Postnatal outcome following fetal aortic valvuloplasty for critical aortic stenosis.

OBJECTIVE: To report our experience of fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS), with a focus on the postnatal evolution of the patients. METHODS: This was a retrospective study including all fetuses with critical AS which underwent FAV in a single center between January 2011 and June 2022. FAV was performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the antegrade aortic flow across the aortic valve. At birth, a biventricular circulation (BVC) strategy was decided assuming the left ventricular (LV) systolic and diastolic function would ensure the systemic circulation. RESULTS: Sixty-three FAV procedures were performed in 58 fetuses, at a median (range) gestational age of 26.2 (20.3-32.2) weeks. The procedure was technically successful in 50/58 (86.2%) fetuses. There were 11/58 (19.0%) cases of in-utero demise and 9/58 (15.5%) terminations of pregnancy. No patient was liveborn after an unsuccessful procedure. Thirty-eight (65.5%) infants were liveborn, at a median (range) gestational age of 38.1 (29.0-40.6) weeks, of whom 21 (55.3%) required prostaglandin treatment. Twenty-eight of the 38 (73.7%) liveborn children (48.3% of the study population) entered the BVC pathway at birth. Among them, 20 (71.4%) required an aortic valvuloplasty procedure at birth (11 (55.0%) percutaneous balloon, nine (45.0%) surgical) and eight (28.6%) did not require any treatment at birth, but, of these, five (62.5%) underwent surgical valvuloplasty between day 26 and day 1200 of age. Eleven (39.3%) of the infants with BVC at birth required a second intervention and four (14.3%) of them required a third intervention. Two (7.1%) infants who entered the BVC pathway at birth underwent conversion to univentricular circulation (UVC). None of the surviving children with BVC developed pulmonary hypertension. The overall survival rate in those with BVC at birth was 22/28 (78.6%) at a median (range) follow-up of 23.3 (2.0-112.6) months. Ten of the 58 (17.2%) patients had UVC at birth. Among these, six (60.0%) received compassionate care from birth and four (40.0%) underwent surgery. Three of the 10 patients who had UVC at birth were still alive at the latest follow-up assessment, at a median (range) gestational age of 24.3 (8.3-48.7) months. CONCLUSIONS: FAV for critical AS led to increase of antegrade aortic flow in 86.2% of fetuses, with BVC being achieved in 48.3% (73.7% of the liveborn cases). Among patients with BVC at birth, the rate of reintervention was high, but 78.6% of these children were alive at the latest evaluation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Enterovirus-related pericarditis and mediastinitis after heart surgery: a case report]. / Péricardite et médiastinite à entérovirus après chirurgie cardiaque: description d'un cas.

We report a case of enterovirus related pericarditis associated to mediastinitis in a hospitalised 53-year-old male after heart surgery. Mediastinitis caused by enterovirus has not previously been described.

[Apoptotic deregulation of endothelial cells and intimal proliferation in pulmonary hypertension of congenital heart disease]. / Dysrégulation apoptotique des cellules endothéliales et prolifération intimale dans l'hypertension artérielle pulmonaire des cardiopathies congénitales.

OBJECTIVES: To assess the cellular and histological basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD). BACKGROUND: Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. As failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis, in subjects with PHT and CHD. METHODS: We assessed anti- and pro-apoptotic markers in vascular and perivascular cells in lung biopsies from 18 patients with CHD; 7 with reversible and 11 with irreversible PHT, and from 6 controls. Immunostaining for eNOS, VEGF and CD34 (markers of vasoactivity and neoangiogenesis) was also performed. RESULTS: The anti-apoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in controls (p<0.001). Intimal proliferation was present in 10/11 irreversible PHT cases but never observed in reversible PHT (p<0.001). Similarly, perivascular inflammatory T-cells expressed more anti-apoptotic proteins in irreversible PHT (p<0.01). Irreversible PHT cases were also more likely to show compensatory up-regulation of VEGF and new small vessel formation at the sites of native vessel stenosis or occlusion (p<0.001). CONCLUSION: Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and anti-apoptotic signalling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing and thereby may contribute to clinical outcomes associated with pulmonary hypertension. Markers of apoptosis and angiogenesis were assessed in lung biopsies of subjects with pulmonary hypertension (PHT) due to congenital heart disease (CHD). The anti-apoptotic protein Bcl-2 was strongly expressed by pulmonary endothelial cells in irreversible PHT (n=11) but never in reversible PHT (n=7) (p<0.01). Irreversible PHT was also associated with up-regulation of VEGF and new vessel formation around occluded native vessels (p<0.01).

Identification and characterization of two genes (MIP-1beta, VE-CADHERIN) implicated in acute rejection in human heart transplantation: use of murine models in tandem with cDNA arrays.

BACKGROUND: Genes and mechanisms of action involved in human acute rejection after allogeneic heart transplantation remain to be elucidated. The use of a murine allograft model in tandem with cDNA arrays and quantitative real-time polymerase chain reaction (Q-PCR) can greatly help in identifying key genes implicated in human heart acute rejection. METHODS AND RESULTS: Hearts from Balb/c mice were either not transplanted or transplanted heterotopically in the abdomen of Balb/c (isografts) and C57BL/6 (allografts) mice. Histological analysis showed acute rejection only in allografts. Total RNA was extracted from isografts (n=3), allografts (n=4), and not transplanted hearts (n=4); reverse transcribed; and labeled with P32. Each probe was hybridized to cDNA macroarrays. Eight genes were overexpressed and 7 genes were underexpressed in allografts compared with isografts. Macrophage inflammatory protein-1beta (MIP-1beta), an overexpressed gene, and VE-cadherin, an underexpressed gene, were validated by immunohistochemistry and Q-PCR in the murine models. Genes of interest, validated in the 3 murine groups, were then investigated in human heart tissues. Immunohistochemistry and Q-PCR performed on endomyocardial biopsies after heart transplantation showing no rejection (n=10) or grade IB (n=10) or IIIA (n=10) rejection, according to International Society of Heart and Lung Transplantation criteria, confirmed the results obtained from the murine model. CONCLUSIONS: We have demonstrated that the upregulation of MIP-1beta and downregulation of VE-cadherin may strongly participate in human acute heart rejection.

Protection from reperfusion injury after cardiac transplantation by inhibition of adenosine metabolism and nucleotide precursor supply.

BACKGROUND: Adenosine (Ado) triggers numerous protective mechanisms in the heart that may attenuate ischemia-reperfusion injury in cardiac grafts. We aimed to establish whether sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors attenuates reperfusion injury in transplanted hearts. METHODS AND RESULTS: Rat hearts were collected after the infusion of St Thomas' Hospital cardioplegic solution, stored at 4 degrees C for 4 hours, and heterotopically transplanted into the abdomen of recipient rats. A solution containing Ado deaminase inhibitor erythro-9(2-hydroxy-3-nonyl)adenine, Ado kinase inhibitor 5'-aminoadenosine, and nucleotide precursors adenine and ribose was administered at the time of reperfusion in the treated group, whereas saline was administered to control animals. After 1 or 24 hours, mechanical function of the transplanted hearts was evaluated in an ex vivo perfusion system followed by the determination of myocardial ATP with related metabolites and measurement of the activity of neutrophil-specific enzyme myeloperoxidase in cardiac homogenates. After 24 hours of reperfusion, maximum left ventricular developed pressure increased from 87.0+/-6.8 mm Hg (mean+/-SEM) in controls to 118.1+/-8.2 mm Hg in the treated group (P<0.05), ATP increased from 11.0+/-0.8 micromol/g dry wt in controls to 15.1+/-1.2 micromol/g dry wt in the treated group (P<0.01), and myeloperoxidase activity decreased from 2.23+/-0.60 U/g wet wt in controls to 0.58+/-0.12 U/g wet wt in the treated group (P<0.001). No differences in cardiac function, ATP, or myeloperoxidase activity were observed between the treated group and controls after 1 hour of reperfusion. CONCLUSIONS: The administration of Ado metabolism inhibitors with nucleotide precursors causes a sustained increase in endogenous Ado production and exerts a potent protective effect against reperfusion injury in transplanted hearts. Improved cardiac function and elevated ATP concentration were accompanied by complete amelioration of neutrophil infiltration in treated hearts, suggesting that reduction in postischemic inflammation could be an important mechanism of this protective effect.

Gene therapy for myocardial protection: transfection of donor hearts with heat shock protein 70 gene protects cardiac function against ischemia-reperfusion injury.

BACKGROUND: Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endothelial function in a protocol mimicking clinical heart preservation. METHODS AND RESULTS: Rat hearts were infused ex vivo with Hemagglutinating Virus of Japan-liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas' No. 1 cardioplegia for 4 hours at 4 degrees C, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in reperfusion effluent. Hearts underwent Western blotting and immunohistochemistry to confirm HSP70 overexpression. Postischemic recovery of mechanical function (% preischemic+/-SEM) was greater in HSP versus CON: Left ventricular developed pressure recovery was 76.7+/-3.9% versus 60. 5+/-3.1% (P:<0.05); dP/dtmax recovery was 79.4+/-4.9% versus 56. 2+/-3.2% (P:<0.05); dP/dtmin recovery was 74.8+/-4.6% versus 57. 3+/-3.6% (P:<0.05). Creatine kinase release was attenuated in HSP versus CON: 0.22+/-0.02 versus 0.32+/-0.04 IU/min/g wet wt. (P:<0. 05). Recovery of coronary flow was greater in HSP versus CON: 76. 5+/-3.8% versus 59.2+/-3.2% (P:<0.05). Recovery of coronary response to 5-hydroxytryptamine (5 x 10(-)(5) mol/L) was 55.6+/-4.7% versus 23. 9+/-3.2% (P:<0.05); recovery of coronary response to glyceryltrinitrate (15 mg/L) was not different between HSP and CON: 87.4+/-6.9% versus 84.3+/-5.8% (NS). CONCLUSIONS: In a clinically relevant donor heart preservation protocol, HSP70 gene transfection protects both mechanical and endothelial function.

[Evolution of the Fontan operation and results in patients with single ventricles or mixed congenital malformations]. / Evolution et résultats des opérations de Fontan dans les cardiopathies congénitales univentriculaires ou assimilées.

STUDY OBJECTIVES: To examine the results of right heart derivations and clinical outcomes according to preoperative characteristics and operative strategy implemented. METHODS: Fontan operations were performed in 65 patients (mean age = 10.3 years, 41 males). The majority of cardiopathies were single ventricles (SV) with (49% of patients) or without (26%) tricuspid atresia. A palliative bidirectional cavo-pulmonary (BCP) anastomosis was performed prior to Fontan in 15 patients. Intra-atrial Fontan tunnelling was performed in 43 patients, Kreutzer-type operations in 10, and extracardiac tubes were used in 8 patients. The mean duration of follow-up was 6.1 +/- 0.3 years. RESULT: The 30-day mortality was 13.8%. Early mortality was higher among patients with SV with than without tricuspid atresia (P < 0.01), and among patients < 4 years old. Early reoperations were required in 5 patients, including dismounting in 1, BCP anastomosis after Kreutzer procedure in 1, and tube thrombosis in 1 patient. A single death occurred past 30 days, and late adverse events included protein-losing enteropathy in 1 patient, complete atrioventricular block in 1, and tube thrombosis treated with heparin in 2 patients. At the end of follow-up, 75% were in New York Heart Association functional class I. CONCLUSION: Our intermediate-term results of Fontan-type operations were satisfactory, and steadily improving. The prognosis was better in patients operated at age 4 or older. A prior BCP anastomosis improved the results. A higher morbidity was observed with intra- than with extra-atrial Fontan procedures. The merit of fenestration procedures with respect to morbidity remains the be evaluated.

Acute rejection and cardiac graft vasculopathy in the absence of donor-derived ICAM-1 or P-selectin.

BACKGROUND: ICAM-1 and P-selectin are molecules that facilitate adhesion of circulating leukocytes to vessel walls. We have investigated the role of donor-derived ICAM-1 and P-selectin in acute and chronic cardiac allograft rejection. METHODS: C57BL/6J (H-2(b)) mice were used as donors for heterotopic heart transplantation into CBA/Ca (H-2(k)) recipients. The donors were wild-type or homozygous for gene mutations of ICAM-1 or P-selectin. We measured acute rejection in non-immunosuppressed recipients by daily palpation and sacrificed mice at Days 2, 4, and 6 for immunohistochemical analysis. For chronic rejection, recipients received monoclonal antibody against CD4+ T cells. We removed hearts at Days 60 to 62 for histologic assessment of vasculopathy using quantitative morphometry to measure intimal thickening. RESULTS: Time (days) to rejection was 7.1 +/- 0.57 for wild-type (n = 10), 7.0 +/- 0.71 for ICAM-1 -/- (not significantly different, n = 7) and 6.1 +/- 0.33 (p = 0.001) for P-selectin -/- donors. ICAM-1 deficiency was associated with delayed infiltrate at Day 4 compared with wild-type. In the model of chronic rejection, elastin-positive vessels showed a mean occlusion of 34% +/- 3% in transplanted wild-type hearts; vessels were divided into those showing 0% to 20%, 20% to 50%, and 50% to 100% occlusion. We observed no difference in the number of affected vessels or the amount of vascular thickening in donors lacking ICAM-1 or P-selectin compared with wild-type controls. CONCLUSIONS: The absence of ICAM-1 or P-selectin in donor tissues neither lengthens the time of allograft survival nor inhibits the vascular lesions associated with chronic rejection. Indeed, the absence of P-selectin may exacerbate alloimmune injury.

[Replacement of the ascending aorta with conservation of the aortic valve. Results of 50 cases using the Tirone David procedure]. / Remplacement de l'aorte ascendante avec conservation valvulaire aortique.

Aortic valve sparing operations are now widely accepted for ascending aortic aneurysm surgery. We herein report our experience of the Tirone David procedure in larger indications. From January 1997 to August 2003, 50 Tirone David procedure have been performed on 36 male and 14 female (mean age: 60 +/- 15). Five patients presented a Marfan disease and 4 acute dissections. Grade III or IV aortic insufficiency was frequent (40%). Aortic diameter was not particularly dilated, ranging from 44 to 78 mm (mean: 57 +/- 10 mm). Mean ejection fraction: 57 +/- 10%. Mean left ventricular end diastolic diameter =63 +/- 7 mm. An associated mitral valve repair and 1 coronary bypass were necessary. Mean cross clamp and bypass times =94 min and 122 +/- 28 min respectively. There was one in-hospital mortality. Secondary mortality affected 2 patients (non-cardiac deaths), for a cumulative follow-up of 946 months. During follow-up continence control was always excellent, only 1 bicuspid valve had an aortic insufficiency >grade II. Tirone David procedure gave satisfactory results as regards both aortic ectasia and aortic regurgitation control. We consider it feasible even in case of aortic dissection but caution is required when facing bicuspid aortic valves.

Link between immune cell infiltration and mitochondria-induced cardiomyocyte death during acute cardiac graft rejection.

Acute cardiac graft rejection (ACGR) is associated with cardiomyocyte apoptosis. We investigated the respective role of the Fas/FasL and mitochondrial permeability transition pore (mPTP) pathways in cardiomyocyte apoptosis accompanying ACGR. Heterotopic cardiac transplantations were performed in 7-9-week old C57BL6 or C3H mice. Wild type or Fas-deficient (lpr) mice underwent syngeneic (GS) or allogeneic (GA) transplantation, and received either saline or NIM811, a specific inhibitor of the mPTP. At day 5, we assessed ACGR by histology, cardiomyocyte apoptosis by caspase-3 activity and cytochrome c release, Ca(2+)-induced mPTP opening by a potentiometric approach, and expression of Fas, FasL, TNFalpha, perforin, granzyme using RT-PCR. Myocardial infiltration of CD8(+) T lymphocytes was performed by immunohistochemistry. Allogenic transplantation increased infiltration of inflammatory cells, upregulated FasL, perforin, granzyme, and TNFalpha, favored Ca(2+)-induced mPTP opening and increased caspase-3 activity and cytochrome c release in WT grafts. NIM811, but not Fas-deficiency, significantly reduced all these effects. NIM811 also limited infiltration of CD8(+) into WT and lpr transplants. These data suggest that the mPTP pathway plays a major role in cardiomyocyte apoptosis associated with ACGR. Inhibition of mPTP opening may attenuate cardiomyocyte apoptosis either directly or indirectly via a limitation of CD8(+) T-cell activation.

Pharmacological preconditioning: comparison of desflurane, sevoflurane, isoflurane and halothane in rabbit myocardium.

BACKGROUND: Recent investigations showed that isoflurane can induce pharmacological preconditioning. The present study aimed to compare the potency of four different halogenated anaesthetics to induce preconditioning. METHODS: Anaesthetized open-chest rabbits underwent 30 min of coronary artery occlusion followed by 3 h of reperfusion. Before this, rabbits were randomized into one of five groups and underwent a treatment period consisting of either no intervention for 45 min (control; n = 10), or 30 min of 1 MAC halogenated anaesthetic inhalation followed by 15 min of washout. End-tidal concentrations of halogenated agents were 3.7% for sevoflurane (n = 11), 1.4% for halothane (n = 9), 2.0% for isoflurane (n = 11), and 8.9% for desflurane (n = 11). Area at risk and infarct size were assessed by blue dye injection and tetrazolium chloride staining. RESULTS: Mean (SD) infarct size was 54 (18)% of the risk area in untreated controls and 40 (18)% in the sevoflurane group (P > 0.05, ns). In contrast, mean infarct size was significantly smaller in the halothane, isoflurane, and desflurane groups: 26 (18)%, 32 (18)% and 16 (17)%, respectively (P < 0.05 vs control). CONCLUSIONS: Halothane, isoflurane and desflurane induced pharmacological preconditioning, whereas sevoflurane had no significant effect. In this preparation, desflurane was the most effective agent at preconditioning the myocardium against ischaemia.