cardiac chambers. On the right heart, these decrements in ITP enhance the filling gradient from the extrathoracic systemic veins, thereby augmenting venous return and increasing right heart filling and output. In contrast, the left heart and its tributary pulmonary veins are entirely intrathoracic. Therefore, inspiratory decrements in ITP are evenly distributed, and thus, mitral valve (MV) flow and left ventricular (LV) filling are essentially unchanged throughout the respiratory cycle.

The pathognomonic feature of RCM is stiffness of the ventricular walls, which impairs diastolic filling, resulting in limited ventricular preload (and therefore stroke volume) despite increased diastolic filling pressures. Echocardiography (echo) documents small ventricles, often with thick walls. By invasive hemodynamic assessment, RCM is characterized by elevated ventricular diastolic pressures (Figures 24–3 and 24–4), often with a mild diastolic “dip and plateau” or “square root” pattern, a nonspecific indicator of stiff noncompliant chambers, a phenomenon also seen in other conditions such as CP (discussed later). Echo-Doppler demonstrates classic features of impaired diastolic function (impaired myocardial relaxation with increased early LV filling velocity, decreased atrial filling velocity, and decreased isovolumic relaxation time). Ventricular systolic function is typically preserved until the later stages of the underlying disease. Biatrial enlargement reflects ventricular noncompliance and may also result from primary atrial myocardial involvement by the disease process (eg, amyloidosis). Atrial filling pressures are elevated, and the X and Y descents tend to be relatively blunted; in cases in which the atria are primarily involved by the restrictive process, the A wave may be depressed (see Figure 24–3). In RCM, a pattern of “elevated and equalized” chamber diastolic filling pressures indicating pancardiac “stiffness” is common, but this nonspecific pattern is also seen in other diseases, particularly pericardial constraint conditions (eg, CP). However, in RCM, left-sided pressures are typically somewhat higher than right due to the greater intrinsic stiffness of the LV. This difference may be amplified by maneuvers that augment ventricular filling such as volume infusion, leg-raising, or post–premature ventricular contraction increased filling time. Disproportionate left heart stiffness may also result in moderate pulmonary hypertension (a subtle distinguishing feature from CP).

In RCM, inspiratory changes in ITP are fully transmitted through the pericardium to the cardiac chambers. However, chamber noncompliance contributes to a relative lack of respiratory variation in cardiac filling, and therefore, mitral and tricuspid flow velocity during respiration are typically decreased. Because of the lack of pericardial constraint and a relatively noncompliant interventricular septum, there is minimal ventricular interdependence, and thus inspiratory effects on ventricular systolic pressures are concordant (ie, there is little change in peak ventricular systolic pressures with respiration and they move in the same direction) (see Figure 24–4); as will be discussed, the pressure pattern in CP is “discordant.” As RCM progresses and right-sided chambers become less distensible, the respiratory swings in pressure diminish further. At its most severe, noncompliance to inflow results in the “Kussmaul sign,” an inspiratory increase in venous return that cannot be accommodated by the stiff right heart, resulting in inspiratory elevation of JVP (see Figure 24–3). Doppler flow patterns show blunting of the expected physiologic respiratory increases in flow across the TV and minimal change across the MV.

Patients with RCM suffer symptoms attributable to biventricular diastolic dysfunction. Systemic venous congestion related to right heart noncompliance typically predominates, characterized by pedal edema, abdominal swelling, and gastrointestinal symptoms related to hepatic/bowel congestion (loss of appetite). Physical exam reveals elevated jugular venous pressure often with Kussmaul sign, peripheral edema, and ascites; with advancing disease, hepatomegaly, ascites, and anasarca develop. Patients typically are limited by dyspnea on exertion attributable to left heart diastolic dysfunction. At the bedside, patients will exhibit signs of right heart failure (eg, elevated JVP with edema, ascites), but the precordial exam will be quiet with no evidence of an RV heave, thus pointing away from other causes of right heart failure such as pulmonary hypertension, dilated cardiomyopathy, or TV regurgitation (all of which will manifest an RV heave/lift in the left parasternal area).

In the early stages of RCM, systolic function is typically preserved, although deterioration in contractility may be observed as the disease progresses; the severity and patterns of dysfunction depend on the specific etiology and severity of the underlying disease entity. Despite preserved systolic ventricular function, impaired diastolic filling limits ventricular preload, thereby rendering the stiff heart limited in its ability to increase cardiac output with exercise, resulting in fatigability. Low output combined with autonomic insufficiency characteristic of some RCMs (eg, amyloidosis) renders patients susceptible to symptoms of orthostatic hypotension. Atrial dilation often leads to atrial fibrillation, which further exacerbates diastolic dysfunction due to high heart rate and loss of atrial contraction.

Myocardial Disorders

Idiopathic or Primary RCM

Idiopathic or primary RCM, often due to hereditary contractile protein mutations, represents approximately 50% of cases and occurs more commonly in older women than men. Wall thickness is commonly increased by echocardiography, and biopsy typically reveals myocyte hypertrophy often with patchy endocardial fibrosis involving both ventricles. Idiopathic diagnosis can only be established in the absence of other identifiable causes (ie, storage, infiltrative, and inflammatory diseases), many of which induce thick ventricular walls and infiltrative/storage damage on biopsy.

Infiltrative Disorders

Cardiac Amyloid

Amyloidosis is the prototypical RCM, arising from a group of disorders resulting in multisystem infiltrative disease with organ involvement, including heart, dependent on the underlying amyloid precursor protein entity. Cardiac amyloid is typically silent until tissue infiltration is extensive, leading to RCM with symptomatically progressive biventricular diastolic dysfunction. Imaging modalities, biochemical tests, and tissue samples establish definitive diagnosis. Echo documentation of thick walls, small cavities, and granular speckled “hyperrefractile” myocardial pattern is nearly diagnostic. Cardiac magnetic resonance imaging (MRI) shows diffuse late gadolinium enhancement throughout both ventricles, particularly the subendocardium. To exclude amyloid of the AL type, monoclonal gammopathy may be evident on urine and serum protein electrophoresis, although immunofixation and assays for serum free light chains are more sensitive. Amyloid deposits can be documented by biopsy of myocardium (by histology, Congo Red staining delineates amyloid deposits between cardiac myocytes); tissue specimens can also be obtained from fat pad or rectum. The general treatment approach is as with any RCM. The mainstay is diuretics to decongest within the limits tolerated by hypotension. These patients are at high risk of thromboembolism, especially with atrial fibrillation, but even in its absence, anticoagulation should be strongly considered. Untreated patients with AL amyloid have a median survival < 6 months after onset of heart failure. Aggressive chemotherapy and stem cell transplantation, followed by cardiac transplantation, have shown promising potential in a small number of cases, but transplantation mortality rate is high and randomized data are lacking.

Hemochromatosis

Cardiac iron overload, due to heritable disorder or chronic and excessive iron administration, is always associated with involvement of multiple organs, giving rise to the classic clinical presentation of heart failure, cirrhosis, impotence, and diabetes. At pathology, hearts are dilated and ventricular walls thickened. Echo shows a nonspecific mixed pattern of systolic and diastolic dysfunction. The condition is commonly complicated by and may be announced by arrhythmias. Laboratory evaluation is usually diagnostic (marked elevations of plasma iron, serum ferritin, and transferrin saturation, but lower normal total iron binding capacity). Cardiac MRI is a sensitive marker of iron deposition and predictive of future events. Endomyocardial biopsy is definitive, but usually not necessary when biochemical testing is diagnostic. Chelation therapy is appropriate and may limit further damage but is unlikely to reverse existing organ dysfunction.

Sarcoidosis

This systemic inflammatory condition results in multiorgan noncaseating granulomatous infiltration, typically in the lungs, reticuloendothelial system, and skin. The heart is involved in 20–30% of cases at autopsy, with patchy granulomatous infiltration in discrete areas of the ventricular walls with a predilection for the posterior LV free wall, basal septum, and conduction system. Cardiac infiltrate may result in fibrotic scars and “microaneurysm” formation. Cardiac sarcoid most commonly presents clinically with conduction block or malignant arrhythmias and less commonly with heart failure due to RCM. The electrocardiogram (ECG) may reveal atypical infarction patterns and various degrees of AV block. Echo varies according to disease activity, with wall thickening due to granulomatous expansion but later wall thinning due to fibrosis. Segmental hypokinesia most commonly localizes to mid and basal segments of the LV free wall and upper septum. Owing to patchy involvement, endomyocardial biopsy provides diagnostic evidence in only 25–50% of autopsy-confirmed cases. Cardiac MRI and positron emission tomography (PET) are more sensitive and correlate with disease severity. If treated early, when inflammation predominates and fibrosis is less advanced, anti-inflammatory therapy (steroids and cyclophosphamide [Cytoxan]) may improve cardiac function. In those with arrhythmias, pacemaker and defibrillator therapy should be considered.

Storage Disorders Due to Heritable Diseases

RCMs may result from heritable metabolic disorders resulting in myocardial accumulation or infiltration of abnormal metabolic products, producing classic RCM. The recent availability of enzyme replacement in some disorders makes early diagnosis increasingly essential. The most common are glycogen storage disorders (Gaucher and Fabry disease) resulting from lysosomal accumulation in the heart and other organs. Gaucher disease commonly presents with RCM in childhood and is responsive to enzyme replacement therapy or, in extreme cases, hepatic transplantation. In Fabry disease, cardiac involvement is typically manifest in the third or fourth decade of life; the thick ventricular walls mimic hypertrophic cardiomyopathy; differentiation by MRI may be helpful. Other less common heritable storage disorders that may result in RCM include the mucopolysaccharidoses, myocardial oxalosis (related to underling primary hyperoxaluria), and Friedreich ataxia (an autosomal recessive neurodegenerative disorder associated with RCM and/or dilated cardiomyopathy in 90–100% of cases).

Endomyocardial Disease

There are two variants of endomyocardial disease, with different pathogenesis but shared and overlapping features. Endomyocardial fibrosis (EMF) refers to a specific syndrome with characteristic geographic epidemiologic features. Other cardiomyopathy syndromes with similar pathologies include Loeffler endocarditis (also called hypereosinophilic endomyocarditis) and other diseases that induce fibrotic changes of the endocardium (eg, carcinoid heart disease).

Endomyocardial Fibrosis

EMF occurs primarily in tropical regions and in subtropical zones, presents at a young age, and is the most common form of RCM worldwide. EMF is characterized by fibrosis of the apical endocardium of the ventricles. The clinical manifestations are classic RCM.

Loeffler “Hypereosinophilic” Endomyocarditis

This group of disorders results from sustained overproduction of eosinophils, leading to eosinophilic infiltration and mediator release, which damages multiple organs. Diagnosis is established by eosinophil counts > 1500 for at least 6 months. The disease may be primary, but it is essential to search for secondary and potentially treatable causes including leukemia, reactive disorders such as parasite infection, allergies, granulomatous syndromes, hypersensitivity, and neoplastic disorders. Eosinophil-mediated heart damage, detected by echo or MRI, evolves through three stages: (1) an acute necrotic stage; (2) an intermediate phase characterized by thrombus formation along the damaged endocardium; and (3) a fibrotic stage. Treatment is aimed at the underlying disease.

Carcinoid Heart Disease

Carcinoid tumors metastatic to the liver elaborating circulating serotonin (and 5-hydroxyindolacetic acid, its primary metabolite) induce fibrous endocardial plaques in 50% of patients. By echo, plaques are typically seen on the endocardium downstream of the TV, commonly resulting in stenotic and regurgitant valvular lesions (especially TV). The observation that the right heart is preferentially affected reflects inactivation of these toxic substances in the lung. Management of the underlying carcinoid is the focus of treatment. Identical pathology results from exposure to the anorectic drug fenfluramine and its related medications.

Cardiac chambers with thick walls, small ventricular cavities with intact systolic function, and dilated atria are also typical of conditions with myocyte hypertrophy such as congenital hypertrophic cardiomyopathy (HCM) or acquired hypertensive and valvular heart disease. Coronary artery disease, especially in diabetics, can also mimic clinical RCM. Careful history, physical examination, noninvasive testing, and arteriography can exclude these acquired conditions, whereas differentiating HCM may pose challenges.

Differentiating RCM versus CP poses one of the most challenging clinical hemodynamic conundrums and deserves special consideration. These two conditions are remarkably similar in their hemodynamic pathophysiology, share nearly identical clinical presentation characterized by systemic and pulmonary congestion due to biventricular diastolic dysfunction with limited cardiac output, and appear quite similar by echocardiography, with small ventricles, dilated atria, and intact systolic function. However, they are distinctly different entities in terms of clinical course, management, and prognosis. CP is “curable” through surgical pericardiectomy, whereas RCM is treated by palliative measures and rarely if ever cured. Because of this important distinction, accurate differentiation is crucial.

First, it is essential to appreciate the subtle similarities and differences in hemodynamic pathophysiology of CP compared to RCM. CP is the result of inflammatory fibrocalcification leading to a thick, inelastic pericardium that encases the heart, inducing biventricular diastolic dysfunction. As in RCM, this process is typically indolent and slowly progressive, with clinical manifestations appearing often years after the initial insult. There is substantial overlap in hemodynamic features, which reflect similarities in pathophysiology rather than differences in disease mechanism. In CP, early ventricular filling is resistance free; however, as the ventricles fill, they abruptly meet the inelastic resistance of the stiff pericardium, at which time filling pressure rises rapidly to an elevated plateau, inscribing an RV “dip and plateau” or “square root” waveform pattern, similar to RCM (see Figure 24–4). In CP, atrial filling pressures are elevated, reflecting both ventricular noncompliance and atrial constraint. The right atrium Y descent is sharper in CP, reflecting the initial rapid, resistance-free early RV filling. In CP, diastolic filling pressures are elevated and equalized, reflecting the common constraining effects of the pericardium. In RCM, the intrinsic cardiac disease more often results in “nearly equalized patterns” with disproportionate elevation of left heart filling pressures. Hemodynamic challenges including rapid volume loading, leg elevation, or exercise to effect a disproportionate rise in LV diastolic pressure suggest RCM but are not diagnostic. The presence of mild-moderate pulmonary hypertension favors the diagnosis of RCM, but may occur in constriction due to preexistent left heart or intrinsic pulmonary disease.

The effects of respiration on cardiac dynamics differ between RCM and CP in subtle but complex ways, findings that may help differentiate these conditions. In CP, increased pericardial resistance more tightly couples the two ventricles and increases their interdependence. Pericardial constraint limits total cardiac volume; consequently, an increase in filling on one side of the heart impedes contralateral filling through intensified septal-mediated interactions. In CP, the inelastic fibrocalcific pericardial shell isolates the heart from the lungs, and therefore, respiratory changes in ITP are not fully transmitted to the cardiac chambers, resulting in dissociation of respiratory effects on ITP and intracardiac flows in the right heart versus the left heart. This represents an important difference compared to RCM. In CP, the inspiratory gradient created between the extrathoracic systemic veins and intrathoracic but extrapericardial cavae augments venous return to the right heart, but the constrictive pericardial shell neither fully facilitates inspiratory augmentation of right heart filling, nor accommodates whatever meager increments in filling occur. The result is an inspiratory increase in jugular venous and right heart filling pressures known as the Kussmaul sign (also seen in RCM). Anatomic–pathophysiologic relationships in the left heart are different: The pulmonary veins are entirely intrathoracic, the LA is not fully encased within the pericardium due to the pericardial reflection around the pulmonary veins, but the LV is fully constrained within the pericardium. Therefore, the inspiratory decrement in ITP is exerted upon the pulmonary veins, but not transmitted to the LV, resulting in reduced transmitral pressure gradient and flow. Because the rigid pericardium fixes total cardiac volume and induces tight ventricular coupling, there is a reciprocal relation between left and right heart filling. This results in inspiratory decrease in LV filling, which allows a small relative increase in tricuspid inflow and RV filling, leading to opposite directional increase in RV but decrease in LV changes in inspiratory ventricular systolic pressures, called “ventricular discordance” (see Figure 24–4), which is indicative of enhanced ventricular interaction and a strong indicator of CP. Analogous findings are evident in Doppler flow velocities including >25% expiratory increase in mitral E velocity and expiratory decrease in hepatic vein diastolic flow velocity and >25% increase in diastolic flow reversals compared with inspiratory velocity. In contrast, in RCM, inspiratory changes in ITP are fully transmitted through the pericardium to the cardiac chambers, but chamber noncompliance limits respiratory augmentation of cardiac filling, which, together with lack of pericardial constraint and a noncompliant interventricular septum, minimizes ventricular interdependence. The result is blunted respiratory flow velocities by Doppler and “concordant” ventricular systolic pressures. These disparate patterns with respiration have been proposed to differentiate CP versus RCM (see Figure 24–4). However, the overall specificity and sensitivity of these hemodynamic criteria, both alone and in combination, have not been sufficient to provide a basis for definitive diagnosis in individual patients.

Since the clinical presentation of these two entities is often similar, separating them on the basis of anatomic and physiologic derangements is essential and requires the use of techniques that visualize the cardiac chambers and the pericardium, in conjunction with modalities that delineate the physiologic manifestations of the anatomic abnormalities. Most important, the single distinctive feature differentiating CP from RCM is anatomic, not physiologic: In patients with CP, the pericardium is almost always thickened and motion of the heart within the pericardium constrained, whereas in RCM patients, this is not the case. Therefore, anatomic documentation of pericardial thickness in patients with constrictive-restrictive physiology is crucial in differentiating these conditions (Figure 24–5). However, it must be emphasized that the finding of pericardial thickening should not be construed as the equivalent of a physiologic disorder because a thickened pericardium does not necessarily constrict. For example, pericardial thickening can be present in patients without physiologic constriction, particularly with tuberculosis or after open-heart surgery. Conversely, there can be physiologic pericardial constriction with normal-appearing pericardium by advanced cardiac imaging modalities.

Traditional and advanced cardiac imaging provides valuable information. The chest x-ray in CP may reveal pericardial calcification. In both conditions, the ECG is nonspecific but often reveals diffuse low voltage with nonspecific ST-T changes. By echocardiography, most RCMs exhibit thick walls, whereas CP does not. RCMs, particularly amyloid, result in the paradox of thick walls by echo but small volts by ECG, a pattern not seen in CP. Cardiac MRI is a powerful tool to evaluate patients with RCM in general and to distinguish it from CP. MRI provides data regarding not only chamber size, wall thickness, and ventricular function, but also the presence or absence of myocardial infiltration, inflammation, or fibrosis, patterns which inform the diagnosis of specific forms of RCM. After establishing that the myocardium appears normal, the delineation of pericardial thickness provides a basis for a therapeutic algorithm to definitively delineate CP versus RCM (see Figure 24–5). MRI provides insight not only regarding pericardial thickness, but also the dynamic nature of myocardial-pericardial interactions, specifically whether the pericardial layers are adherent to the heart and whether the heart slides normally in a smooth independent pattern within the pericardium during cardiac motion. Documentation of a thickened pericardium adherent to the epicardium and lack of independent motion are sufficient to diagnose CP, although RCM and CP may coexist (eg, radiation induced).

In patients with a clinical presentation and echo-Doppler findings consistent with either diagnosis, invasive hemodynamics should be performed with documentation of pericardial thickness “in hand.” Employing this strategy, if pericardial imaging is confirmatory and hemodynamic findings consistent, biopsy is unnecessary and surgical exploration and pericardiectomy are warranted. In patients without these findings, assiduous clinical search for disease entities that result in RCM (eg, amyloidosis, hemochromatosis, scleroderma) will often result in delineation of the underlying etiology. Although clinical features and biochemical testing (eg, serum/urine protein electrophoresis, iron studies) may be sufficient, endomyocardial biopsy may be necessary to confirm its presence in the heart. However, if imaging fails to demonstrate constrictive features, then endomyocardial biopsy can be performed at the time of cardiac catheterization. Finally, it is important to emphasize that some patients with severe pericardial constriction proven at surgical exploration may have normal pericardial thickness by imaging techniques. Accordingly, in patients with severe clinical manifestations, lack of increased pericardial thickness, and normal endomyocardial biopsy, thoracoscopy or minimally invasive exploratory thoracotomy with provisional planned pericardiectomy should be considered.

Since few cases of RCM have treatable primary disease etiologies, management is based on diuretics to ameliorate pulmonary and systemic venous congestion. Frustratingly, optimal diuretic doses in RCM may reduce ventricular preload, leading to decreased cardiac output and symptoms of fatigability and light-headedness and even signs of hypotension and hypoperfusion. The development of atrial fibrillation and concomitant loss of atrial contractile contribution to filling of these stiff ventricles may worsen existing diastolic dysfunction and low output; in addition, rapid ventricular response may further compromise cardiovascular function. Thus, it is important to maintain sinus rhythm if feasible. However, digoxin should be used with caution, since it is potentially arrhythmogenic, particularly in patients with amyloidosis; other medications such as amiodarone should be considered. Atrial fibrillation renders patients prone to thromboemboli, and amyloid patients are at particular risk; therefore, anticoagulation should be strongly considered. When systolic dysfunction ensues, vasodilators may be tried, but caution should be employed due to predilection to orthostatic hypotension. Depending on the cause, cardiac transplantation may be considered but is often contraindicated because of the underlying primary disease.

Typically, by the time a patient develops symptoms attributable to RCM, the disease is pathologically advanced and largely irreversible (with few exceptions; eg, acute inflammatory stages of sarcoid responsive to immunosuppression). Clinical progression is typically rapid over a short interval, and although RCM carries a variable prognosis dependent on etiology, the majority of patients die within a few years. The prognosis in amyloid is particularly grim (although the familial transthyretin-related form is more protracted compared with the immunoglobulin-associated disease).