The CarboMedics prosthetic heart valve: experience with 1,084 implants

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate our clinical experience with the CarboMedics heart valve prosthesis. METHODS: Between October 1991 and December 2000, 942 consecutive patients (514 males, 428 females; mean age 58+/-11 years; range: 6-78 years) underwent mechanical valve implantation with the CarboMedics prosthesis. Preoperatively, 47% of patients were in NYHA class III and 22% in class IV; in addition, 134 patients (14.2%) had undergone a previous cardiac operation. Aortic valve replacement (AVR) was performed in 469 patients (49.8%), mitral valve replacement (MVR) in 330 (35.0%), double valve replacement (DVR) in 142 (15.1%), and isolated tricuspid valve replacement (TVR) in one patient. Eighty-eight patients (9.3%) underwent associated myocardial revascularization. Mean cardiopulmonary bypass and aortic cross-clamp times for the entire group were 107+/-39 min and 74+/-24 min, respectively. RESULTS: Overall early mortality was 2.3% (6/469 AVR, 1.2%; 12/330 MVR, 3.6%; 4/142 DVR, 2.8%). Late mortality was 3.1% (n = 29; including 17 cardiac deaths (10 were valve-related). Mean follow up was 66+/-31 months (range: 1-109 months), and was 98% complete yielding a total follow up of 4959 years. Actuarial survival at five years for the entire group was 89.3+/-1.6% (AVR 91.1%, MVR 86.4%, DVR 90.5%). Thromboembolism occurred in 26 patients (2.8%, 0.52%/pt-year) and major hemorrhagic events in 20 (2.1%, 0.4%/pt-year). Nine patients (0.9%) required a reoperation, in three cases (0.3%) after Staphylococcus epidermidis-mediated endocarditis. No structural deterioration occurred. Among 891 survivors, 94% of the patients are currently in NYHA classes I or II (p <0.05). CONCLUSION: This study confirmed the safety and reliability of the CarboMedics mechanical valve prosthesis, even in old age groups. This bileaflet prosthesis showed no structural deterioration, and a low incidence of overall complications.     

Are the benefits of a high‐intensity progressive resistance training program sustained in rheumatoid arthritis patients? A 3‐year followup study

Objective

Rheumatoid arthritis (RA) patients were reassessed for body composition and physical function mean ± SD 39 ± 6 months after commencing a randomized controlled trial involving 24 weeks of either high‐intensity progressive resistance training (PRT) or low‐intensity range of movement exercise (control) to determine whether the benefits of PRT (i.e., reduced fat mass [FM], increased lean mass [LM], and improved function) were retained.

Methods

Nine PRT and 9 control subjects were reassessed for body composition (dual x‐ray absorptiometry) and function (knee extensor strength, chair test, arm curl test, 50‐foot walk) approximately 3 years after resuming normal activity following the exercise intervention.

Results

At followup, PRT subjects remained significantly leaner than control subjects (P = 0.03), who conversely had accumulated considerable FM during the study period (approximately ?1.0 kg versus +2.4 kg, PRT versus controls). PRT subjects also retained most of the improvement in walking speed gained from training (P = 0.03 versus controls at followup). In contrast, the PRT‐induced gains in LM and strength‐related function were completely lost. Data from the controls suggest that established and stable RA patients have similar rates of LM loss but elevated rates of FM accretion relative to age‐matched sedentary non‐RA controls.

Conclusion

We found that long‐term resumption of normal activity resulted in loss of PRT‐induced improvements in LM and strength‐related function, but substantial retention of the benefits in FM reduction and walking ability. The relatively long‐term benefit of reduced adiposity, in particular, is likely to be clinically significant, as obesity is very prevalent among RA patients and is associated with their disability and exacerbated cardiovascular disease risk.

     

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin-treated primary neurons release signaling molecules derived from mitochondria: hydrogen peroxide, mitochondrial DNA, and cytochrome c. These molecules activate isolated primary Schwann cells, Schwann cells cocultured with neurons and at neuromuscular junction in vivo through the MAPK pathway. We propose that this inter- and intracellular signaling is involved in triggering the regeneration of peripheral nerve terminals affected by other forms of neurodegenerative diseases.The venoms of the black widow spider Latrodectus mactans, the Australian taipan snake Oxyuranus scutellatus scutellatus, and the Taiwan krait Bungarus multinctus cause the paralysis of peripheral skeletal and autonomic nerve terminals in envenomated subjects. Such paralysis is completely reversible, and within a month or so, patients, supported by mechanical ventilation, recover completely (1–3). Paralysis in mice/rodents has a shorter duration, and again recovery is complete (4, 5). Major presynaptic toxins of these venoms are α-latrotoxin (α-Ltx), taipoxin (Tpx), and β-bungarotoxin (β-Btx), respectively (6, 7). α-Ltx induces a very rapid nerve terminal paralysis by forming transmembrane ion channels that cause a massive Ca²⁺ entry, with exocytosis of synaptic vesicles and mitochondrial damage (7–11). This is followed by Ca²⁺-induced degeneration of motor axon terminals, which is remarkably limited to the unmyelinated endplate. Complete regeneration is achieved in mice within 8–10 d (4). Tpx and β-Btx are representative of a large family of presynaptic snake neurotoxins endowed with phospholipase A2 activity (SPANs), which are important, although neglected, human pathogens (12–15). We have contributed to the definition of their mechanism of action, which involves generation of lysophospholipids and fatty acids on the external layer of the plasma membrane (16, 17). The mixture of these lipid products favors exocytosis of ready-to-release synaptic vesicles and mediates the rise of cytosolic Ca²⁺, presumably via transient lipid ion channels (16, 18). In turn, this Ca²⁺ influx causes a massive release of synaptic vesicles and mitochondrial damage, with ensuing complete degeneration of axon terminals (5, 18–20). Similar to α-Ltx, SPANs-induced peripheral paralysis is followed by a complete recovery: regeneration and functional reinnervation are almost fully restored in rats by 5 d (20). The similar outcome and time-course of the paralysis induced by the two types of presynaptic neurotoxins suggest that the common property of inducing Ca²⁺ entry into the nerve terminals is the main cause of nerve terminal degeneration (21). Indeed, these neurotoxins cause activation of the calcium-activated calpains that contribute to cytoskeleton fragmentation (22).Although clearly documented (4, 5, 20), the regeneration of the motor axon terminals after presynaptic neurotoxins injection is poorly known in its cellular and molecular aspects. Available evidence indicates that, in general, regeneration of mechanically damaged motor neuron terminals relies on all three cellular components of the neuromuscular junction (NMJ): the neuron, the perisynaptic Schwann cells (PSCs), and the muscle cells (23, 24). The regeneration steps that take place on animal neurotoxin poisoning are likely to be similar to those after the cut or crush of nerves, as a closely similar cascade of toxic events occurs in both conditions (i.e., calcium overload, mitochondrial impairment, and cytoskeleton degradation). Similar neurodegenerative events are also shared by traumatized patients. However, the model system used here provides the advantage of being much more controlled and more reproducible. In addition, it does not involve the death of many cell types, as it follows a well-characterized biochemical lesion of the end plate only (7, 8, 10–12, 16, 18). Therefore, the mouse NMJ treated with α-Ltx, Tpx, or β-Btx represents a relevant model of acute motor axon terminal degeneration and regeneration, which is likely to provide information useful to the understanding of the pathogenesis not only of envenomation but also, more in general, of other human pathological syndromes.Cell death and injury often lead to the release or exposure of intracellular molecules called damage-associated molecular patterns (DAMPs) or alarmins. Recently, mitochondria have emerged as major sources of DAMPs (25). Mitochondria are abundant subcellular components of the NMJ that have been recently shown to release mitochondrial DNA (mtDNA) and cytochrome c (Cyt c) after trauma or snake myotoxin-induced muscle damage, thus contributing to the systemic or local inflammatory responses associated with such conditions (26, 27). In this study, we tested whether α-Ltx and SPANs induce the release of mitochondrial signaling molecules from primary neuronal cultures and found that, in addition to mtDNA and Cyt c, hydrogen peroxide (H₂O₂) is released. First candidate targets of these mitochondrial mediators released by damaged neurons are nonmyelinating PSCs, which are intimately associated with the end plate. They play an active role in the formation, function, maintenance, and repair of the NMJ (28–33). PSC activation parallels nerve degeneration and contributes to neuronal regeneration by phagocytosis of cellular debris and by extension of processes that guide reinnervation (34, 35). We therefore investigated whether mitochondrial DAMPs released by injured neurons were able to activate SCs, and through which downstream pathway. Using isolated primary cells, neuron-Schwann cell cocultures, and the NMJ in vivo, we found that PSCs are activated by mitochondrial alarmins and that the MAPK signaling pathway is involved in this process.