Vascular disease can lead to interruption of blood flow to the heart (myocardial infarction [MI]). The resulting loss of contractile mass causes an acute reduction in cardiac pump function. Cardiac output and blood pressure are initially maintained by activation of sympathetic reflex responses that increase myocyte contractility in regions of the heart where blood flow is maintained. Soon after MI, the ventricles begin to remodel (dilate), which further increases the work demands (systolic wall stress) on the surviving myocardium.
Myocyte contractility is increased after MI through activation of adrenergic signaling pathways that increase Ca2+
influx and sarcoplasmic reticulum (SR) uptake, storage, and release. The increased myocyte Ca2+
transients that enhance contractile function after MI are also thought to induce myocyte hypertrophy,1–3
increasing contractile mass and partially normalizing the increased systolic wall stress. However, persistent pathological stress in the remodeled, post-MI heart is associated with abnormal myocyte contractile properties4,5
and increases in the rate of myocyte death.6–8
These two changes develop with congestive heart failure (CHF) and increase during its progression.6,9
The respective contributions of myocyte contractile abnormalities (weak myocytes) and myocyte death (not enough myocytes) in the induction and progression of HF after MI is still not clearly defined. We studied this issue by preventing depression of myocyte contractile function in genetically modified mice subjected to MI.
Persistent pathological stress (MI and hypertension) induces abnormalities in myocyte Ca2+
and sympathetic signaling cascades.11
uptake rates are slowed; Ca2+
transient and action potential durations are prolonged5,12
; and inotropic responses to sympathetic agonists are blunted.13
These changes are centrally involved in the slowing of contraction and relaxation rates, prolongation of contractile duration, and depressed contractility reserve.14,15
What is still not clear is whether these Ca2+
handling alterations induce cardiac decompensation and cause its progression or whether they are secondary to the ever increasing demand for enhanced myocyte function in the pathological heart.
The depressed myocyte contractility hypothesis predicts that HF therapies that increase myocyte contractility will improve cardiac pump function, HF symptoms, and survival. Unfortunately, most inotropic therapies that have been tested in patients over the past few decades have either had no effect on survival16
or have increased death rates.17,18
that have clinical benefit in HF, inhibitors of excess renin–angiotensin and β
-adrenergic signaling, reduce rather than enhance myocyte contractility,19,20
suggesting that myocyte contractile abnormalities in HF might be the consequence of the excessive contractility demands rather than the cause of HF per se.
HF induction and progression is also associated with an increased rate of myocyte death from apoptosis and necrosis.8
Excessive activation of sympathetic and renin–angiotensin signaling pathways in HF,21
as well as oxidative stress, cytokine accumulation,22
and persistent activation of Ca2+
are all thought to contribute.25,26
Our working hypothesis is that excessive demands for contractility in HF increase cell death and it is cell death rather than reduced myocyte contractile function that causes HF progression.
The objective of our present study was to determine whether preventing depressed myocyte contractility after MI, without activating the sympathetic nervous system, improves cardiac pump function and slows CHF progression. To explore this topic we developed a genetically modified mouse in which we could increase Ca2+
influx by conditional, cardiac specific overexpression of the β
2a subunit of the L-type Ca2+
channel (termed β
This approach increases Ca2+
influx and myocyte contractility26,27
without requiring sympathetic nerve activity. If depressed myocyte contractility causes abnormal pump function and CHF after MI, then we would expect better cardiac pump function in our β
2a mice in which depressed myocyte contractility is prevented. If on the other hand the remodeling of myocyte Ca2+
handling after MI is a response to the excessive demands for enhanced function, and in part this remodeling protects the myocyte from Ca2+
-mediated damage, then maintaining high Ca2+
might increase myocyte death and exacerbate the depression of cardiac pump function.