Hypertrophic cardiomyopathy (HCM) is a genetically-determined disease that affects 1 in 500 people and which is characterized by ventricular hypertrophy, interstitial fibrosis, myocyte disarray and diastolic dysfunction 
. Its clinical outcomes range from entirely asymptomatic disease to chronic progressive heart failure, arrhythmias and sudden cardiac death 
. Molecular genetic studies have led to the concept of HCM as a disease of the sarcomere, since almost all of the known HCM disease genes encode sarcomeric proteins, in particular MYH7
(which encodes β-myosin heavy chain, β-MyHC) and MYBPC3
(encoding cardiac myosin binding protein-C, cMyBP-C), with each accounting for about one-third of the known HCM-associated mutations [1–3]
. However, it remains the case that 40–60% of HCM patients screened appear to have no mutation in any sarcomeric protein so far implicated in HCM [4,5]
The mechanisms linking myocardial dysfunction in human HCM, either directly or indirectly, with changes in sarcomeric proteins are unclear. The characteristic diastolic dysfunction (compromised myocardial relaxation and passive filling) is largely a consequence of increased ventricular stiffness, which may be due to the ventricular hypertrophy, disarray of myocytes, interstitial fibrosis, or possible myocardial ischaemia [3,6]
. However, there could also be an increased intrinsic stiffness of the myocytes. Myocyte passive stiffness is largely due to titin in the sarcomere [7–9]
and an increase in the proportion of the stiffer (N2B) isoform of titin relative to the more compliant (N2BA) isoform was reported in an animal model of hypertrophy 
and in patients exhibiting diastolic heart failure with concentric LV hypertrophy 
. In addition, myocyte viscoelasticity, which would contribute to the dynamic stiffness of the myocardium during chamber filling, was increased in pressure-overload hypertrophy in animal models 
. However there has been no detailed investigation of the passive viscoelasticity of human myocytes to examine whether this may contribute to the increased stiffness of the HCM myocardium.
Systolic performance too is often compromised in HCM, particularly during tachycardia. Cardiac output may be reduced by the impairment of diastolic filling. In addition, in approximately 25% of HCM patients there is upper septal hypertrophy associated with mitral valve dysfunction (systolic anterior motion), which obstructs the outflow tract (hypertrophic obstructive cardiomyopathy, HOCM). It is not clear whether there are also changes in the contractile properties of myocytes that could either contribute to, or help to compensate for, the altered cardiac function in HCM. Results from studies with transgenic animals or isolated proteins have generally reported that HCM is associated with increased myofilament Ca2+
sensitivity, with variable effects on maximum force or ATPase activity 
, though a common (and perhaps unifying) feature is an increased energetic cost of contraction 
. In the only previous study (to our knowledge) with myocytes from human HCM hearts, permeabilized (“skinned”) ventricular myocytes from patients with one of two truncation mutations in the MYBPC3
gene showed a reduced maximum steady-state force production but elevated myofibrillar Ca2+
. However, it was not clear whether these changes were specific to the two MYBPC3
mutations studied or are a general characteristic of the myocardium in all HCM patients. Furthermore, cross-bridge cycling kinetics were not determined, so no inference could be made about the dynamics of myocardial contraction and relaxation in HCM.
To investigate the role of the myocytes in determining the passive and active properties of the HCM myocardium, we examined in detail the steady-state and dynamic characteristics of passive stiffness and active force production in the myocytes from a representative group of HCM patients (with mutations in MYBPC3, MYH7, or neither gene), compared with myocytes from non-diseased hearts. By comparing results between individual patients, we explored whether the changes in contractile phenotype were gene-specific or were common to all the HCM patients. While passive viscoelasticity was not changed significantly, we found consistent alterations in the active properties of the HCM myocytes that likely contribute to the pathophysiology of the HCM myocardium. Most of these changes are likely to be secondary consequences of the disease process.