Infiltrative diseases
Anderson-Fabry’s disease
AFD disease is caused by an X-linked deficiency of lysosomal α-galactosidase A. It has been
reported in up to 6% of men and 12% of women with late-onset HCM1. Lysosomal α-galactosidase
A deficiency results in multiorgan damage determined by glycosphingolipid deposition2. In the
heart, glycosphingolipid deposition is accompanied by secondary changes, such as myocyte
hypertrophy, which can mimic the morphological and clinical picture of HCM3.
Chest pain is a common clinical symptom in patients with AFD, being reported in up to 60% of
homozygous males and heterozygous females with or without significant LVH. It is often
associated with electrocardiographic ST-segment and T wave abnormalities and with severely
impaired CFR at PET imaging and is caused by accumulation of glycosphingolipids in endothelial
cells and SMC4. Progressive deterioration of LV function and myocardial scarring occurs in a
significant number of patients5. Accordingly, growing evidence suggests that LGE may identify
areas of myocardial damage. In particular, one study showed that patients with AFD disease–related
LVH exhibit LV LGE with a typical pattern, characterized by the involvement of the infero-lateral
basal or mid basal segments and a by a mesocardial distribution6.
A timely diagnosis of AFD has relevant therapeutic implications because enzyme replacement and
enzyme enhancement therapy have been revealed to be effective in treating the disease. This
treatable disease, however, is frequently undiagnosed. Measurement of α-galactosidase A activity in
peripheral blood in patients with LVH has been proposed to detect patients with AFD; however,
this assessment may be unreliable in female carriers and in male patients with specific gene
mutations, in whom the nearly normal enzymatic activity and the lack of systemic manifestations,
including angiokeratomas, make its identification more difficult7. Unfortunately, clinical
characteristics and ECG findings do not provide a reliable and definite diagnosis of AFD.
In AFD enzyme replacement treatment with alpha galactosidase A reduces left ventricular mass
and improves cardiac function as well as clinical outcome, while it does not seem to improve
CMD8. It remains to establish whether a longer period of replacement therapy may lead to
improvement of CMD.
Amyloidosis
Cardiac amyloidosis is classified by the protein precursor as primary, secondary (reactive), senile
systemic, hereditary, isolated atrial, and hemodialysis-associated amyloidosis. These distinct forms
are differentiated by means of immuno-histochemical and genetic testing, and prognosis and
therapeutic strategies differ among these subtypes9.
A sizeable proportion of patients with primary cardiac amyloidosis report typical chest pain
caused by CMD. Indeed, amyloid deposits typically spare the epicardial vessels, while involvement
of the intramural vasculature is present in 90% of patients with primary cardiac amyloidosis
although it is much less frequent in senile amyloidosis 10. Vascular deposition of amyloid first
occurs in the media but, with disease progression, it involves the adventitia and intima. Although
severe vascular obstruction is rare, occurring in about 5% of cases, diffuse involvement leads to
numerous endocardial foci of ischemia, microinfarctions, and eventual fibrosis, further contributing
to myocardial dysfunction and, in case of involvement of the conduction system, cardiac electrical
disorders. Clinical studies have confirmed a reduction of CFR in patients with primary amyloidosis
and angina noninvasively using contrast echocardiography11 and invasively using a Doppler wire12.
Treatment of amyloidosis depends on the type of the disease. To the best of our knowledge no study
has hitherto assessed the effects of specific or nonspecific forms of therapy on CMD in
amyloidosis.
Treatment of iatrogenic CMD
In the setting of PCI for obstructed saphenous vein grafts mechanical prevention of distal
embolization by filters13 or proximal protection devices14 has been demonstrated to reduce the
occurrence of peri-procedural myocardial infarction and of major cardiac events.
With regard to pharmacological treatment, a loading dose of aspirin15 and clopidogrel16, in
patients already on treatment, has been found to reduce peri-procedural myocardial infarction.
GPIIb/IIIa inhibitors also have been shown to reduce peri-procedural infarction in several
clinical trials, a finding confirmed in a meta-analysis17. However, in the era of double platelet
antiaggregation, GPIIb/IIIa inhibitors are recommended only in high risk patients with
intracoronary thrombus18.
Importantly, administration of statins has shown to reduce peri-procedural infarction both during
elective19,20,21,22 and urgent PCI. A meta-analysis23 confirmed that statin administration prior to PCI
almost halves the rate of peri-procedural myocardial infarction. More recently an atorvastatin load
(120 mg) before PCI was shown to reduce post-procedural CK-MB and TnI elevation in patients
with non ST elevation ACS who were on previous statin therapy24, while this effect was not
observed in patients with stable angina.
With regard to the treatment of functional CMD alterations, Rimoldi et al. using PET
demonstrated in a randomized, double blind, placebo controlled trial that oral pre-treatment with the
1-adrenergic antagonist doxazosin restored CFR immediately after PCI in patients treated with the
active drug, but not in controls25.
In the setting of CABG ischemic preconditioning was the first ‘conditioning’ strategy applied in
man in the attempt to reduce myocardial damage26. In a recent meta-analysis preconditioning has
been found to be associated with fewer ventricular arrhythmias and need for inotropic support in the
absence, however, of any benefit on clinical end-points27. Remote preconditioning also has been
assessed in one study and was found to reduce peri-operative myocardial injury measured by the
72-hour area-under-the-curve of serum TnT concentrations28. Subsequent studies, however, gave
discordant results29,30.
With regard to pharmacological treatment, adenosine has been shown in several clinical studies
to reduce peri-operative myocardial injury and improve cardiac indices when administered either as
an intravenous therapy or when added to the cardioplegic solution31. However, the results of these
studies are rather conflicting32.
Volatile anesthetic agents have been shown to induce conditioning in experimental studies33. A
meta-analysis compared volatile vs intravenous anesthetics: patients who received volatile
anesthetic agents exhibited better cardiac function, less requirement for inotropic response, less
peri-operative myocardial injury, as assessed by serum TnI levels, and a shorter duration of
mechanical ventilation and hospital stay. However, no differences were observed in the incidence of
infarction, intensive care unit stay and in-hospital mortality. Other meta-analyses confirmed these
data34.
Finally, in a recent meta-analysis pre-operative or early post-operative statin administration was
found to be associated with a lower rate of all-cause mortality, atrial fibrillation, and stroke in the
absence of any beneficial effect on post-operative infarction or renal failure35. Thus, in the setting of
both PCI and CABG statins appear to be beneficial, probably through improvement of CMD related
to their pleiotropic effects.
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