Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

Sequential development of mutant clones in an imatinib resistant chronic myeloid leukaemia patient following sequential treatment with multiple tyrosine kinase inhibitors: an emerging problem?

With the increasing use of new tyrosine kinase inhibitors it has been suggested that the spectrum of kinase domain mutations may change and possible selection of new resistant clones may occur. We describe a Ph + chronic myeloid leukaemia (CML) patient with primary resistance to imatinib who received without success sequential therapy with multiple TKIs, and developed sequential emergence of kinase domain mutations after these treatments

Ventricular dysfunction in a family with long QT syndrome type 3

<p>Long QT syndrome (LQTS) type 3 is characterized by prolonged ventricular repolarization due to persistent sodium inward current secondary to a mutation in SCN5a, the gene encoding for the -subunit of the sodium channel. We speculated that by disrupting calcium homeostasis the persistent inward sodium current in patients with LQTS type 3 might cause derangement of diastolic function. We aimed to identify functional myocardial alterations in a family with a sodium channelopathy with a phenotype of both LQTS type 3 and Brugada syndrome.</p><p>The study group comprised 12 SCN5a mutation carriers (SCN5a-1795insD), 9 females and 3 males, mean age 35.7 7.3 years, and 12 healthy controls. In addition to conventional echocardiographic measurements, two-dimensional speckle tracking was performed to assess tissue properties. Mean e was lower in the patients compared with the controls (5.6 0.75 vs. 6.7 0.98 cm/s, P 0.006). Onset QRS to maximum s was longer in the patients than in the controls (0.20 0.04 vs. 0.15 0.05 s, P 0.007), and the number of segments with post-systolic shortening was higher (6.58 2.54 vs. 1.83 1.64, P 0.001).</p><p>Patients in this family with LQTS type 3 showed post-systolic shortening, as well as both left and right ventricular diastolic dysfunction. The underlying mechanism remains to be elucidated but the persistent sodium inward current leading to calcium overload might play a role, in particular regarding diastolic dysfunction.</p>