Background-Infants born with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum face a neonatal mortality of at least 48% despite early postnatal left atrial decompression and palliative surgery. Prenatal left atrial decompression has been suggested as a means of improving these outcomes. This study reports the feasibility of fetal catheterization to create an interatrial communication and describes technical considerations. Methods and Results-Seven fetuses at 26 to 34 weeks' gestation with hypoplastic left heart syndrome and intact or highly restrictive atrial septum underwent attempted prenatal intervention. Under ultrasound guidance, the atrial septum was approached with a needle introduced percutaneously from the maternal abdominal surface. In 6 of 7 fetuses, the atrial septum was successfully perforated, with balloon dilation of this iatrogenic defect resulting in a small but persistent interatrial communication. There were no maternal complications. One fetus died after the procedure. The remaining fetuses were liveborn at term, although 4 died as neonates. Conclusions-Ultrasound-guided fetal atrial septoplasty consisting of septal puncture and balloon dilation is feasible and can be performed percutaneously to minimize maternal risk. Although we have not demonstrated any positive clinical impact to date, it is our hope that further technical evolution will ultimately enable prenatal left atrial decompression and improvement of outcomes in fetuses with hypoplastic left heart syndrome and intact atrial septum.

Defective cardiac muscle relaxation plays a causal role in heart failure. Shown here is the new in vivo application of parvalbumin, a calcium-binding protein that facilitates ultrafast relaxation of specialized skeletal muscles. Parvalbumin is not naturally expressed in the heart. We show that parvalbumin gene transfer to the heart in vivo produces levels of parvalbumin characteristic of fast skeletal muscles, causes a physiologically relevant acceleration of heart relaxation performance in normal hearts, and enhances relaxation performance in an animal model of slowed cardiac muscle relaxation. Parvalbumin may offer the unique potential to correct defective relaxation in energetically compromised failing hearts because the relaxation-enhancement effect of parvalbumin arises from an ATP-independent mechanism. Additionally, parvalbumin gene transfer may provide a new therapeutic approach to correct cellular disturbances in calcium signaling pathways that cause abnormal growth or damage in the heart or other organs.J. Clin. Invest. 107:191-198 (2001).questions: (a) Could physiologically relevant levels of parvalbumin be achieved in the left ventricle at 6 days after gene transfer? (b) Under physiological conditions, can parvalbumin alter mechanical relaxation properties of the left ventricle? (c) Can parvalbumin improve heart performance in an experimental model of abnormally slow myocardial relaxation? MethodsCardiac gene transfer in vivo. Adult, female Sprague-Dawley rats (250 g) were anesthetized with sodium pentobarbital (30 mg/kg body weight intraperitoneally). Animals were intubated and placed on artificial ventilation (50-60 breaths per minute). A thoracotomy was performed over the third intercostal space of the left thorax to expose the heart. An insulin syringe was inserted into the LV free wall (apical to base), using the left anterior descending coronary artery as a guide, and then slowly injecting 50-100 µl solution (parvalbumin titer, 1.87 × 10 10 PFU/ml; AdlacZ titer, 1.00 × 10 10 PFU/ml, each in PBS/10% glycerol; vehicle was PBS/10% glycerol) while withdrawing the syringe. The chest was closed and negative pleural pressure reestablished before extubation. Animals were given antibiotics via the drinking water. At day 6 after gene (or vehicle) transfer, heart parvalbumin expression and/or heart mechanical function was evaluated. This procedure has been approved by the University Committee on the Use and Care of Animals at the University of Michigan.Myocardial relaxation performance. At day 6 after gene transfer, hearts were isolated, retrogradely perfused with oxygenated Krebs-Henseleit buffer warmed to 37°C, and electrically paced at 4 Hz (supramaximal, 5-millisecond pulses; Model S5 Stimulator; Grass Instruments, Quincy, Massachusetts, USA). Cardiac twitch contractile parameters (see Figure 3) were obtained from Langendorff perfused hearts by placing monofilament sutures at the apical and the base regions of the LV wall (between the circumflex and lateral descending coronary arteries). The base sutu...

Abstract-Familial hypertrophic cardiomyopathy (FHC) has been linked to mutations in proteins of the cardiac contractile apparatus, including ␣-tropomyosin (Tm). Mice expressing ␣Tm in the heart were developed to determine the effects of FHC mutant Tm on cardiac structure and function from single cardiac myocytes to whole organ function in vivo. Expression of E180G mutant Tm did not produce cardiac hypertrophy or detectable changes in cardiac muscle morphology. However, E180G mutant Tm expression increased the Ca 2ϩ sensitivity of force production in single cardiac myocytes in a transgene expression-dependent manner. Contractile dysfunction in single myocytes manifested organ level dysfunction, as conductance-micromanometry showed E180G Tm mice had significantly slowed relaxation (diastolic dysfunction) under physiological conditions. The diastolic dysfunction in E180G Tm mice was no longer evident during ␤-blockade because propranolol eliminated the effect of E180G Tm to slow myocardial relaxation. Cellular and organ level dysfunction were evident in E180G Tm mice in the absence of significant cardiac structural abnormalities normally associated with FHC. These findings therefore suggest that diastolic dysfunction in FHC may be a direct consequence of FHC mutant protein expression. In addition, because diastolic dysfunction in E180G Tm mice is dependent on inotropic status, cardiovascular stress may play an important role in FHC pathogenesis.