NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status.

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM SMP ), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM SMN ). Genotype-specific differences have been reported in cardiac function. Moreover, HCM SMN patients have later disease onset and a better prognosis than HCM SMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group. Methods: A proteomics screen was performed in cardiac tissue from 39 HCM SMP patients, 11HCM SMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC3 2373insG mouse model was used to confirm functional relevance of our proteomic findings. Results: In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCM SMP than in HCM SMN and controls. Higher tubulin detyrosination was also found in 2 unrelated MYBPC3 mouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes. Conclusions: Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCM SMP . This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCM SMP , whereas a beneficial effect may be limited in patients with HCM SMN .

. Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure-volume loops. Am J Physiol Heart Circ Physiol 291: H1580 -H1586, 2006. First published May 5, 2006; doi:10.1152/ajpheart.00286.2006.-In many patients with congenital heart disease, the right ventricle (RV) is subjected to abnormal loading conditions. To better understand the state of compensated RV hypertrophy, which could eventually progress to decompensation, we studied the effects of RV pressure overload in rats. In the present study, we report the biventricular adaptation to 6 wk of pulmonary artery banding (PAB). PAB resulted in an RV pressure overload to ϳ60% of systemic level and a twofold increase in RV mass (P Ͻ 0.01). Systemic hemodynamic parameters were not altered, and overt signs of heart failure were absent. Load-independent measures of ventricular function (end-systolic pressure-volume relation, preload recruitable stroke work relation, maximum first time derivative of pressure divided by end-diastolic volume), assessed by means of pressure-volume (PV) loops, demonstrated a two-to threefold increase in RV contractility under baseline conditions in PAB rats. RV contractility increased in response to dobutamine stimulation (2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) both in PAB and sham-operated rats in a similar fashion, indicating preserved RV contractile reserve in PAB rats. Left ventricular (LV) contractility at baseline was unaffected in PAB rats, although LV volume in PAB rats was slightly decreased. LV contractility increased in response to dobutamine (2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ), both in PAB and sham rats, whereas the response to a higher dose of dobutamine (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was blunted in PAB rats. RV pressure overload (6 wk) in rats resulted in a state of compensated RV hypertrophy with preserved RV contractile reserve, whereas LV contractile state at baseline was not affected. Furthermore, this study demonstrates the feasibility of performing biventricular PV-loop measurements in rats. right ventricle; hypertrophy; congenital heart disease; pressure-volume loops RIGHT VENTRICULAR (RV) function is an important determinant of long-term outcome in patients with complex congenital heart disease, chronic pulmonary obstructive diseases, or pulmonary hypertension. In many of these patients, the RV is subjected to (residual) abnormal loading conditions, including pressure overload. Although compensated hypertrophy will develop initially, ultimately RV failure will ensue. The mechanisms underlying the progression from compensated RV hypertrophy to decompensated RV hypertrophy (i.e., RV failure) have not been well defined. As the survival of the patients improves, a better understanding of these mechanisms becomes mandatory to be able to design preventive strategies and to time surgical (re)intervention in these patients.To study the mechanisms underlying the transition from a compensated state of hypertrophy to a decompensated state in patients is very difficult, because invasive data cannot...

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