Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.

Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.

Plasma Kallikrein as a Forgotten Clotting Factor.

For decades, it was considered that plasma kallikrein's (PKa) sole function within the coagulation cascade is the activation of factor (F)XII. Until recently, the two key known activators of FIX within the coagulation cascade were activated FXI(a) and the tissue factor-FVII(a) complex. Simultaneously, and using independent experimental approaches, three groups identified a new branch of the coagulation cascade, whereby PKa can directly activate FIX. These key studies identified that (1) FIX or FIXa can bind with high affinity to either prekallikrein (PK) or PKa; (2) in human plasma, PKa can dose dependently trigger thrombin generation and clot formation independent of FXI; (3) in FXI knockout murine models treated with intrinsic pathway agonists, PKa activity results in increased formation of FIXa:AT complexes, indicating direct activation of FIX by PKa in vivo. These findings suggest that there is both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation. These three recent studies are described within this review, alongside historical data that hinted at the existence of this novel role of PKa as a coagulation clotting factor. The implications of direct PKa cleavage of FIX remain to be determined physiologically, pathophysiologically, and in the context of next-generation anticoagulants in development.

The Role of Fibrin(ogen) in Wound Healing and Infection Control.

Fibrinogen, one of the most abundant plasma proteins playing a key role in hemostasis, is an important modulator of wound healing and host defense against microbes. In the current review, we address the role of fibrin(ogen) throughout the process of wound healing and subsequent tissue repair. Initially fibrin(ogen) acts as a provisional matrix supporting incoming leukocytes and acting as reservoir for growth factors. It later goes on to support re-epithelialization, angiogenesis, and fibroplasia. Importantly, removal of fibrin(ogen) from the wound is essential for wound healing to progress. We also discuss how fibrin(ogen) functions through several mechanisms to protect the host against bacterial infection by providing a physical barrier, entrapment of bacteria in fibrin(ogen) networks, and by directing immune cell function. The central role of fibrin(ogen) in defense against bacterial infection has made it a target of bacterial proteins, evolved to interact with fibrin(ogen) to manipulate clot formation and degradation for the purpose of promoting microbial virulence and survival. Further understanding of the dual roles of fibrin(ogen) in wound healing and infection could provide novel means of therapy to improve recovery from surgical or chronic wounds and help to prevent infection from highly virulent bacterial strains, including those resistant to antibiotics.

Affimer proteins as a tool to modulate fibrinolysis, stabilize the blood clot, and reduce bleeding complications.

Bleeding complications secondary to surgery, trauma, or coagulation disorders are important causes of morbidity and mortality. Although fibrin sealants are considered to minimize blood loss, this is not widely adopted because of its high cost and/or risk for infection. We present a novel methodology employing nonantibody fibrinogen-binding proteins, termed Affimers, to stabilize fibrin networks with the potential to control excessive bleeding. Two fibrinogen-specific Affimer proteins, F5 and G2, were identified and characterized for their effects on clot structure/fibrinolysis, using turbidimetric and permeation analyses and confocal and electron microscopy. Binding studies and molecular modeling identified interaction sites, whereas plasmin generation assays determined effects on plasminogen activation. In human plasma, F5 and G2 prolonged clot lysis time from 9.8 ± 1.1 minutes in the absence of Affimers to 172.6 ± 7.4 and more than 180 minutes (P < .0001), respectively, and from 7.6 ± 0.2 to 28.7 ± 5.8 (P < .05) and 149.3 ± 9.7 (P < .0001) minutes in clots made from purified fibrinogen. Prolongation in fibrinolysis was consistent across plasma samples from healthy control patients and individuals at high bleeding risk. F5 and G2 had a differential effect on clot structure and G2 profoundly altered fibrin fiber arrangement, whereas F5 maintained physiological clot structure. Affimer F5 reduced fibrin-dependent plasmin generation and was predicted to bind fibrinogen D fragment close to tissue plasminogen activator (tPA; residues γ312-324) and plasminogen (α148-160) binding sites, thus interfering with tPA-plasminogen interaction and representing 1 potential mechanism for modulation of fibrinolysis. Our Affimer proteins provide a novel methodology for stabilizing fibrin networks with potential future clinical implications to reduce bleeding risk.

Chronic thromboembolic pulmonary hypertension in Australia and New Zealand: An analysis of the PHSANZ registry.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious condition occurring in 2%-4% of patients after acute pulmonary embolism. Pulmonary endarterectomy (PEA) is a potential cure for technically operable disease. The epidemiology and long-term outcomes of CTEPH have not been previously described in Australia and New Zealand. METHODS: Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry for patients diagnosed with CTEPH between January 2004 and March 2020. Baseline characteristics, treatment strategies, outcome data and long-term survival are reported. RESULTS: A total of 386 patients were included with 146 (37.8%) undergoing PEA and 240 (62.2%) in the non-PEA group. PEA patients were younger (55 ± 16 vs. 62 ± 16 years, p < 0.001) with higher baseline 6-min walk distance (6MWD; 405 ± 122 vs. 323 ± 146 m, p = 0.021), whilst both groups had similar baseline pulmonary haemodynamics. Pulmonary hypertension-specific therapy was used in 54% of patients post-PEA and 88% in the non-PEA group. The 1-, 3- and 5-year survival rates were 93%, 87% and 84% for the PEA group compared to 86%, 73% and 62%, respectively, for the non-PEA group (p < 0.001). Multivariate survival analysis showed baseline 6MWD was an independent predictor of survival in both operated and medically managed patients. CONCLUSION: In this first multicentre report of CTEPH in Australia and New Zealand, long-term survival is comparable to that in other contemporary CTEPH registries. However, PEA was only performed in a minority of CTEPH patients (37.8%) and significantly less than overseas reports. Greater awareness of PEA and improved patient access to experienced CTEPH centres are important priorities.

Management of Maternal Complex Congenital Heart Disease During Pregnancy.

PURPOSE OF THE REVIEW: The purpose of this review is to discuss the risk stratification and management of pregnancy in women with complex congenital heart disease. RECENT FINDINGS: Classifying congenital heart defects (CHD) including both anatomy and physiology is important for maternal risk stratification. Although most women with CHD can tolerate the physiological challenge of pregnancy, some may experience serious risks both to their health and that of their foetus. The WHO maternal risk classification model remains the best-validated risk measure. Ideally, women with CHD should have pre-conception assessment with a CHD cardiologist. General principles of management, such as need for expert centre delivery, a multidisciplinary team, epidural and mode of delivery are based on WHO risk in combination with expert assessment of status. CHD is increasingly prevalent in women of child-bearing age. Assessment by an adult CHD cardiologist, ideally pre-conception, is key in assessing and minimising risk to mother and foetus.

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics.

Thrombus formation remains a major cause of morbidity and mortality worldwide. Current antiplatelet and anticoagulant therapies have been effective at reducing vascular events, but at the expense of increased bleeding risk. Targeting proteins that interact with fibrinogen and which are involved in hypofibrinolysis represents a more specific approach for the development of effective and safe therapeutic agents. The antifibrinolytic proteins alpha-2 antiplasmin (α2AP), thrombin activatable fibrinolysis inhibitor (TAFI), complement C3 and plasminogen activator inhibitor-2 (PAI-2), can be incorporated into the fibrin clot by FXIIIa and affect fibrinolysis by different mechanisms. Therefore, these antifibrinolytic proteins are attractive targets for the development of novel therapeutics, both for the modulation of thrombosis risk, but also for potentially improving clot instability in bleeding disorders. This review summarises the main properties of fibrinogen-bound antifibrinolytic proteins, their effect on clot lysis and association with thrombotic or bleeding conditions. The role of these proteins in therapeutic strategies targeting the fibrinolytic system for thrombotic diseases or bleeding disorders is also discussed.

Impella-assisted chronic total occlusion percutaneous coronary interventions: A multicenter retrospective analysis.

INTRODUCTION: Patients with coronary chronic total occlusions (CTO) often have concurrent higher-risk anatomy and physiology (significant calcium, left ventricular dysfunction, multivessel disease) that increase their procedural risk. We present a retrospective multicenter case series describing use of the Impella percutaneous ventricular assist device (p-VAD) during CTO PCI. METHODS: We performed a retrospective analysis of self-reported data from five large referral centers from 2013 to 2017 and identified patients that underwent elective, hemodynamically supported CTO PCI with the Impella p-VAD device (2.5 or CP). Preprocedural demographics, procedural invasive hemodynamics and characteristics, and in-hospital outcomes were reported. RESULTS: About 57 patients (2% of the overall CTO volume of these centers) were included in this retrospective cohort. The primary indication in the majority (78.9%) of cases was chronic angina; in 21.1% the primary indication was for chronic congestive heart failure because of an ischemic cardiomyopathy. The median LVEF was 20% (15%, 30%) and 63.2% were surgical turndowns. Significant proportions of the group underwent multivessel PCI (91.2%), intervention on an unprotected left main or last remaining conduit vessel (35.1%), and/or atherectomy (17.5%). Technical success was 87.7%. In-hospital procedural complications included: vascular injury (5.3%), all-cause death (5.3%), major bleeding (3.5%), stroke (1.8%), and coronary perforation resulting in tamponade (1.8%). CONCLUSION: Impella-assisted CTO PCI can be performed with high technical success rates. However, assiduous attention to appropriate case selection is critical, given the periprocedural complication rates reported in this patient population.

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk.

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition.

Longitudinal analysis left ventricular chamber responses under durable LVAD support.

BACKGROUND: Left ventricular assist device (LVAD) support offers remodeling potential in some patients. Our goal was to use noninvasively derived pressure-volume (PV) loops to understand the effect of demographic and device variables on serial changes in cardiac function under pump support. METHODS: Thirty-two consecutive Medtronic HeartWare Ventricular Assist Device (HVAD) patients (mean 55.9 ± 12.3 years, 81.3% male) were prospectively recruited. Single-cycle ventricular pressure and volume were estimated using a validated algorithm. PV loops (n = 77) and corresponding cardiac chamber dynamics were derived at predefined postimplant timepoints (1, 3, 6 months). Changes in PV loop parameters sustained across the 6-month period were characterized using mixed-effects modeling. The influence of demographic and device variables on the observed changes was assessed. RESULTS: Across a 6-month period, the mean ventricular function parameters remained stable. Significant predictors of monthly improvement of stroke work include: lower pump speeds (2400 rpm vs 2500-2800 rpm) [0.0.051 mm Hg/liter/month (p = 0.001)], high pulsatility index (>1.0 vs <1.0) [0.052 mm Hg/liter/month (p = 0.012)], and ischemic cardiomyopathy indication for LVAD implantation (vs nonischemic) [0.0387 mm Hg/liter/month (p = 0.007)]. Various other cardiac chamber function parameters including cardiac power, peak systolic pressure, and LV elastance also showed improvements in these cohorts. CONCLUSIONS: Factors associated with improvement in ventricular energetics and hemodynamics under LVAD support can be determined with noninvasive PV loops. Understanding the basis of increasing ventricular load to optimize myocardial remodeling may prove valuable in selecting eligible recovery candidates.

Is There an Association Between Lateralization of Chronic Pain in the Body and Depression?

Depression commonly co-occurs with chronic pain and can worsen pain outcomes. Recent theoretical work has hypothesized that pain localized to the left hemibody is a risk factor for worse depression due to overlap in underlying neural substrates. This hypothesis has not been tested a priori. Using a large sample of treatment-seeking adults with mixed-etiology chronic pain (N = 1,185), our cross-sectional study tested whether patients with left-sided pain endorse worse depressive symptoms. We also examined differences in other pain-related functioning measures. We tested 4 comparisons based on painful body areas using the CHOIR body map: 1) only left-sided (OL) versus any right-sided pain; 2) only right-sided (OR) versus any left-sided pain; 3) OL versus OR versus bilateral pain; and 4) more left-sided versus more right-sided versus equal-sided pain. Analysis of variance models showed OL pain was not associated with worse depression (F = 5.50, P = .019). Any left-sided pain was associated with worse depression, though the effect was small (F = 8.58, P = .003, Cohens d = .29). Bilateral pain was associated with worse depression (F = 8.05, P < .001, Cohens d = .24-.33). Regardless of pain location, more body areas endorsed was associated with greater depression. Although a more rigorous assessment of pain laterality is needed, our findings do not support the hypothesis that left-lateralized pain is associated with worse depression. PERSPECTIVE: Pain lateralized to the left side of the body has been hypothesized as a risk factor for worse depression in chronic pain, despite never being tested in a large, real-world sample of patients with chronic pain. Findings showed that more widespread pain, not pain laterality, was associated with worse depression.

Patient Reported Outcome Measures in Adults with Fontan Circulatory Failure.

Background: Patient reported outcomes (PROs) are important measures in acquired heart disease but have not been well defined in Adult Congenital Heart Disease (ACHD). Our aim was to explore the discriminatory capacity of PRO survey tools in Fontan circulatory failure (FCF). Methods: Consecutive adults were enrolled from our ambulatory clinics. Inclusion criteria were age ≥18 years, a Fontan circulation or a hemodynamically insignificant shunt lesion, and sufficient cognitive/language abilities to complete PROs. A comprehensive package of PRO measures, designed to assess perceived health-related quality of life (HRQOL) was administered (including the Kansas City Cardiomyopathy Questionnaire [KCCQ-12], EuroQol-5-dimension [EQ5D], Short Form Health Status Survey [SF-12], self-reported New York Heart Association [NYHA] Functional Class, and Specific Activity Scale [SAS]). Results: We compared 54 Fontan patients (35 ± 10 years) to 25 simple shunt lesion patients (34 ± 11 years). The KCCQ-12 score was lower in Fontan versus shunt lesion patients (87 [IQR 79, 95] versus 100 [IQR 97, 100], p-value < 0.001). The FCF subgroup was associated with lower KCCQ-12 scores as compared with the non-FCF subgroup (82 [IQR 56, 89] versus 93 [IQR 81, 98], p-value = 0.002). Although the KCCQ-12 had the best discriminatory capacity for determination of FCF of all PRO tools studied (c-statistic 0.75 [CI 0.62, 0.88]), superior FCF discrimination was achieved when the KCCQ-12 was combined with all PRO tools (c-statistic 0.82 [CI 0.71, 0.93]). Conclusions: The KCCQ-12 questionnaire demonstrated good discriminatory capacity for the identification of FCF, which was further improved through the addition of complementary PRO tools. Further research will establish the value of PRO tools to guide management strategies in ACHD.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy.

BACKGROUND: Current guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with cardiopulmonary comorbidities, despite limited available evidence to guide management. RESEARCH QUESTION: Do left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of patients with PAH? STUDY DESIGN AND METHODS: The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial criteria was used to define the phenotype of patients with PAH with risk factors for LHD. Treatment strategy, functional outcome, long-term survival, and risk discrimination were compared with a reference PAH cohort using the Pulmonary Hypertension Society of Australia and New Zealand Registry. RESULTS: A total of 487 incident patients with PAH diagnosed between 2011 and 2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors, with 384 (78.9%) remaining as the reference group. Patients in the PAH with LHD risk factors group were older (66 ± 13 vs 58 ± 19 years; P < .001), had lower pulmonary vascular resistance (393 ± 266 vs 708 ± 391 dyn.s/cm5; P = .031), and had worse 6-min walk distance (286 ± 130 vs 327 ± 136 m; P = .005) at diagnosis. The PAH with LHD risk factors group was less likely to receive initial combination therapy (27% vs 44%; P = .02). Changes in 6-min walk distance at 12 months were similar in both groups (43 ± 77 m in the PAH with LHD risk factors group and 50 ± 90 m in the reference group; P = .50), including when stratified by initial treatment strategy (PAH with LHD risk factors group vs reference PAH group: monotherapy: 40 ± 81 vs 38 ± 95 m, P = .87; combination therapy: 53 ± 78 vs 64 ± 106 m, P = .511). Functional class improvements were also similar in both groups. REVEAL Registry 2.0 risk score effectively discriminated risk in both populations (C statistic = 0.756 for the PAH with LHD risk factors group and C statistic = 0.750 for the reference PAH group). There was no difference in survival between the two groups (log-rank test, P = .29). INTERPRETATION: In a real-world cohort, patients with PAH with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected patients with PAH with LHD risk factors who were treated with initial combination therapy derived similar functional response compared with the reference group. Further studies are needed to phenotype patients with PAH with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Case Volumes and Outcomes Among Early-Career Interventional Cardiologists in the United States.

BACKGROUND: Little is known about the procedural characteristics, case volumes, and mortality rates for early- vs non-early-career interventional cardiologists in the United States. OBJECTIVES: This study examined operator-level data for patients who underwent percutaneous coronary intervention (PCI) between April 2018 and June 2022. METHODS: Data were collected from the National Cardiovascular Data Registry CathPCI Registry, American Board of Internal Medicine certification database, and National Plan and Provider Enumeration System database. Early-career operators were within 5 years of the end of training. Annual case volume, expected mortality and bleeding risk, and observed/predicted mortality and bleeding outcomes were evaluated. RESULTS: A total of 1,451 operators were early career; 1,011 changed their career status during the study; and 6,251 were non-early career. Overall, 514,540 patients were treated by early-career and 2,296,576 patients by non-early-career operators. The median annual case volume per operator was 59 (Q1-Q3: 31-97) for early-career and 57 (Q1-Q3: 28-100) for non-early-career operators. Early-career operators were more likely to treat patients presenting with ST-segment elevation myocardial infarction and urgent indications for PCI (both P < 0.001). The median predicted mortality risk was 2.0% (Q1-Q3: 1.5%-2.7%) for early-career and 1.8% (Q1-Q3: 1.2%-2.4%) for non-early-career operators. The median predicted bleeding risk was 4.9% (Q1-Q3: 4.2%-5.7%) for early-career and 4.4% (Q1-Q3: 3.7%-5.3%) for non-early-career operators. After adjustment, an increased risk of mortality (OR: 1.08; 95% CI: 1.05-1.17; P < 0.0001) and bleeding (OR: 1.08; 95% CI: 1.05-1.12; P < 0.0001) were associated with early-career status. CONCLUSIONS: Early-career operators are caring for patients with more acute presentations and higher predicted risk of mortality and bleeding compared with more experienced colleagues, with modestly worse outcomes. These data should inform institutional practices to support the development of early-career proceduralists.

Prognostic role of pulmonary impedance estimation to predict right ventricular dysfunction in pulmonary hypertension.

BACKGROUND: The effect of pulmonary hypertension (PH) on right ventricular (RV) afterload is commonly defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). In humans however, one-third to half of the hydraulic power in the PA is contained in pulsatile components of flow. Pulmonary impedance (Zc) expresses opposition of the PA to pulsatile blood flow. We evaluate pulmonary Zc relationships according to PH classification using a cardiac magnetic resonance (CMR)/right heart catheterization (RHC) method. METHODS: Prospective study of 70 clinically indicated patients referred for same-day CMR and RHC [60 ± 16 years; 77% females, 16 mPAP <25 mmHg (PVR <240 dynes.s.cm-5 /mPCWP <15 mmHg), 24 pre-capillary (PrecPH), 15 isolated post-capillary (IpcPH), 15 combined pre-capillary/post-capillary (CpcPH)]. CMR provided assessment of PA flow, and RHC, central PA pressure. Pulmonary Zc was expressed as the relationship of PA pressure to flow in the frequency domain (dynes.s.cm-5 ). RESULTS: Baseline demographic characteristics were well matched. There was a significant difference in mPAP (P < 0.001), PVR (P = 0.001), and pulmonary Zc between mPAP<25 mmHg patients and those with PH (mPAP <25 mmHg: 47 ± 19 dynes.s.cm-5 ; PrecPH 86 ± 20 dynes.s.cm-5 ; IpcPH 66 ± 30 dynes.s.cm-5 ; CpcPH 86 ± 39 dynes.s.cm-5 ; P = 0.05). For all patients with PH, elevated mPAP was found to be associated with raised PVR (P < 0.001) but not with pulmonary Zc (P = 0.87), except for those with PrecPH (P < 0.001). Elevated pulmonary Zc was associated with reduced RVSWI, RVEF, and CO (all P < 0.05), whereas PVR and mPAP were not. CONCLUSIONS: Raised pulmonary Zc was independent of elevated mPAP in patients with PH and more strongly predictive of maladaptive RV remodelling than PVR and mPAP. Use of this straightforward method to determine pulmonary Zc may help to better characterize pulsatile components of RV afterload in patients with PH than mPAP or PVR alone.

Major adverse kidney events predict reduced survival in ventricular assist device supported patients.

AIMS: There is limited data describing major adverse kidney events (MAKE) in patients supported with ventricular assist devices (VAD). We aim to describe the association between MAKE and survival, risk factors for MAKE, and renal trajectory in VAD supported patients. METHODS AND RESULTS: We conducted a single-centre retrospective analysis of consecutive VAD implants between 2010 and 2019. Baseline demographics, biochemistry, and adverse events were collected for the duration of VAD support. MAKE was defined as the first event to occur of sustained drop (>50%) in estimated glomerular filtration rate (eGFR), progression to stage V chronic kidney disease, initiation or continuation of renal replacement therapy beyond implant admission or death on renal replacement therapy at any time. One-hundred and seventy-three patients were included, median age 56.8 years, 18.5% female, INTERMACS profile 1 or 2 in 75.1%. Thirty-seven patients experienced MAKE. On multivariate analysis, post-implant clinical right ventricular failure and the presence of chronic haemolysis, defined by the presence of schistocytes on blood film analysis, were significantly associated with increased risk of MAKE (adjusted odds ratio 9.88, P < 0.001 and adjusted odds ratio 3.33, P = 0.006, respectively). MAKE was associated with reduced survival (hazard ratio 4.80, P < 0.001). Patients who died or experienced MAKE did not demonstrate the expected transient 3-month improvement in eGFR, seen in other cohorts. CONCLUSIONS: MAKE significantly impacts survival. In our cohort, MAKE was predicted by post-implant right ventricular failure and chronic haemolysis. The lack of early eGFR improvement on VAD support may indicate higher risk for MAKE.

Characteristic changes to pulsatile and steady-state load according to pulmonary hypertension classification.

It is of increasing importance to understand and predict changes to the systemic and pulmonary circulations in pulmonary hypertension (PH). To do so, it is necessary to describe the circulation in complete quantitative terms. Characteristic impedance (Zc) expresses opposition of the circulation to pulsatile blood flow. Evaluation of systemic and pulmonary Zc relationships according to PH classification has not previously been described. Prospective study of 40 clinically indicated patients referred for CMR and RHC (56 ± 18 years; 70% females, eight mPAP ≤ 25 mmHg, 16 pre-capillary [Pre-cPH], eight combined pre- and post-capillary [Cpc-PH] and eight isolated left-heart disease [Ipc-PH]). CMR provided assessment of ascending aortic (Ao) and pulmonary arterial (PA) flow, and RHC, central Ao and PA pressure. Systemic and pulmonary Zc were expressed as the relationship of pressure to flow in the frequency domain. Baseline demographic characteristics were well-matched across PH subclasses. In those with a mPAP ≤25mHg, systemic Zc and SVR were >2 times higher than pulmonary Zc and PVR. Only Pre-cPH was associated with inverse pulsatile (systemic Zc 58 [45-69] vs pulmonary Zc 70 [58-85]), but not steady-state (SVR 1101 [986-1752] vs. PVR 483 [409-557]) relationships. Patients with CpcPH and IpcPH had concordant pulsatile and steady-state relationships (Graphical Abstract). Measurement of, and the relationship between, systemic and pulmonary Zc in patients according to PH sub-classification has not previously been described. Systemic Zc was routinely higher than pulmonary Zc, except in patients with newly diagnosed Pre-cPH, where inverse pulsatile but not steady-state relationships were observed.

Tetralogy of Fallot Across the Lifespan: A Focus on the Right Ventricle.

Tetralogy of Fallot is a cyanotic congenital heart disease, for which various surgical techniques allow patients to survive to adulthood. Currently, the natural history of corrected tetralogy of Fallot is underlined by progressive right ventricular (RV) failure due to pulmonic regurgitation and other residual lesions. The underlying cellular mechanisms that lead to RV failure from chronic volume overload are characterized by microvascular and mitochondrial dysfunction through various regulatory molecules. On a clinical level, these cardiac alterations are commonly manifested as exercise intolerance. The degree of exercise intolerance can be objectified and aid in prognostication through cardiopulmonary exercise testing. The timing for reintervention on residual lesions contributing to RV volume overload remains controversial; however, interval assessment of cardiac function and volumes by echocardiography and magnetic resonance imaging may be helpful. In patients who develop clinically important RV failure, clinicians should aim to maintain a euvolemic state through the use of diuretics while paying particular attention to preload and kidney function. In patients who develop signs of cardiogenic shock from right heart failure, stabilization through the use of inotropes and pressor is indicated. In special circumstances, the use of mechanical support may be appropriate. However, cardiologists should pay particular attention to residual lesions that may impact the efficacy of the selected device.

De nombreuses techniques chirurgicales permettent aux patients présentant une tétralogie de Fallot (TF), une forme de cardiopathie congénitale, de survivre jusqu'à l'âge adulte. À l'heure actuelle, l'évolution naturelle de la TF corrigée est caractérisée par une insuffisance ventriculaire droite (VD) progressive attribuable à une régurgitation pulmonaire et à d'autres lésions résiduelles. Les mécanismes cellulaires sous-jacents qui mènent à l'insuffisance VD due à une surcharge volumique chronique sont caractérisés par une dysfonction microvasculaire et mitochondriale faisant intervenir diverses molécules régulatrices. Sur le plan clinique, ces atteintes cardiaques se manifestent par une intolérance à l'effort qui peut être évaluée au moyen d'une épreuve d'effort cardiorespiratoire, ce qui permet de faciliter l'établissement d'un pronostic. Le moment propice pour une réintervention en cas de lésions résiduelles contribuant à la surcharge volumique du ventricule droit demeure controversé; toutefois, il peut être utile d'évaluer régulièrement la fonction et les volumes cardiaques au moyen d'une échocardiographie et de tests d'imagerie par résonance magnétique. En présence d'une insuffisance VD cliniquement importante, les cliniciens doivent tenter de maintenir les patients dans un état euvolémique en utilisant des diurétiques, tout en accordant une attention particulière à la précharge et à la fonction rénale. Si les patients manifestent des signes de choc cardiogénique associé à une insuffisance cardiaque droite, il convient de leur administrer des inotropes et des vasopresseurs pour stabiliser leur état. Dans certains cas, l'utilisation d'un dispositif d'assistance mécanique peut être appropriée. Cependant, les cardiologues doivent être attentifs aux lésions résiduelles, car elles peuvent influencer l'efficacité de ce dispositif.