**4. Apoptosis imaging in heart failure and cardiomyopathy**

In spite of dramatic improvement of therapies in acute coronary syndrome, post acute myocardial infarction mortality has reached a plateau and post infarction heart failure due to ventricular remodeling is on the increase. About 15 to 25 % of acute myocardial infarction patients develop heart failure that remains a progressive despite of continuous pharmacological therapy. It has been reported that myocardial apoptosis shortly after acute myocardial infarction might be a strong predictor of unfavorable LV remodeling and early post infarction symptomatic heart failure in 16 patients dying ≥10 days after myocardial infarction (Abbate, et al., 2003).

In rats with anterior myocardial infarction, 28-day infusion of caspase inhibitor after infarction ameliorated apoptosis, preserved myocardial contractile proteins, decreased myocardial interstitial collagen deposite, reduced systolic dysfunction, and attenuated LV remodeling (Chandrashekhar, et al., 2004). If so, apoptosis imaging could be a promising noninvasive method to identify patients at risk of heart failure development due to LV remodeling and to monitor the treatment effect if some specific anti-apoptotic agents will reach the stage of clinical study.

In patients with advanced heart failure, low but abnormal rate of cardiac myocyte apoptosis persist for months (0.08% to 0.25% in heart failure vs 0.001% to 0.002% in normal subjects), thereby ultimately might result in a large loss of functional cardimyocytes (Olivetti, et al.,

or stress induced ischemia. However, several questions yet to be answered concerning the clinical application of 99mTc-annexin V imaging. In vivo imaging 1 hr after tracer injection is feasible in rats because blood clearance of 99mTc-annexin V was rather fast, although, the earliest optimal time for imaging after tracer injection should be investigate in human. In heart transplantation patients, it was revealed that 99mTc-annexin V SPECT imgaing was possible 1 h after tracer injection (Narula, et al., 2001). Speedy imaging after tracer injection is crucial especially in emergency situation. Are therapeutic interventions beneficial for all annexin-positive myocardium, or in only specific pathological status, or in only limited time window? How much of the shift from necrosis to apoptosis by therapeutic intervention is cardioprotective (Narula, et al., 2003)? Necrosis is more harmful than apoptosis, because cells are removed without inflammation in apoptosis but cells are removed with inflammation and fibrosis follows in necrosis. Is annexin V positive scan in stress induced ischemia related to subsequent prognosis, or indication of PCI? These potential imaging concepts of the assessment of myocardial injury, stress, cell death in acute ischemia should

It has been increasingly clear that apoptosis is a major contributor to early cardiomyocyte cell death after acute myocardial infarction, and is involved in post myocardial infarction ventricular dysfunction and adverse remodeling that develop heart failure. These findings emphasize the need for the reliable in-vivo imaging of apoptosis that assess the ongoing pathology so that rational preventive therapies can be applied and to assess the consequence of therapies. 99mTc-annexin V imaging might be applied to assess myocardium at risk or cell death in acute coronary syndrome and prediction of the ventricular remodeling after myocardial infarction and heart failure by allowing visualization of ongoing PS externalization that might precede or underlie change in pathophysiology, morphology, and

In spite of dramatic improvement of therapies in acute coronary syndrome, post acute myocardial infarction mortality has reached a plateau and post infarction heart failure due to ventricular remodeling is on the increase. About 15 to 25 % of acute myocardial infarction patients develop heart failure that remains a progressive despite of continuous pharmacological therapy. It has been reported that myocardial apoptosis shortly after acute myocardial infarction might be a strong predictor of unfavorable LV remodeling and early post infarction symptomatic heart failure in 16 patients dying ≥10 days after myocardial

In rats with anterior myocardial infarction, 28-day infusion of caspase inhibitor after infarction ameliorated apoptosis, preserved myocardial contractile proteins, decreased myocardial interstitial collagen deposite, reduced systolic dysfunction, and attenuated LV remodeling (Chandrashekhar, et al., 2004). If so, apoptosis imaging could be a promising noninvasive method to identify patients at risk of heart failure development due to LV remodeling and to monitor the treatment effect if some specific anti-apoptotic agents will

In patients with advanced heart failure, low but abnormal rate of cardiac myocyte apoptosis persist for months (0.08% to 0.25% in heart failure vs 0.001% to 0.002% in normal subjects), thereby ultimately might result in a large loss of functional cardimyocytes (Olivetti, et al.,

**4. Apoptosis imaging in heart failure and cardiomyopathy** 

be validated in clinical studies.

infarction (Abbate, et al., 2003).

reach the stage of clinical study.

LV dysfunction.

1997; Saraste, et al., 1999; Guerra, et al., 1999). In study with transgenic mice that express a conditionally active caspase exclusively in the myocardium, low rate of cardiomyocyte apoptosis as 0.023% is sufficient to cause a lethal dilated cardiomyopathy. Conversely, inhibition of cardiac myocyte apoptosis by caspase inhibitor in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, indicating that myocyte apoptosis may be a causal mechanism of heart failure, and inhibition of this cell death process may constitute the basis for novel therapies (Wencker, et al., 2003). The low level of cell death due to apoptosis in heart failure makes detection of apoptosis with the current techniques very challenging.

In recent study in 9 consecutive patients with advanced nonischemic cardiomyopathy (8 dilated and 1 hypertrophic cardiomyopathy) and 2 relatives, 5 patients showed focal or global 99mTc-annexin V uptake in the left ventricular myocardium. Interestingly, these 5 patients with 99mTc-annexin V uptake had experienced a significant worsening or a recent onset of heart failure, on the contrary, 4 patients without 99mTc-annexin V uptake had no recent evidence of worsening of heart failure. In addition, during a follow up of 1 year, 4 patients with 99mTc-annexin V uptake showed a decline of LVEF, on the other hand, in patients without 99mTc-annexin V uptake, clinical status and LVEF remained stable (Kietselaer, et al., 2007). These data indicate that the 99mTc-annexin V imaging in advanced non-ischemic cardiomyopathy, may identify the patients with high risk who might benefite from cell death blocking therapies.
