No abstract

Hypoxia-inducible factors (HIF) are transcription factors that serve essential regulatory roles in cellular and molecular responses to oxygen debt. HIFs are composed of hypoxiadependent a subunits (1a, 2a, 3a) and an oxygen-independent b subunit. Previously we demonstrated that HIF-1, the master regulator of hypoxic responses, is expressed in the adult rat testis. We hypothesized that HIF-1 is involved in regulating responses to oxygen tension in the testis. Goals of this study were to determine if HIF-2a and HIF-3a are expressed in rat testis, identify testis cell types that express HIF-1a, and examine patterns of testicular HIF-1a protein expression under conditions of ischemia and hypoxia in vivo and in vitro. Reverse transcriptase polymerase chain reaction revealed that mRNA for Hif-1a, Hif-2a, and Hif-3a is expressed in the testis. The HIF-1a protein is the predominant subunit in testis. HIF-1a protein was abundant in normoxic testis, and its levels remained unchanged following ischemia created by surgically induced testicular torsion and reperfusion. Immunoblot and immunocytochemical experiments demonstrated that Leydig cells are the major source of HIF-1a in normoxic and hypoxic testes. To examine potential mechanisms of testicular HIF-1 stabilization, nuclear proteins from Leydig cells cultured in 5% or 21% oxygen, or cells cultured with H 2 O 2 , were analyzed by immunoblotting. Levels of HIF1a were significantly diminished in 5% or 21% oxygen cultures compared with freshly isolated cells. Treating Leydig cells with H 2 O 2 as a source of reactive oxygen species did not affect HIF-1a levels. High levels of constitutively expressed HIF-1a in normoxic Leydig cells suggest potentially unique roles for HIF-1 in Leydig cell responsiveness to oxygen.

Mechanical circulatory support with durable continuous-flow ventricular assist devices has become an important therapeutic management strategy for patients with advanced heart failure. As more patients have received these devices and the duration of support per patient has increased, the postimplantation complications have become more apparent, and the need for approaches to manage these complications has become more compelling. Continuous-flow ventricular assist devices, including axial-flow and centrifugal-flow pumps, are the most commonly used mechanical circulatory support devices. Continuous-flow ventricular assist devices and the native heart have a constant physiological interplay dependent on pump speed that affects pressure-flow relationships and patient hemodynamics. A major postimplantation complication is cerebrovascular vascular accidents. The causes of cerebrovascular vascular accidents in ventricular assist device recipients may be related to hypertension, thromboembolic events, bleeding from anticoagulation, or some combination of these. The most readily identifiable and preventable cause is hypertension. Hypertension management in these patients has been hampered by the fact that it is difficult to accurately measure blood pressure because these ventricular assist devices have continuous flow and are often not pulsatile. Mean arterial pressures have to be identified by Doppler or oscillometric cuff and treated. Although guidelines for hypertension management after ventricular assist device implantation are based largely on expert consensus and conventional wisdom, the mainstay of treatment for hypertension includes guideline-directed medical therapy for heart failure with reduced ejection fraction because this may reduce adverse effects associated with hypertension and increase the likelihood of favorable ventricular remodeling. The use of systemic anticoagulation in ventricular assist device recipients may at a given blood pressure increase the risk of stroke.

Despite improved outcomes of modern continuous‐flow left ventricular assist devices (CF‐LVADs), device exchange is still needed for various indications. While the majority of CF‐LVADs are exchanged to the same model, exchange to a different pump model is occasionally warranted. In this meta‐analysis, we sought to consolidate the existing evidence to better elucidate the indications and outcomes in these cases. A comprehensive systematic search of adult patient cohorts who underwent CF‐LVAD exchange to a different CF‐LVAD model was performed. Study‐level data from 10 studies comprising 98 patients were extracted and pooled for analysis. Mean patient age was 58 (95% CI: 48‐65) and 81% were male. Indication for initial CF‐LVAD was ischemic cardiomyopathy in 45% (34‐57). Initial device was HeartMate II LVAD (HMII) in 93 (94.9%) and HeartWare HVAD (HW) in 5 (5.1%) patients. After mean CF‐LVAD support time of 18.8 (15.2‐22.4) months, exchange indications included thrombosis in 71% (43‐89), infection in 21% (8‐47) and device malfunction in 12% (7‐21). HMII to HW exchange occurred in 53 (54.1%) patients, HMII to HeartMate III (HM3) in 32 (32.7%), and HM II to either HW or HM3 in 13 (13.2%) patients. Postoperatively, right ventricular assist device was required in 16% (8‐32). Overall, 20% (8‐40) of patients experienced a stroke, while HW patients had a significantly higher stroke incidence than HM3 patients (HW: 21% (8‐47) vs. HM3: 5% (1‐24), P < .01). Overall 30‐day mortality was 10% (6‐17), while HW had a significantly worse 30‐day mortality than HM3 (HW: 13% (7‐24) vs. HM3: 5% (1‐24), P = .03). Following device exchange from a different CF‐LVAD model, HM3 is associated with lower stroke and higher survival when compared to HW.

Treatment of giant cell myocarditis (GCM) can require bridging to orthotopic heart transplantation (OHT) or recovery with mechanical circulatory support (MCS). Since the roles of MCS and immunotherapy are not well-defined in GCM, we sought to analyze outcomes of patients with GCM who required MCS. A systematic search was performed in June 2019 to identify all studies of biopsy-proven GCM requiring MCS after 2009. We identified 27 studies with 43 patients. Patient-level data were extracted for analysis. Median patient age was 45 (interquartile range (IQR): 32–57) years. 42.1% (16/38) were female. 34.9% (15/43) presented in acute heart failure. 20.9% (9/43) presented in cardiogenic shock. Biventricular (BiVAD) MCS was required in 76.7% (33/43) of cases. Of the 62.8% (27/43) of patients who received immunotherapy, 81.5% (22/27) used steroids combined with at least one other immunosuppressant. Cyclosporine was the most common non-steroidal agent, used in 40.7% (11/27) of regimens. Immunosuppression was initiated before MCS in 59.3% (16/27) of cases, after MCS in 29.6% (8/27), and not specified in 11.1% (3/27). Immunosuppression started prior to MCS was associated with significantly better survival than MCS alone (p = 0.006); 60.5% (26/43) of patients received bridge-to-transplant MCS; 39.5% (17/43) received bridge-to-recovery MCS; 58.5% (24/41) underwent OHT a median of 104 (58–255) days from diagnosis. GCM recurrence after OHT was reported in 8.3% (2/24) of transplanted cases. BiVAD predominates in mechanically supported patients with GCM. Survival and bridge to recovery appear better in patients on immunosuppression, especially if initiated before MCS.