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Amyloid Cardiomyopathy
17
nevertheless associated with a lower percentage of hematological responses
and particularly with high early mortality [82, 83].
A number of current studies documents an effective treatment of AL
amyloidosis patients with new biological medications: thalidomide,
lenalidomide, pomalidomide and in particular bortezomib.
Bortezomib acts as a reversible proteasome inhibitor, and combined
therapeutic schemes are used to treat a number of plasmocellular dyscrasias,
namely multiple myeloma. In case of AL, combined regimens of bortezomib
with cyclophosphamide and dexamethasone (CyBorD) are associated with 81–
94% treatment response (71% of complete remissions) in previously untreated
patients, including those with advanced cardiac involvement [84 – 86]. A
study of Jaccard et al. targeting patients with advanced cardiac failure (Mayo
III) determined a 68% rate of hematological treatment response, while cardiac
response was reported in 32% of patients [85]. Similar results were published
by Venner et al., where 94% of patients in Mayo III stage treated with CyBorD
combination attained two-year survival [86]. A comparison of bortezomib and
MDex combination vs. MDex is presently subject of a clinical study. The most
frequent adverse effects of bortezomib include peripheral sensory neuropathy,
hypotension or dyspepsia. The combinations of thalidomide with
dexamethasone and dexamethasone with cyclophosphamide are associated
with 48% and 74% hematological response, respectively. Nevertheless, the
treatment is associated with relatively frequent side effects, namely fluid
retention [87, 88]. Palladini et al. evaluated the thalidomide-MDex
combination in 22 patients with advanced cardiac failure. 36% of patients
attained hematological response, and median survival was only 5.3 months
[89]. Therapeutic combination of lenalidomide with dexamethasone is
associated with 40–67% treatment response. Combinations with alkylating
cytostatics achieve treatment response of 55–60%. However, the treatment is
not associated with a marked effect in case of advanced cardiac involvement
[90, 91]. Dinner et al. evaluated the effect of lenalidomide-MDex combination
in 25 AL patients; only 22% of Mayo III stage (n = 9) attained one-year
survival [92]. The most severe side effects are hematological toxicity, edemas
and fatigue. Lenalidomide therapy is also associated with the increase of NT-
proBNP levels, which makes the evaluation of organ and cardiac treatment
problematic. The recommended initial dose, associated with a better
tolerability, is 15 mg. Dispenzieri et al. evaluated the effect of pomalidomide
with dexamethasone in refractory AL patients. Therapy was associated with
48% of hematological treatment responses, and organ response was reported in
4 out of 27 patients [93]. Considering the lower tolerance of IMIDs by AL
Tomas Pika and Jiri Vymetal
18
patients, their use can be anticipated more likely in relapsing patients resistant
to bortezomib therapy or in patients with significant polyneuropathy. Further
clinical study data are needed for a definitive assessment of benefits of the
combined regimens with IMIDs.
Several clinical studies evaluating the benefits of new preparations are
currently under way. CPHPC (R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-
hexanoyl]pyrrolidine-2-carboxylic acid) appears to be one of the most
effective substances. CPHPC binds to the SAP and the resulting complex is
excreted by the liver, which leads to plasmatic SAP depletion. A follow-up
combined therapy with CPHPC and anti-SAP IgG antibodies may reduce
amyloid masses within tissues [94].
Heart transplantation may be considered in young patients with advanced
isolated cardiac involvement. Heart transplantation alone or a transplantation
followed by chemotherapy was associated with five-year survival in 20–36%
of patients. If, however, a high-dose therapy with autologous stem cell
transplantation follows after the heart transplantation, one-year survival is as
high as 75%. The autologous transplantation should be optimally carried out
within 6–12 months of the heart transplantation. Therefore, the heart
transplantation facilitates the bridging of the symptomatic cardiac failure
period with an intensive follow-up therapy in patients who would be otherwise
ineligible for this therapy [95 – 97].
TTR AMYLOIDOSIS THERAPY
Liver transplantation represents a very effective therapy for the
neuropathic forms of mTTR. It is known, however, that cardiac involvement
often further progresses in the non-Val30Met forms despite the liver
transplantation, apparently due to continuing deposition of native transthyretin.
Therefore, a combined heart and liver transplantation ought to be considered in
mTTRs with cardiac involvement. Tafamidis meglumine is a preparation
stabilizing transthyretin tetramers, presently registered in Europe for the
treatment of type I FAP. Studies evaluating the effect of tafamidis in mTTR
with dominant cardiac involvement are presently under way. Diflunisal, a non-
steroid anti-inflammatory drug, has an identical effect. A combination of
tauroursodeoxycholic acid (TUDCA) with doxycycline has effect on the
disruption of amyloid masses; clinical studies are likewise in progress [11 –
13, 98, 99].
Amyloid Cardiomyopathy
19
Proper symptomatic therapy represents the most important aspect of SSA
therapy. Studies evaluating the effect of tafamidis meglumine or therapeutic
combination of TUDCA with doxycycline are under way.
CONSERVATIVE SYMPTOMATIC AND
SUPPORTIVE TREATMENT
Cardiac amyloidosis therapy focuses both on influencing the principal
process leading to amyloid production, and on the supportive treatment of
cardiac failure, which is often of symptomatic nature. It is necessary to point
out that, unlike the treatment of congestive heart failure secondary to ischemic
heart disease, pharmacological treatment of cardiac failure in case of
amyloidosis has a number of differences and limitations which must be
respected. Generally speaking, supportive medication treatment is more
effective in senile systemic amyloidosis than in AL amyloidosis. ACE
inhibitors or sartans are mostly poorly tolerated and must be administered
titrated and with great caution, because even very low doses may potentially
cause severe hypotension, particularly in AL amyloidosis. So far there are no
clinical studies that would prove unambiguous benefit in this group of patients.
Therefore loop diuretics, administered again in titrated dosage accompanied by
blood pressure and renal function monitoring, remain the foundation of
treatment as in the case of ACEI. In the presence of significant fluid retention
and edemas, continuous parenteral application of diuretics is necessary even at
high doses. In case of chronic hypotension, it is acceptable to try alpha-
adrenergic receptor agonist midodrine, or possibly fludrocortisone, which,
however, may have the adverse effect of fluid retention. Beta blockers, on the
other hand, may aggravate the manifestations of cardiac failure in amyloidosis
patients, whose cardiac output depends on heart rate with low fixed stroke
volume, and may also worsen hypotension. Calcium channel blockers of the
verapamil and diltiazem type are counterindicated in cardiac failure. Due to its
binding to amyloid fibrils, digoxin often leads to manifestation of digitalis
toxicity even at therapeutic serum levels, and therefore is not recommended in
amyloidosis patients. Amiodarone tends to be well tolerated for frequency and
rhythm control in case of atrial fibrillation. Pacemaker implantation, possibly
in combination with an ICD, may be indicated in patients with a significant
symptomatic bradyarrhythmia. Patients with cardiac amyloidosis are at high
risk of intracardiac thrombus development and are indicated for an adequate
Tomas Pika and Jiri Vymetal
20
anticoagulation treatment after individual assessment of hemorrhage risk with
concomitant involvement of other organs. Anticoagulation treatment is
indicated not only for intracardiac thrombi and patients with atrial fibrillation,
but is also recommended in case of sinus rhythm and atrial hypocontractility
detectable in echocardiographic examination [8 – 10, 100].
CONCLUSION
Cardiac involvement in the form of amyloid cardiomyopathy is the most
important prognostic factor for all types of amyloidoses. Early diagnosis,
individually selected therapy and multi-disciplinary cooperation represent the
key aspects of care for patients with amyloid cardiomyopathy. Despite the
progress in diagnostics and therapy, prognosis in case of cardiac involvement
remains very unfavorable.
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