Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy.

BACKGROUND: Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown. METHODS AND RESULTS: We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed approximately 50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca2+ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca2+ content was increased in the recovery compared with the nonrecovery group. CONCLUSIONS: These results show that specific changes in excitation-contraction coupling, and not regression of cellular hypertrophy, are specifically associated with clinical recovery after LVAD and further identify sarcoplasmic reticulum Ca2+ handling as a key functional determinant in patients with heart failure.

Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation.

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.

Aortic root characteristics of human pulmonary autografts.

BACKGROUND: After pulmonary autograft replacement of the aortic valve and root, the pulmonary artery (PA) wall is subjected to higher pressures. Concern exists that this may lead to structural and functional changes in the implanted autograft and subsequent aortic root dilatation and neoaortic regurgitation. We therefore assessed root dimensions and neoaortic regurgitation, morphological structure, and mechanical behavior in patients who underwent the Ross operation. METHODS AND RESULTS: Seventy-four patients who were randomized to undergo aortic valve replacement with an aortic homograft or a pulmonary autograft were followed up echocardiographically for up to 4 years and had their aortic root dimensions measured at the level of the annulus, sinuses, and sinotubular junction. In a separate series of 18 patients who underwent pulmonary autograft surgery and 8 normal organ donors, samples from the PA and aorta were analyzed for medial wall thickness, distribution of the staining of collagen and elastin, and elastin fragmentation. Finally, stress-strain curves were obtained from samples of the PA and aorta from 9 patients who underwent pulmonary autograft surgery and from 1 patient in whom a 4-month-old autograft was explanted. No patient in either group had aortic dilatation at any level of >20% or more than mild aortic regurgitation at up to 4 years of follow-up. The aortic media was thicker in both autografts and normal donors (P:<0.01), and there was a trend for the PA media to be thicker in the autograft group. Elastic fiber in all aortas showed little or no variation, whereas in the PA, there was considerable variation in fragmentation. Patients with higher preoperative PA pressures tended to have lower fragmentation scores (chi(2) P:<0.01). The lower stiffness modulus, higher stiffness modulus, and maximum tensile strength of the aorta was 34% to 38% higher than that of the PA (P:<0.01); however, the 4-month-old autograft appeared to show adaptation in mechanical behavior. CONCLUSIONS: In our series of patients, there was no significant progressive dilatation of the aortic root. We demonstrated differences in the anatomic structure and mechanical behavior of the PA in vitro and highlighted histological and mechanical modes of adaptation.

Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts.

BACKGROUND: Myocardial dysfunction is a common and important problem in donor hearts. The mechanisms responsible remain unclear. We have studied the cytokines tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) in the myocardium and serum from donors with myocardial dysfunction (unused donors) and compared them with donors with good ventricular function (used donors) and patients with advanced heart failure (HF). METHODS AND RESULTS: Clinical details and ventricular function were assessed in 46 donors (31 used, 15 unused). Real-time reverse transcription-polymerase chain reaction, Western blotting, and immunocytochemistry were performed on myocardium and immunoassays on serum. TNF-alpha mRNA was 1.6-fold higher in unused than in used donors (P:<0.005) and 1.74-fold higher than in 36 patients with HF. IL-6 mRNA was 2.4-fold higher in unused than in used donors (P:<0.0001) and 4.67-fold higher than in HF (P:<0.0001). Western blotting showed higher TNF-alpha in unused (218. 3+/-6.4, n=4 versus 187.3+/-5.4, n=3 OD units) than used donors (P:<0.05). TNF-alpha expression was localized to cardiac myocytes. Serum TNF-alpha was higher in unused (8.72+/-1.3 pg/mL, n=13) than in used (6.12+/-0.8 pg/mL, n=25, P:<0.05) donors and HF (4.0+/-0.4 pg/mL, n=17, P:<0.005). Serum TNF-alpha receptors did not differ between unused (4.3+/-0.8 and 8.6+/-1.6 ng/mL, n=10) and used (3. 5+/-0.4 and 6.5+/-1.1 ng/mL, n=24) donors. There was a trend for higher serum IL-6 in unused (16.5+/-2.9 pg/mL, n=9) compared with used (13.9+/-1.6 pg/mL, n=26, P:=NS) donors. CONCLUSIONS: This study documented an increase in the expression of TNF-alpha and IL-6 in the myocardium of all donor hearts that was more marked in the dysfunctional (unused) donor hearts. This was accompanied by similar changes in the serum. This might have important therapeutic implications.

Quantitative myocardial cytokine expression and activation of the apoptotic pathway in patients who require left ventricular assist devices.

BACKGROUND: Molecular mechanisms underlying the deterioration of patients undergoing LV assist device (LVAD) implantation remain poorly understood. We studied the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta and IL-6 and the terminal stage of the apoptotic pathway in patients with decompensating heart failure who required LVAD support and compared them with patients with less severe heart failure undergoing elective heart transplantation. METHODS AND RESULTS: Myocardial and serum samples from 23 patients undergoing LVAD implantation were compared with those from 36 patients undergoing elective heart transplantation. Myocardial TNF-alpha mRNA (1.71-fold; P<0.05) and protein (3.43+/-0.19 versus 2.95+/-0.10 pg/mg protein; P<0.05) were elevated in the LVAD patients. Immunocytochemistry demonstrated TNF expression in the myocytes. Serum TNF-alpha was also elevated (12.5+/-1.9 versus 4.0+/-0.4 pg/mL; P<0.0001) in the LVAD patients. IL-6 mRNA (2.57-fold higher; P<0.005) and protein (27.83+/-9.35 versus 4.26+/-1.24 pg/mg protein; P<0.001) were higher in the LVAD candidates, as was serum IL-6 (79.3+/-23.6 versus 7.1+/-1.6 pg/mL; P<0.0001). Interleukin-1beta mRNA expression was 9.78-fold higher in the LVAD patients (P<0.001). iNOS mRNA expression was similar to that in advanced heart failure patients and was not further elevated in the LVAD patients. Levels of procaspase-9 (8.02+/-0.91 versus 6.16+/-0.43 oligodeoxynucleotide [OD] units; P<0.01), cleaved caspase-9 (10.02+/-1.0 versus 7.34+/-0.40 OD units; P<0.05), intact and spliced DFF-45 (4.58+/-0.75 versus 2.84+/-0.23 OD units; P<0.05) were raised in LVAD patients, but caspase-3 and human nuclease CPAN were not. CONCLUSIONS: Elevated TNF-alpha, IL-1beta, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF-alpha and IL-6 in serum of deteriorating patients who required LVAD support. These occurrences may have therapeutic implications and influence the timing of LVAD insertion.

Association of improved cardiac function in donors with C34T mutation of the AMP deaminase 1 gene.

Possession of the C34T mutation in AMP deaminase (AMPD1) gene has been shown to be associated with attenuation of the progression of heart failure and improved survival in ischemic heart disease. In this study, we examined the frequency of the mutation in the heart with good and poor cardiac function and in healthy controls. We found that there was no difference in the frequency of the mutation between the patients with heart failure and healthy controls. However, the frequency of the mutation in the healthy donor hearts was much higher when compared to healthy controls or donors with failing hearts.

AMPD1 C34T mutation selectively affects AMP-deaminase activity in the human heart.

Possession of the nonsense mutation in AMPD 1 C34T gene has been linked to improved survival in patients with heart failure, possibly by promoting the formation of adenosine. This mutation is known to decrease the activity of AMP-deaminase in skeletal muscle. We have found that the AMPD1 mutation decreases the activity of AMP-deaminase in the heart without changing the activity of any other enzymes of adenine nucleotide metabolism. Protective mechanism of this mutation may be thus induced by local cardiac metabolic changes.

Activation of apoptotic and inflammatory pathways in dysfunctional donor hearts.

BACKGROUND: Myocardial dysfunction is common after brain death, but the mechanisms remain unclear. Apoptosis is tightly regulated by enzymes termed the caspases. We have investigated the caspases involved in the terminal part of the apoptotic pathway in dysfunctional (nontransplanted) donor hearts and their relation to inflammatory markers and compared them to hearts with good ventricular function (transplanted donors). METHODS: Thirty-one donor hearts assessed for transplantation were examined. Western blotting was used to measure pro-caspase-9, caspase-3, DFF45, the activated nuclease CPAN and poly (ADP-ribose) polymerase, a DNA repair enzyme inactivated by caspase-3. Caspase-3 activity was also measured. Histologic and immunocytochemical analysis for HLA Class II and Real Time polymerase chain reaction for tumor necrosis factor-alpha and interleukin 6 were performed to detect inflammatory activation. RESULTS: Cleaved caspase-9 was higher (5.53+/-0.6 vs. 3.64+/-0.4 O.D. units, P<0.01) in nontransplanted compared with transplanted donors and there was a trend for higher pro-caspase-9 (5.20+/-1.0 vs. 4.22+/-0.4 O.D. units, P=NS). Levels of pro-caspase-3 were higher in nontransplanted (9.66+/-0.5 vs. 5.15+/-0.5 O.D. units, P<0.00001) donors and cleavage products of caspase-3 were elevated in 14 of 14 nontransplanted and 2 of 17 transplanted donors. Intact DFF-45 (8.94+/-0.36 vs. 6.14+/-0.30 O.D. units, P<0.000005), its spliced product (2.38+/-0.35 vs. 0.4+/-0.21 O.D. units, P=0.0001) and the nuclease caspase-activated nuclease (2.01+/-0.3 vs. 0.66+/-0.16 OD units, P=0.001) were higher in nontransplanted donors. The caspase-3 substrate poly (ADP-ribose) polymerase was higher in nontransplanted (1.16+/-0.13 vs. 0.61+/-0.22 O.D. units, P=0.57) donors. CONCLUSIONS: The caspases are elevated in dysfunctional donor hearts compared with hearts with good ventricular function with a possible link to inflammatory activation supporting the concept that brain death causes inflammatory activation which can lead to apoptosis with a possible important effect on function.

Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root.

OBJECTIVES: There is still no agreement about the best method of dealing with malfunction of the aortic valve caused by aneurysm or dissection of the aortic root. The experience, rationale, and development of a valve-preserving technique introduced and used since 1979 is described. METHODS: During this period 158 patients (78% of all patients undergoing resection of aneurysm of the ascending aorta) were operated on using this technique. Their ages ranged from 2 to 72 years (mean 46.6 years). Of the patients 107 were male and 51 were female. A total of 68 patients had skeletal manifestations of Marfan's syndrome. The original disease was chronic aneurysm of the ascending aorta or root in 92 (58.2%), chronic dissection in 17 (10.8%), and acute dissection in 49 (31%) patients. One hundred eleven additional procedures were performed in 84 patients. In all there were five early deaths (4.6% +/- 2%) in the 109 patients with chronic aneurysm and one death in the 103 patients operated on electively (0.97% +/- 0.9%). Actuarial survival for patients operated on for chronic aneurysm was 93.3%, 88.0%, 79.0%, and 57.9% at 1, 5, 10, and 15 years and 96.8%, 91.2%, 82.0%, and 60.0% for those operated on electively. Actuarial survival for patients operated on for acute dissection was 72.8%, 63.4%, and 53.3% at 1, 5, and 10 years. The probability of needing reoperation was 3.0% +/- 2%, 11% +/- 0.5%, and 11% +/- 0.5% at 1, 5, and 10 years. There were no instances of infective endocarditis or thromboembolic complications except in two patients operated on early in the series who had cusp extension. No anticoagulants were used. Echocardiography showed reduction in left ventricular end-systolic and end-diastolic dimensions, which was maintained. At the end of follow-up trivial or no aortic regurgitation was demonstrated in 63.6%, mild to moderate in 33.3%, and severe in 3%. CONCLUSIONS: Valve-sparing operations are possible in a large proportion of patients with aneurysms of the ascending aorta and the medium and long-term results are encouraging.

A prospective study of plasma nitrates following human heart transplantation-relevance to myocardial function.

BACKGROUND: Nitric oxide (NO) has been shown to affect myocardial function in positive and negative inotropic ways. Expression of inducible nitric oxide synthase and release of nitric oxide into the circulation has been associated with acute rejection in animal studies. The role of NO and the associated myocardial dysfunction seen during acute rejection in humans has not been adequately defined. In a prospective sequential study, we have studied the relationship between plasma nitrate and biopsy-proven acute rejection, and systolic and diastolic function after heart transplantation. METHODS: Biopsies were performed weekly and then fortnightly up to 12 weeks after transplantation and on clinical indication of rejection in 37 patients. Plasma nitrates were obtained on the morning of each biopsy (total 341). An echocardiogram was performed immediately prior to each biopsy in which the systolic parameters, ejection fraction (EF) and fractional shortening (fs), and the diastolic parameters, isovolumetric relaxation time (IVRT), mitral valve pressure half-time (MVPHT), mitral valve deceleration time (MVDT), e:a ratio, and a wave duration, were measured. RESULTS: Plasma-nitrate level showed no significant correlation with the systolic parameters, EF or fs, or with changes in EF or fs. No significant correlation was found between plasma-nitrate level and the diastolic parameters IVRT, MVPHT, MVDT, mitral valve a wave duration, or e:a ratio. CONCLUSIONS: This study has shown no correlation between plasma nitrate and impaired systolic or diastolic function after heart transplantation. Instead there was a weak trend for elevated nitrate to be associated with better systolic function.

Incidence and clinical management of life-threatening left ventricular assist device failure.

BACKGROUND: Mechanical device failure can be life-threatening and is becoming increasingly important as left ventricular assist devices (LVADs) are being used for longer periods as a bridge to transplantation (period lengthening due to donor shortage) or recovery, or as destination therapy. However, its incidence and clinical management have not been widely studied. METHODS: We investigated the incidence and management of major device failure for a total of 102 Thoratec/TCI HeartMate and Thoratec PVAD devices implanted at our institution since 1995. RESULTS: The cumulative probability of device failure was 6%, 12%, 27% and 64% at 6 months, 1 year, 18 months and 2 years, respectively. Major failure occurred in 8 (7.8%) patients. Four patients presented as emergency cases with vented electric (VE) failure, and 3, with failure due to a seized motor, were supported on the pneumatic driver to explantation, transplantation or device change. Another patient had a ruptured pump diaphragm and was maintained for 12 hours, but died of a Type B aortic dissection. Four patients underwent elective device change, including 2 of a VE pump, 1 with inlet valve regurgitation and fractured power cable at 414 days, and 1 with inlet valve regurgitation at 656 days, all of whom underwent transplantation or explantation. One patient with VE failure was maintained on the pneumatic driver, then underwent Thoratec paracorporeal ventricular assist device (PVAD) implantation and was transplanted. One Thoratec PVAD patient developed LVAD thrombus, underwent pump replacement, and was transplanted. A further patient on the implantable pneumatic (IP) HeartMate developed a pneumoperitoneum due to a leak at the junction of the pneumatic driveline, which was repaired by inserting a new driveline, and underwent heart/kidney transplantation. CONCLUSIONS: Life-threatening mechanical device failure is not uncommon and increases with time, but can be managed successfully in most patients. Improvements in design and manufacture should further enhance outcome with LVADs.

The aortic outflow and root: a tale of dynamism and crosstalk.

Although the aortic outflow and root (AoR) constitute a short channel connecting the left ventricle to the aorta, its different components have been shown to be highly specialized structures, interacting with each other as well as with surrounding structures, thus providing a "tale of dynamism and crosstalk." Thorough knowledge of the AoR and morphological and structural changes, that occur during pathological processes, can have important implications in evolving and executing surgical procedures designed to preserve and restore the "dynamism and crosstalk." The crown-shaped annulus, fibrous trigones, aortic cusps components, aortic sinuses, and the sinotubular junction share a dynamic coordinated behavior, which can be partially or completely restored in various repair or replacement procedures of the AoR. The interaction and the specific operations are presented with evidence supporting the notion that the dynamic behavior of the root does influence the pattern of instantaneous movements of the aortic cusps after different types of operations. Further studies are required to evaluate the influence of adopting these ideas on the long-term results of operative procedures.

The role of nitric oxide and cytokines in heart failure.

Heart failure is a common problem associated with considerable mortality and morbidity. The mechanisms underlying the heart failure syndrome, which remain poorly understood, may involve an inflammatory process. Nitric oxide (NO) and various cytokines could play an important role in this inflammatory process. Recent evidence has emerged in both animal models and humans suggesting that both of these mediators may play an important role in heart failure. NO is synthesized by the NO synthase family of enzymes. Two of these enzymes are constitutive, endothelial NO synthase and neuronal NO synthase. The third enzyme, inducible NO synthase, is capable of producing large amounts of NO once induced by mediators such as interleukin (IL)-1, IL-2, IL-6, tumour necrosis factor (TNF)-alpha, and interferon-gamma. Endothelial NO synthase is present in the heart in the endocardium, cardiac myocytes, and cardiac conduction tissue. Inducible NO synthase is present in cardiac myocytes, endocardium, vascular smooth muscle cells, and infiltrating inflammatory cells. Evidence from both animal models and patients suggests that NO exerts a negative inotropic effect. Increased inducible NO synthase, TNF-alpha, and IL-6 have been found in patients with heart failure in several studies. In other studies, decreased endothelial NO synthase was found in patients with heart failure. TNF-alpha and IL-6 may be produced in heart failure and may induce inducible NO synthase, resulting in NO production, which acts as a negative inotrope. Endothelial NO synthase may be decreased as a result of downregulation by TNF-alpha or inducible NO synthase. The possible role of these mediators in heart failure needs further evaluation because these findings could have novel therapeutic implications.

Pulmonary autograft versus aortic homograft for aortic valve replacement: interim results from a prospective randomized trial.

BACKGROUND AND AIM OF THE STUDY: Although pulmonary autografts offer advantages over aortic homografts, they may also carry additional risks. We reviewed the interim results of a prospective randomized trial of autograft versus homograft aortic valve replacement (AVR) to determine if the greater complexity of the autograft insertion is justified, particularly with regard to time-related hemodynamic function. METHODS: A total of 182 patients (82% male, 18% female; mean age 37.2 +/- 14.3 years; range: 2-64 years) with isolated aortic valve disease were randomized to pulmonary autograft (group A, n = 97) or aortic homograft (group H, n = 85); 42% had previous aortic valve surgery and 19% had native or prosthetic valve endocarditis. Follow up included annual outpatient visits and echocardiography. RESULTS: Autograft AVR required longer cross-clamp (41%) and bypass (43%) times, but did not result in significantly more bleeding, longer recovery or more complications. One 30-day death occurred in group A (1%), and three deaths in group H (4%). Median follow up was 33.9 months (range: 1-61 months). There was one late death in each group, three reoperations in group A (all for pulmonary homografts), and three in group H (including two aortic homograft reoperations, both in children). There were no autograft reoperations. There were no other valve-related events. At 48 months, actuarial survival and reoperation-free survival rates were 97.8% and 94.2% in group A, and 95.3% and 87.7% in group H (p = NS). Echocardiography showed near-perfect function in all autografts, but early signs of subclinical dysfunction in many homografts. CONCLUSION: Both autograft and homograft AVR are safe and produce good intermediate-term results. Early homograft degeneration appears to favor autografts in children. The echocardiographic findings may translate into superior long-term autograft durability and hemodynamics.

A quantitative study of calcium deposition in the aortic wall following Medtronic Freestyle compared with homograft aortic root replacement. A prospective randomized trial.

BACKGROUND AND AIM OF THE STUDY: Unstented aortic valve substitutes offer many of the theoretical advantages of homografts such as superior hemodynamic performance and enhanced durability, particularly when inserted as a root. Many of these depend on the maintained flexibility of the valve components. Calcification of the aortic wall may adversely affect these phenomena. Electron beam computed tomography has been used to evaluate aortic wall calcification in patients undergoing aortic root replacement in a prospective randomized trial designed to compare the Medtronic Freestyle valve with the homograft valve replacement. METHODS: Patients were followed with electron beam computed tomography scans of the aortic root at six-monthly intervals after surgery. A calcification score (Hounsfield units) and a calcified volume score (mm3) were obtained from each scan using a new modified technique. Results were related to hemodynamic data from echocardiography. The prevalence of calcification was also related to the homograft donor age. RESULTS: Seventy-six patients (age range: 40-79 years) were randomized to root replacement with either homograft (n = 31) or Freestyle (n = 45) valves. Fifty-three scans of the aortic root were performed postoperatively in 37 patients. No statistical difference between the two groups was found at six and 12 months after surgery. However, after 18 months the calcified volume score was 5903.8+/-2356.8 mm3 in the homograft versus 2725.6+/-1500.5 mm3 in the Freestyle group (p = 0.017). There was a correlation between calcification score, calcified volume score and left ventricular mass (r = 0.323, p = 0.093 and r = 0.350, p = 0.068, respectively) on the one hand, and calcification score, calcified volume score and valve size on the other hand (r = 0.178, p = 0.466 and r = 0.068, p = 0.780, respectively). CONCLUSIONS: Electron beam computed tomography provides a powerful tool for the detection of calcium in the aortic wall of valve grafts. There is a low rate of calcification during the first 18 months in the Medtronic Freestyle valve, and this appears to be lower than that observed in homografts. Longer-term follow up of the aortic root in these patients is required. This is an ongoing study.

Left ventricular assist devices.

Left ventricular assist device (LVAD) insertion in patients with advanced heart failure with deteriorating clinical status is life saving, and LVADs are now being inserted into an increasing number of patients with advanced heart failure. They were initially inserted as a bridge to transplantation, and the decreased availability of donor hearts means that an increasing number of patients are requiring LVAD support for survival when their clinical status deteriorates. There is strong evidence that with LVAD unloading, particularly when combined with pharmacological treatment, the patients' myocardial function can also recover, allowing device removal and avoiding the need for transplantation, immunosuppression and its associated complications. This indication, known as "bridge to recovery" is a newer and expanding indication. The future use of LVADs, particularly as survival continues to increase, is extending to their wider use as destination therapy, when the device is inserted lifelong as an alternative to transplantation, and this role is likely to increase further. LVAD technology is evolving quickly, survival is improving, the incidence of complications is decreasing and durability of the devices is improving.