Shunei Kyo

In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells.

The characterization of mesenchymal stem cells (MSCs) is of biological and clinical interest. We demonstrate that isolated MSCs, defined by CD34(low) c-kit(+) CD140a(+) Sca-1(high), are able to differentiate into cardiomyocytes, endothelial cells, and pericytes or smooth muscle cells by direct injection into adult heart. In skeletal muscle and lung, they also contributed to formation of the vasculature. MSCs did not transform into malignant cells or form excess extracellular matrix. This study suggests that MSCs may supply an ideal donor source of cardiovascular cells in patients with cardiopulmonary diseases.

Intravascular ultrasound assessment of regional aortic wall stiffness, distensibility, and compliance in patients with coarctation of the aorta ☆ ☆☆ ★ ★★

BACKGROUND Impaired aortic pulsatility has been demonstrated by angiography in children and in studies of experimental animals with coarctation of the aorta. OBJECTIVES The purpose of this study was to assess regional aortic stiffness, distensibility, and compliance before and after balloon dilation in patients with coarctation of the aorta. METHODS AND RESULTS Intravascular ultrasound examination was performed in 13 pediatric patients with the diagnosis of coarctation of the aorta to yield aortic diameter. Area transverse sections at both systolic and diastolic period were measured at three aortic levels: the proximal, distal, and coarctation segments. Balloon dilation was also performed in eight of 13 patients. By using pressures measured in the same areas, an aortic stiffness index (beta) was calculated as In(Ps/Pd)/(Ds-Dd), where In is natural logarithm, Ps is systolic pressure, Pd is diastolic pressure, Ds is systolic diameter, and Dd is diastolic diameter. Aortic distensibility and an estimation of aortic compliance were also calculated. The beta stiffness index of the coarctation and the proximal segments of the aorta were significantly greater than that of the distal segment of the aorta (p < 0.01). The aortic wall stiffness beta index did not acutely change after successful balloon dilation, but the distensibility and compliance of distal aorta were nonetheless significantly decreased after balloon dilation (p < 0.01, p < 0.05) as a function of changes of pulsatility of flow. CONCLUSIONS Abnormal proximal aortic stiffness may be a strong contributing factor that promotes the genesis of hypertension in patients with coarctation even after successful repair or balloon angioplasty.

Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation.

The Impella microaxial-flow pump can directly unload left ventricle (LV) in cases of acute heart failure. Extracorporeal membrane oxygenation (ECMO) is widely used for circulatory support. Although the clinical effectiveness of ECMO has been demonstrated, insufficient LV loading reduction may not be advantageous for myocardial recovery. The objective was to compare ventricular loading reduction and reversibility of ventricular fibrillation (VF) with either Impella or ECMO. Six dogs were used. Extracorporeal membrane oxygenation was established by the femoral artery and right atrium. The Impella LD was inserted in LV by the ascending aorta. An acute failing heart was created by sequential coronary artery ligations. Pressure–volume (PV) relationships were acquired without a device and with ECMO or Impella. When VF occurred, direct cardioversion was performed while supported by either ECMO or Impella. The PV area, which is a measure of ventricular unloading and is correlated with myocardial oxygen consumption, decreased more with Impella than with ECMO. Successful defibrillation was achieved more effectively while under Impella support. Superior ventricular unloading with the Impella device may provide higher recovery potential to damaged hearts than ECMO and may have a significant impact not only on intensive care of patients with heart failure but also on resuscitation.

Arterial haemodynamics in patients after repair of tetralogy of Fallot: influence on left ventricular after load and aortic dilatation

Background: Recent histological studies of the aortic wall of patients with tetralogy of Fallot (TOF) have shown massive degeneration of the tunica media of the aorta. Such changes in arterial wall structure may significantly alter arterial wall mechanical properties, and thus cause abnormal arterial haemodynamics. Objective: To test the hypothesis that after repair of TOF, there are abnormal arterial haemodynamics which are associated with aortic dilatation and which increased after load on the left ventricle. Methods and results: The subjects comprised 38 patients who had undergone complete repair of TOF, and 55 control subjects. Systemic arterial haemodynamics were investigated by measuring aortic input impedance during cardiac catheterisation. The patients with TOF had significantly higher characteristic impedance (158 (43) dyne.s.cm−5.m2 vs 105 (49) dyne.s.cm−5.m2) and pulse wave velocity (561 (139) cm/s vs 417 (91) cm/s) and significantly lower total peripheral arterial compliance (0.93 (0.39) ml/mm Hg/m2 vs 1.24 (0.58) ml/mm Hg/m2) than the controls (for all three variables, p<0.01 vs controls), suggesting that central and peripheral arterial wall stiffness are increased after TOF repair. Additionally, patients with TOF had significantly higher arterial wave reflection than the controls (reflection coefficient: 0.21 (0.12) vs 0.16 (0.06)). These abnormalities in patients with TOF increased the pulsatile load on the left ventricle and significantly contributed to decreased cardiac output, even when right ventricular function was taken into account by multivariate regression analysis. The increase in aortic wall stiffness was closely associated with the increase in aortic root diameter. Conclusion: These results indicating abnormal arterial haemodynamics after TOF repair highlight the importance of regular monitoring of the systemic arterial bed and potentially relevant cardiovascular events in long-term follow-up of TOF.

Ventricular-vascular stiffening in patients with repaired coarctation of aorta: integrated pathophysiology of hypertension.

Background— Despite successful repair, patients with coarctation of the aorta (COA) often show persistent hypertension at rest and/or during exercise. Previous studies indicated that the hypertension is mainly due to abnormalities in the arterial bed and its regulatory systems. We hypothesized that ventricular systolic stiffness also contributes to the hypertensive state in these patients in addition to increased vascular stiffness. Methods and Results— The study involved 43 patients with successfully repaired COA and 45 age-matched control subjects. Ventricular systolic stiffness (end systolic elastance) and arterial stiffness (effective arterial elastance) were measured invasively by ventricular pressure-area relationship during varying preload before and after &bgr;-adrenergic stimulation. The mean systolic blood pressure was significantly higher with concomitant increases in both end systolic elastance and effective arterial elastance in patients with COA compared with control subjects (113.2±16.8 versus 91.0±9.1 mm Hg, 44.5±17.0 versus 19.2±6.7 mm Hg/mL/m2, and 27.8±11.4 versus 20.2±4.8 mm Hg/mL/m2, respectively; P<0.01 for each). End systolic elastance and effective arterial elastance of patients with COA showed exaggerated responses to &bgr;-adrenergic stimulation, further amplifying blood pressure elevation. Quantification analyses assuming that ventricular systolic stiffness of patients with COA is equal to that of the control revealed that ventricular systolic stiffness accounts for approximately 50% to 70% of the elevated blood pressure in patients with COA. Furthermore, combined ventricular-arterial stiffening amplified systolic pressure sensitivity to increased preload during abdominal compression and limited stroke volume gain/relaxation improvement induced by &bgr;-adrenergic stimulation. Conclusions— Increased ventricular systolic stiffness, coupled with increased arterial stiffness, plays important roles in hypertension in patients with repaired COA. Thus, ventricular systolic stiffness is a potentially suitable target for reduction of blood pressure and improvement of prognosis of patients with COA.

Deep sternal wound infection after cardiac surgery

BackgroundDeep sternal wound infection (DSWI) is a serious postoperative complication of cardiac surgery. In this study we investigated the incidence of DSWI and effect of re-exploration for bleeding on DSWI mortality.MethodsWe reviewed 73,700 cases registered in the Japan Adult Cardiovascular Surgery Database (JACVSD) during the period from 2004 to 2009 and divided them into five groups: 26,597 of isolated coronary artery bypass graft (CABG) cases, 23,136 valvular surgery cases, 17,441 thoracic aortic surgery cases, 4,726 valvular surgery plus CABG cases, and 1,800 thoracic aortic surgery plus CABG cases. We calculated the overall incidence of postoperative DSWI, incidence of postoperative DSWI according to operative procedure, 30-day mortality and operative mortality of postoperative DSWI cases according to operative procedure, 30-day mortality and operative mortality of postoperative DSWI according to whether re-exploration for bleeding, and the intervals between the operation and deaths according to whether re-exploration for bleeding were investigated. Operative mortality is defined as in-hospital or 30-day mortality. Risk factors for DSWI were also examined.ResultsThe overall incidence of postoperative DSWI was 1.8%. The incidence of postoperative DSWI was 1.8% after isolated CABG, 1.3% after valve surgery, 2.8% after valve surgery plus CABG, 1.9% after thoracic aortic surgery, and 3.4% after thoracic aortic surgery plus CABG. The 30-day and operative mortality in patients with DSWI was higher after more complicated operative procedures. The incidence of re-exploration for bleeding in DSWI cases was 11.1%. The overall 30-day/operative mortality after DSWI with re-exploration for bleeding was 23.0%/48.0%, and it was significantly higher than in the absence of re-exploration for bleeding (8.1%/22.0%). The difference between the intervals between the operation and death according to whether re-exploration for bleeding had been performed was not significant. Age and cardiogenic shock were significant risk factors related to re-exploration for bleeding, and diabetes control was a significant risk factor related to DSWI for all surgical groups. Previous CABG was a significant risk factor related to both re-exploration for bleeding and DSWI for all surgical groups.ConclusionsThe incidence of DSWI after cardiac surgery according to the data entered in the JACVSD registry during the period from 2004 to 2009 was 1.8%, and more complicated procedures were followed by higher incidence and mortality. When re-exploration for bleeding was performed, mortality was significantly higher than when it was not performed. Prevention of DSWI and establishment of an effective appropriate treatment for DSWI may improve the outcome of cardiac surgery.

A novel counterpulsation mode of rotary left ventricular assist devices can enhance myocardial perfusion

The effect of rotary left ventricular assist devices (LVADs) on myocardial perfusion has yet to be clearly elucidated, and several studies have shown decreased coronary flow under rotary LVAD support. We have developed a novel pump controller that can change its rotational speed (RS) in synchronization with the native cardiac cycle. The aim of our study was to evaluate the effect of counterpulse mode, which increases the RS in diastole, during coronary perfusion. Experiments were performed on ten adult goats. The EVAHEART LVAD was installed by the left ventricular uptake and the descending aortic return. Ascending aortic flow, pump flow, and coronary flow of the left main trunk were monitored. Coronary flow was compared under four conditions: circuit-clamp, continuous mode (constant pump speed), counterpulse mode (increased pump speed in diastole), and copulse mode (increased pump speed in systole). There were no significant baseline changes between these groups. In counterpulse mode, coronary flow increased significantly compared with that in continuous mode. The waveform analysis clearly revealed that counterpulse mode mainly resulted in increased diastolic coronary flow. In conclusion, counterpulse mode of rotary LVADs can enhance myocardial perfusion. This novel drive mode can provide great benefits to the patients with end-stage heart failure, especially those with ischemic etiology.

Electrocardiogram‐Synchronized Rotational Speed Change Mode in Rotary Pumps Could Improve Pulsatility

Continuous-flow left ventricular assist devices (LVADs) have greatly improved the prognosis of patients with end-stage heart failure, even if continuous flow is different from physiological flow in that it has less pulsatility. A novel pump controller of continuous-flow LVADs has been developed, which can change its rotational speed (RS) in synchronization with the native cardiac cycle, and we speculated that pulsatile mode, which increases RS just in the systolic phase, can create more pulsatility than the current system with constant RS does. The purpose of the present study is to evaluate the effect of this pulsatile mode of continuous-flow LVADs on pulsatility in in vivo settings. Experiments were performed on eight adult goats (61.7 ± 7.5 kg). A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed by the apex drainage and the descending aortic perfusion. A pacing lead for the detection of ventricular electrocardiogram was sutured on the anterior wall of the right ventricle. In the present study, we compared pulse pressure or other parameters in the following three conditions, including Circuit-Clamp (i.e., no pump support), Continuous mode (constant RS), and Pulsatile mode (increase RS in systole). Assist rate was calculated by dividing pump flow (PF) by the sum of PF and ascending aortic flow (AoF). In continuous and pulsatile modes, these assist rates were adjusted around 80-90%. The following three parameters were used to evaluate pulsatility, including pulse pressure, dp/dt of aortic pressure (AoP), and energy equivalent pulse pressure (EEP = (∫PF*AoP dt)/(∫PF dt), mm Hg). The percent difference between EEP and mean AoP is used as an indicator of pulsatility, and normally it is around 10% of mean AoP in physiological pulse. Both pulse pressure and mean dp/dt max were decreased in continuous mode compared with clamp condition, while those were regained by pulsatile mode nearly to clamp condition (pulse pressure, clamp/continuous/pulsatile, 25.0 ± 7.6/11.7 ± 6.4/22.6 ± 9.8 mm Hg, mean dp/dt max, 481.9 ± 207.6/75.6 ± 36.2/351.1 ± 137.8 mm Hg/s, respectively). In clamp condition, %EEP was 10% higher than mean AoP (P = 0.0078), while in continuous mode, %EEP was nearly equivalent to mean AoP (N.S.). In pulsatile mode, %EEP was 9% higher than mean AoP (P = 0.038). Our newly developed pulsatile mode of continuous-flow LVADs can produce pulsatility comparable to physiological pulsatile flow. Further investigation on the effect of this novel drive mode on organ perfusion is currently ongoing.

Aortic Insufficiency in Patients With Sustained Left Ventricular Systolic Dysfunction After Axial Flow Assist Device Implantation

BACKGROUND Predicting the occurrence of aortic insufficiency (AI) during left ventricular assist device (LVAD) support has remained unsolved. METHODS AND RESULTS We enrolled 52 patients who had received continuous flow LVAD (14 axial and 38 centrifugal pumps) and who been followed for ≥6 months between Jun 2006 and Dec 2013. Native aortic valve (AV) opening was observed in 18 patients (35%) with improved LV systolic function, and none of them had AI. On multivariate logistic regression analysis preoperative shorter heart failure duration was the only independent predictor of postoperative native AV opening (P=0.042; odds ratio [OR], 0.999). Of the remaining 34 patients (65%) with closed AV, 11 had AI with enlargement of the aortic root and narrow pulse pressure. Among those with closed AV, axial pump use (n=13) was the only significant predictor of the development of AI (P=0.042; OR, 4.950). Patients with AI had lower exercise capacity and a higher readmission rate than those without AI during 2-year LVAD support (55% vs. 8%; P<0.001). CONCLUSIONS Native AV opening during LVAD support is profoundly associated with reversal of LV systolic function, especially in patients with preoperative shorter heart failure duration. Among those in whom the native AV remains closed, low pulsatility of axial flow pump may facilitate aortic root remodeling and post-LVAD AI development that results in worse clinical outcome.

Plasminogen Activator Inhibitor-1 in Patients with Kawasaki Disease: Diagnostic Value for the Prediction of Coronary Artery Lesion and Implication for a New Mode of Therapy

Kawasaki disease (KD) in children takes the form of acute systemic vasculitis, which causes coronary artery dilation and aneurysm formation in 10% to 15% of the patients. We have recently shown that matrix metalloproteinases (MMPs) are intimately involved in coronary arterial wall destruction and the resultant formation of coronary artery lesions (CALs) in this disease. Plasminogen activators (PAs) are known to be a major pathway of MMP activation, and this suggests that their inhibitor, plasminogen activator inhibitor-1 (PAI-1), also plays important roles in the development of CALs in KD. The present study was conducted to test the hypothesis that circulating levels of PAI-I are related to CAL formation in KD. Plasma levels of PAI-1 were measured by enzyme-linked immunoassay in 37 KD patients without CALs (group 1) and 7 KD patients with CALs (group 2). Blood samples were obtained before and after i.v. gammaglobulin therapy (IVGG), and in the convalescent stage. Levels of PAI-1 were significantly higher in KD patients before IVGG than in 18 age-matched healthy control subjects (p < 0.01). More importantly, both pre-IVGG and post-IVGG levels of PAI-1 were significantly higher in group 2 than in group 1 (p < 0.01). Furthermore, PAI-1 levels of 9 patients from group 1 who showed pre-IVGG PAI-1 levels higher than the minimum PAI-1 level in group 2 significantly decreased after IVGG, whereas PAI-1 levels of group 2 patients remained persistently elevated, further suggesting a close association between PAI-1 and CAL development in KD. Thus, PAI-1 may be useful as a predictive marker for CAL development in KD. Studies of the effects of PA inhibition on coronary outcome may provide evidence that PA is a viable therapeutic target for the prevention of KD-related CALs.