Impact of right ventricular and pulmonary vascular characteristics on Impella hemodynamic support in biventricular heart failure: A simulation study.

BACKGROUND: Impella (Abiomed, Danvers, MA, USA) is a percutaneous ventricular assist device commonly used in cardiogenic shock, providing robust hemodynamic support, improving the systemic circulation, and relieving pulmonary congestion. Maintaining adequate left ventricular (LV) filling is essential for optimal hemodynamic support by Impella. This study aimed to investigate the impact of pulmonary vascular resistance (PVR) and right ventricular (RV) function on Impella-supported hemodynamics in severe biventricular failure using cardiovascular simulation. METHODS: We used Simulink® (Mathworks, Inc., Natick, MA, USA) for the simulation, incorporating pump performance of Impella CP determined using a mock circulatory loop. Both systemic and pulmonary circulation were modeled using a 5-element resistance-capacitance network. The four cardiac chambers were represented by time-varying elastance with unidirectional valves. In the scenario of severe LV dysfunction (LV end-systolic elastance set at a low level of 0.4 mmHg/mL), we compared the changes in right (RAP) and left atrial pressures (LAP), total systemic flow, and pressure-volume loop relationship at varying degrees of RV function, PVR, and Impella flow rate. RESULTS: The simulation results showed that under low PVR conditions, an increase in Impella flow rate slightly reduced RAP and LAP and increased total systemic flow, regardless of RV function. Under moderate RV dysfunction and high PVR conditions, an increase in Impella flow rate elevated RAP and excessively reduced LAP to induce LV suction, which limited the increase in total systemic flow. CONCLUSIONS: PVR is the primary determinant of stable and effective Impella hemodynamic support in patients with severe biventricular failure.

Novel closed-loop control system of dual rotary blood pumps in total artificial heart based on the circulatory equilibrium framework: a proof-of-concept in vivo study.

OBJECTIVE: Total artificial heart (TAH) using dual rotary blood pumps (RBPs) is a potential treatment for end-stage heart failure. A well-noted challenge with RBPs is their low sensitivity to preload, which can lead to venous congestion and ventricular suction. To address this issue, we have developed an innovative closed-loop control system of dual RBPs in TAH. This system emulates the Frank-Starling law of the heart in controlling RBPs while monitoring stressed blood volume (V) based on the circulatory equilibrium framework. We validated the system in in-vivo experiments. METHODS: In 9 anesthetized dogs, we prepared a TAH circuit using 2 centrifugal-type RBPs. We first investigated whether the flow and inlet atrial pressure in each RBP adhered to a logarithmic Frank-Starling curve. We then examined whether the RBP flows and atrial pressures were maintained stably during aortic occlusion (AO) and pulmonary cannula stenosis (PS), whether averaged flow of dual RBPs and bilateral atrial pressures were controlled to their predefined target values for a specific V, and whether this system could maintain the atrial pressures within predefined control ranges under significant changes in V. RESULTS: This system effectively emulated the logarithmic Frank-Starling curve. It robustly stabilized the flow and atrial pressures during AO and PS without venous congestion or ventricular suction, accurately achieved target values in averaged flow and atrial pressures, and efficaciously maintained these pressures within the control ranges. CONCLUSION: This system controls dual RBPs in TAH accurately and stably. SIGNIFICANCE: This system may accelerate clinical application of TAH with dual RBPs.

Automated control of Impella maintains optimal left ventricular unloading during periods of unstable hemodynamics and prevents myocardial damage in acute myocardial infarction.

BACKGROUND: Left ventricular (LV) unloading by Impella, an intravascular microaxial pump, has been shown to exert dramatic cardioprotective effects in acute clinical settings of cardiovascular diseases. Total Impella support (no native LV ejection) is far more efficient in reducing LV energetic demand than partial Impella support, but the manual control of pump speed to maintain stable LV unloading is difficult and impractical. We aimed to develop an Automatic IMpella Optimal Unloading System (AIMOUS), which controls Impella pump speed to maintain LV unloading degree using closed-feedback control. We validated the AIMOUS performance in an animal model. METHODS: In dogs, we identified the transfer function from pump speed to LV systolic pressure (LVSP) under total support conditions (n = 5). Using the transfer function, we designed the feedback controller of AIMOUS to keep LVSP at 40 mmHg and examined its performance by volume perturbations (n = 9). Lastly, AIMOUS was applied in the acute phase of ischemia-reperfusion in dogs. Four weeks after ischemia-reperfusion, we assessed LV function and infarct size (n = 10). RESULTS: AIMOUS maintained constant LVSP, thereby ensuring a stable LV unloading condition regardless of volume withdrawal or infusion (±8 ml/kg from baseline). AIMOUS in the acute phase of ischemia-reperfusion markedly improved LV function and reduced infarct size (No Impella support: 13.9 ± 1.3 vs. AIMOUS: 5.7 ± 1.9%, P < 0.05). CONCLUSIONS: AIMOUS is capable of maintaining optimal LV unloading during periods of unstable hemodynamics. Automated control of Impella pump speed in the acute phase of ischemia-reperfusion significantly reduced infarct size and prevented subsequent worsening of LV function.

Left-Ventricular Unloading With Impella During Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation (ECPR) is the implementation of venoarterial extracorporeal membrane oxygenation (VA-ECMO) during refractory cardiac arrest. The role of left-ventricular (LV) unloading with Impella in addition to VA-ECMO ("ECMELLA") remains unclear during ECPR. This is the first systematic review and meta-analysis to characterize patients with ECPR receiving LV unloading and to compare in-hospital mortality between ECMELLA and VA-ECMO during ECPR. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, and abstract websites of the three largest cardiology societies (American Heart Association, American College of Cardiology, and European Society of Cardiology). STUDY SELECTION: Observational studies with adult patients with refractory cardiac arrest receiving ECPR with ECMELLA or VA-ECMO until July 2023 according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. DATA EXTRACTION: Patient and treatment characteristics and in-hospital mortality from 13 study records at 32 hospitals with a total of 1014 ECPR patients. Odds ratios (ORs) and 95% CI were computed with the Mantel-Haenszel test using a random-effects model. DATA SYNTHESIS: Seven hundred sixty-two patients (75.1%) received VA-ECMO and 252 (24.9%) ECMELLA. Compared with VA-ECMO, the ECMELLA group was comprised of more patients with initial shockable electrocardiogram rhythms (58.6% vs. 49.3%), acute myocardial infarctions (79.7% vs. 51.5%), and percutaneous coronary interventions (79.0% vs. 47.5%). VA-ECMO alone was more frequently used in pulmonary embolism (9.5% vs. 0.7%). Age, rate of out-of-hospital cardiac arrest, and low-flow times were similar between both groups. ECMELLA support was associated with reduced odds of mortality (OR, 0.53 [95% CI, 0.30-0.91]) and higher odds of good neurologic outcome (OR, 2.22 [95% CI, 1.17-4.22]) compared with VA-ECMO support alone. ECMELLA therapy was associated with numerically increased but not significantly higher complication rates. Primary results remained robust in multiple sensitivity analyses. CONCLUSIONS: ECMELLA support was predominantly used in patients with acute myocardial infarction and VA-ECMO for pulmonary embolism. ECMELLA support during ECPR might be associated with improved survival and neurologic outcome despite higher complication rates. However, indications and frequency of ECMELLA support varied strongly between institutions. Further scientific evidence is urgently required to elaborate standardized guidelines for the use of LV unloading during ECPR.

Efficacy and safety of post-closure technique using Perclose ProGlide/ProStyle device for large-bore mechanical circulatory support access sites.

PURPOSE: Mechanical circulatory support (MCS) using a venoarterial extracorporeal membrane oxygenation (VA-ECMO) device or a catheter-type heart pump (Impella) is critical for the rescue of patients with severe cardiogenic shock. However, these MCS devices require large-bore cannula access (14-Fr and larger) at the femoral artery or vein, which often requires surgical decannulation. METHODS: In this retrospective study, we evaluated post-closure method using a percutaneous suture-mediated vascular closure system, Perclose ProGlide/ProStyle (Abbott Vascular, Lake Bluff, IL, Perclose), as an alternative procedure for MCS decannulation. Closure of 83 Impella access sites and 68 VA-ECMO access sites performed using Perclose or surgical method between January 2018 and March 2023 were evaluated. RESULTS: MCS decannulation using Perclose was successfully completed in all access sites without surgical hemostasis. The procedure time of ProGlide was shorter than surgical decannulation for both Impella and VA-ECMO (13 min vs. 50 min; p < 0.001, 21 min vs. 65 min; p < 0.001, respectively). There were no significant differences in the 30-day survival rate and major adverse events by decannulation including arterial dissection requiring endovascular treatment, hemorrhage requiring a large amount of red blood cell transfusion, and access site infection. CONCLUSION: Our results suggest that the post-closure technique using the percutaneous suture-mediated closure system appears to be a safe and effective method for large-bore MCS decannulation.

Mechanical circulatory support in cardiogenic shock.

Cardiogenic shock is a complex and diverse pathological condition characterized by reduced myocardial contractility. The goal of treatment of cardiogenic shock is to improve abnormal hemodynamics and maintain adequate tissue perfusion in organs. If hypotension and insufficient tissue perfusion persist despite initial therapy, temporary mechanical circulatory support (t-MCS) should be initiated. This decade sees the beginning of a new era of cardiogenic shock management using t-MCS through the accumulated experience with use of intra-aortic balloon pump (IABP) and venoarterial extracorporeal membrane oxygenation (VA-ECMO), as well as new revolutionary devices or systems such as transvalvular axial flow pump (Impella) and a combination of VA-ECMO and Impella (ECPELLA) based on the knowledge of circulatory physiology. In this transitional period, we outline the approach to the management of cardiogenic shock by t-MCS. The management strategy involves carefully selecting one or a combination of the t-MCS devices, taking into account the characteristics of each device and the specific pathological condition. This selection is guided by monitoring of hemodynamics, classification of shock stage, risk stratification, and coordinated management by the multidisciplinary shock team.

Fibromuscular dysplasia of the brachial artery in patients with spontaneous coronary artery dissection: a case series and literature review.

Spontaneous coronary artery dissection (SCAD) is diagnosed in a very small percentage of patients with suspected acute coronary syndromes who undergo emergency coronary angiography. Although fibromuscular dysplasia (FMD) is known to coexist in patients with SCAD, the vascular sites of FMD and their frequency have not yet been clarified. We retrospectively reviewed the medical records of 16 patients who were diagnosed with and treated for SCAD at our hospital between 1 January 2011 and 31 January 2023. We have summarized their baseline and clinical characteristics and medical variables, including coronary and upper extremity angiography and in-hospital outcomes. One of our patients had concurrent cardiac tamponade requiring pericardial drainage, and another went into hemorrhage shock the following day from dissection of the gastric retroperitoneal artery. Characteristic angiographic features of partial or diffuse nonatherosclerotic stenosis were observed mainly in the distal parts of the coronary arteries or their branches. Notably, in six patients with SCAD who underwent upper extremity angiography, FMD of the brachial artery was revealed. For the first time, to our knowledge, we found a high prevalence of multifocal FMD of the brachial artery in patients with SCAD.

Incidence, Risk Factors, and Treatment of Venous Thromboembolism after a Serious Disaster: The Kumamoto Twin Earthquakes.

Objective: On April 16, 2016, earthquakes struck Kumamoto. In this report, the incidence and treatment of venous thromboembolism (VTE) in patients presenting to our hospital are summarized. Materials and Methods: We reviewed the details of 22 consecutive patients who were diagnosed with VTE at our hospital during the 2 weeks after the earthquakes. Results: Nineteen of the 22 patients stayed in their cars overnight after the earthquakes. Particularly, during the first 4 days, seven consecutive patients were hospitalized for pulmonary thromboembolism. All seven patients had sheltered in their cars after the earthquakes. The two patients transported on days 2.42 and 3.54 were the most severe cases. One patient was admitted after emergency initiation of venoarterial extracorporeal membrane oxygenation for treatment of hemodynamic collapse, whereas the other patient was admitted after resuscitation. By contrast, deep vein thrombosis (DVT) alone occurred within 5-9 days of the earthquakes. Bilateral DVT was the most common, which was followed by DVT on the right side only. Conclusion: The incidence of VTE might be higher after an earthquake, and an overnight stay in a car might be a risk factor for VTE. Stable patients based on the D-dimer concentration can be managed with nonwarfarin oral anticoagulants.

Impella Motor Current Amplitude Reflects the Degree of Left Ventricular Unloading under ECPELLA Support.

The combination of venoarterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, referred to as ECPELLA, is a powerful transient mechanical circulatory support for patients with severe cardiogenic shock (CS). During ECPELLA support, VA-ECMO loads the left ventricle (LV) and Impella unloads the LV. Therefore, evaluating the degree of LV unloading during ECPELLA may be a prerequisite to protect the injured myocardium. Here we report a patient with CS due to an inferior ST-elevation myocardial infarction in which the degree of LV unloading on ECPELLA was confirmed by direct LV pressure (LVP) measurement. After the percutaneous coronary intervention for the right coronary artery on ECPELLA, the aortic pressure became nonpulsatile and the peak systolic LVP was reduced at approximately 10 mmHg with 20 mA of the Impella motor current (MC) amplitude, which we referred to as the total LV unloading condition. We maintained the condition in the early phase of ECPELLA by monitoring the Impella MC amplitude at 20 mA and less with nonpulsatile aortic pressure. The patient was successfully weaned off VA-ECMO on day 3, and Impella was explanted on day 8. Prior to the Impella explant, the Impella MC amplitude increased more than 100 mA and the estimated pressure gradient between the aortic pressure and LVP was well matched with the directly measured LVP. In this case, the patient was successfully treated by ECPELLA with the total LV unloading condition, and we showed that the degree of LV unloading on ECPELLA can be estimated from the aortic pressure and Impella MC amplitude at given Impella flows.

Impact of extracorporeal CPR with transcatheter heart pump support (ECPELLA) on improvement of short-term survival and neurological outcome in patients with refractory cardiac arrest - A single-site retrospective cohort study.

Aim: Extracorporeal cardiopulmonary resuscitation (E-CPR) using veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a novel lifesaving method for refractory cardiac arrest. Although VA-ECMO preserves end-organ perfusion, it may affect left ventricular (LV) recovery due to increased LV load. An emerging treatment modality, ECPELLA, which combines VA-ECMO and a transcatheter heart pump, Impella, can simultaneously provide circulatory support and LV unloading. In this single-site cohort study, we assessed impact of ECPELLA support on clinical outcomes of refractory cardiac arrest patients. Method: We retrospectively reviewed 165 consecutive cardiac arrest patients, who underwent E-CPR by VA-ECMO with or without intra-aortic balloon pump (IABP) or ECPELLA from January 2012 to September 2021. We assessed 30-day survival rate, neurological outcome, hemodynamic data, and safety profiles including hemolysis, acute kidney injury, blood transfusion and embolic cerebral infarction. Results: Among 165 E-CPR patients, 35 patients were supported by ECPELLA, and 130 patients were supported by conventional VA-ECMO with or without IABP. Following propensity score matching of 30 ECPELLA and 30 VA-ECMO patients, the 30-day survival (ECPELLA: 53%, VA-ECMO: 20%, p < 0.01) and favorable neurological outcome determined by the Cerebral Performance Category score 1 or 2 (ECPELLA: 33%, VA-ECMO: 7%, p < 0.01) were significantly higher with ECPELLA. Patients receiving ECPELLA also showed significantly higher total mechanical circulatory support flow and lower arterial pulse pressure for the first 3 days (p < 0.01) of treatment. There were no statistical differences in safety profiles between treatment groups. Conclusion: ECPELLA may be associated with improved 30-day survival and neurological outcome in patients with refractory cardiac arrest.

Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED-J Study.

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

Predictors of hypoxemia in type-B acute aortic syndrome: a retrospective study.

Acute aortic syndrome (AAS) can be life-threatening owing to a variety of complications, and it is managed in the intensive care unit (ICU). Although Stanford type-B AAS may involve hypoxemia, its predictors are not yet clearly understood. We studied clinical factors and imaging parameters for predicting hypoxemia after the onset of type-B AAS. We retrospectively analyzed patients diagnosed with type-B AAS in our hospital between January 2012 and April 2020. We defined hypoxemia as PaO2/FiO2 ≤ 200 within 7 days after AAS onset and used logistic regression analysis to evaluate prognostic factors for hypoxemia. We analyzed 224 consecutive patients (140 males, mean age 70 ± 14 years) from a total cohort of 267 patients. Among these, 53 (23.7%) had hypoxemia. The hypoxemia group had longer ICU and hospital stays compared with the non-hypoxemia group (median 20 vs. 16 days, respectively; p = 0.039 and median 7 vs. 5 days, respectively; p < 0.001). Male sex (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.24-6.63; p = 0.014), obesity (OR 2.36; 95% CI 1.13-4.97; p = 0.023), patent false lumen (OR 2.33; 95% CI 1.09-4.99; p = 0.029), and high D-dimer level (OR 1.01; 95% CI 1.00-1.02; p = 0.047) were independently associated with hypoxemia by multivariate logistic analysis. This study showed a significant difference in duration of ICU and hospital stays between patients with and without hypoxemia. Furthermore, male sex, obesity, patent false lumen, and high D-dimer level may be significantly associated with hypoxemia in patients with type-B AAS.

Increased and continuous coronary arterial flow was induced by LV uncoupling condition using combined treatment of a microaxial heart pump and venoarterial extracorporeal membrane oxygenation.

An emerging therapeutic modality, ECPELLA, which combines a transvalvular microaxial left ventricular (LV) assist device, Impella, and venoarterial membrane oxygenation (VA-ECMO), has been applied for patients with refractory cardiogenic shock. During ECPELLA support, VA-ECMO increases the LV load, whereas the Impella reduces the LV load. Studies reported that coronary perfusion is influenced by LV unloading conditions, and the effective degree of LV unloading to increase the coronary perfusion on ECPELLA support remains to be determined. Here, we reported a cardiogenic shock case whose coronary arterial flow was assessed by transesophageal echocardiography during ECPELLA support. The left anterior descending coronary artery (LAD) peak blood flow velocity and the velocity time integral (VTI) were not significantly increased when blood was ejected from the LV (partial LV unloading). When the LV blood ejection was completely bypassed by Impella confirmed by non-pulsatile aortic pressure with significantly reduced LV pressure with no aortic valve opening (LV uncoupling: no blood ejection from the LV), both peak velocity and VTI of the LAD were markedly increased and the blood flow became continuous throughout the cardiac cycle. Our case suggests that the coronary arterial flow in the injured myocardium is sensitive to degrees of LV unloading on ECPELLA support.

Successful emergent transcatheter aortic valve implantation and left ventricular unloading by Impella in a patient with severe aortic stenosis who experienced cardiogenic shock after primary percutaneous coronary intervention for ST-elevation myocardial infarction: a case report.

BACKGROUND: Determining the treatment strategy for cardiogenic shock following ST-elevation myocardial infarction in a patient with severe aortic stenosis remains challenging and is a matter of debate. CASE SUMMARY: An 84-year-old man with chest pain was transferred to our institute and subsequently diagnosed with ST-elevation myocardial infarction and Killip class III heart failure. The patient was intubated, and urgent coronary angiography revealed severe tandem stenosis from the proximal to mid-left anterior descending coronary artery. We performed a primary percutaneous coronary intervention (PCI) and deployed drug-eluting stents from the left main trunk to mid-left anterior descending coronary artery. Although the procedure was successful, the patient went into cardiogenic shock a few hours later. Transthoracic echocardiography revealed low cardiac function and severe aortic stenosis. We decided to perform transcatheter aortic valve implantation using a self-expandable valve, followed by the insertion of a left ventricular assist device. The combination of procedures achieved haemodynamic stability. DISCUSSION: It is difficult to treat cardiogenic shock that develops in patients with severe aortic stenosis and ST-elevation myocardial infarction. This case report demonstrates that combined transcatheter aortic valve replacement using a self-expanding valve and left ventricular assist device placement can be safe and effective after a primary PCI.

Impact of Smoking Status on Growth Differentiation Factor 15 and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study.

Background Whether circulating growth differentiation factor 15 (GDF-15) levels differ according to smoking status and whether smoking modifies the relationship between GDF-15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF-15 and the impact of smoking status on the association between GDF-15 and all-cause death. GDF-15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF-15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log-transformed GDF-15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF-15. The prognostic value of GDF-15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

Distinct Characteristics of VEGF-D and VEGF-C to Predict Mortality in Patients With Suspected or Known Coronary Artery Disease.

Background VEGF-D (vascular endothelial growth factor D) and VEGF-C are secreted glycoproteins that can induce lymphangiogenesis and angiogenesis. They exhibit structural homology but have differential receptor binding and regulatory mechanisms. We recently demonstrated that the serum VEGF-C level is inversely and independently associated with all-cause mortality in patients with suspected or known coronary artery disease. We investigated whether VEGF-D had distinct relationships with mortality and cardiovascular events in those patients. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The serum level of VEGF-D was measured. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death and major adverse cardiovascular events defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. During the 3-year follow-up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for possible clinical confounders, cardiovascular biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-I, and high-sensitivity C-reactive protein), and VEGF-C, the VEGF-D level was significantly associated with all-cause death and cardiovascular death but not with major adverse cardiovascular events.. Moreover, the addition of VEGF-D, either alone or in combination with VEGF-C, to the model with possible clinical confounders and cardiovascular biomarkers significantly improved the prediction of all-cause death but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within patients over 75 years old. Conclusions In patients with suspected or known coronary artery disease undergoing elective coronary angiography, an elevated VEGF-D value seems to independently predict all-cause mortality.

VEGF-C and Mortality in Patients With Suspected or Known Coronary Artery Disease.

Background The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease. However, the relationships of vascular endothelial growth factor-C ( VEGF -C), a central player in lymphangiogenesis, with mortality and cardiovascular events in patients with suspected or known coronary artery disease are unknown. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The primary predictor was serum levels of VEGF -C. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. During the 3-year follow-up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for established risk factors, VEGF -C levels were significantly and inversely associated with all-cause death (hazard ratio for 1- SD increase, 0.69; 95% confidence interval, 0.60-0.80) and cardiovascular death (hazard ratio, 0.67; 95% confidence interval, 0.53-0.87), but not with major adverse cardiovascular events (hazard ratio, 0.85; 95% confidence interval, 0.72-1.01). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF -C levels further improved the prediction of all-cause death, but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within 1717 patients with suspected coronary artery disease. Conclusions In patients with suspected or known coronary artery disease, a low VEGF -C value may independently predict all-cause mortality.

Incidence and Risk Factors of Stroke or Systemic Embolism in Patients With Atrial Fibrillation and Heart Failure　- The Fushimi AF Registry.

BACKGROUND: Heart failure (HF) is a heterogeneous syndrome, but the effect of the type and severity of HF on the incidence of stroke or systemic embolism (SE) in atrial fibrillation (AF) patients is unclear.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 3,749 patients. We defined pre-existing HF as having one of the following: prior hospitalization for HF, presence of HF symptoms (NYHA ≥2), or reduced ejection fraction (<40%). At baseline, 1,008 (26.9%) patients had pre-existing HF. On multivariate analysis, the incidence of stroke/SE was not associated with pre-existing HF (hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.92-1.64) or each criterion for the definition of pre-existing HF, but was associated with high B-type natriuretic peptide (BNP) or N-terminal proBNP levels (above the median of the pre-existing HF group) at baseline (HR, 1.65; 95% CI, 1.06-2.53). Stroke/SE was markedly increased in the initial 30-day period following hospital admission for HF (HR, 12.0; 95% CI, 4.59-31.98). CONCLUSIONS: The effect of HF on the incidence of stroke/SE may depend on the stage or severity of HF in patients with AF. The incidence of stroke/SE was markedly increased in the 30 days after admission for HF, but compensated 'stable' HF did not appear to confer an independent risk.

Relationship of Hypertension and Systolic Blood Pressure With the Risk of Stroke or Bleeding in Patients With Atrial Fibrillation: The Fushimi AF Registry.

BACKGROUND: Hypertension is considered a major risk factor of stroke and systemic embolism (SE) as well as bleeding in patients with atrial fibrillation (AF). The purpose of this study was to investigate the relationship of hypertension and systolic blood pressure (SBP) with the risk of stroke/SE or bleeding in AF patients. METHODS: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in Fushimi-ku, Kyoto. Fushimi-ku is densely populated with a total population of 283,000. Follow-up data were available for 3,713 patients (follow-up rate 90.0%) as of August 2015, and the median follow-up period was 1,035 days. RESULTS: We compared the clinical backgrounds at baseline, and follow-up outcomes of AF patients between those with hypertension (HTN; n = 2,304, 62.1% of total) and those without (non-HTN; n = 1,409). History of hypertension was neither associated with the incidence of stroke/SE, ischemic stroke, hemorrhagic stroke nor major bleeding. However, when we divided the HTN group by baseline SBP ≥150 mm Hg (HTN-high blood pressure [HBP]: n = 305, 13.3% of HTN group) or <150 mm Hg (HTN-low blood pressure [LBP]: n = 1,983), HTN-HBP group was significantly associated with a higher incidence of both stroke/SE (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.08-2.72) and major bleeding (HR: 2.01, 95% CI: 1.21-3.23) compared with the non-HTN group. In contrast, HTN-LBP group was not associated with the risk of stroke/SE or major bleeding, compared with the non-HTN group. CONCLUSION: The incidences of stroke/SE and bleeding were higher in AF and hypertension patients with elevated SBP. UMIN Clinical Trials Registry: UMIN000005834.