Theophylline-Induced Left Ventricular Relaxation Disturbance in Magnesium-Deficient Rats: Improvement by K201, a Novel 1,4-Benzothiazepine Derivative.

BACKGROUND: Although magnesium deficiency induces left ventricular dysfunction, it is not known whether both systolic and diastolic functions are altered to the same extent. In this study, we investigated the effects of theophylline on left ventricular function in rats fed a normal diet or a magnesium-deficient diet for 1 month, and determined whether K201, a multi-channel blocker, modulated the effects of theophylline. METHODS: Theophylline was infused at 5 mg/kg/min for 15 min in 6 control rats and 6 magnesium-deficient rats, and hemodynamic measurements were performed. In another 6 magnesium-deficient rats, K201 was infused at 0.1 mg/kg/min for 15 min simultaneously with theophylline. RESULTS: Theophylline induced persistent increases in heart rate, peak positive first derivative of left ventricular pressure (+dP/dt), and a transient increase in left ventricular end-diastolic pressure (LVEDP), but did not affect left ventricular systolic pressure (LVSP) and peak negative first derivative of left ventricular pressure (-dP/dt) in the control rats. In contrast, in the magnesium-deficient rats, there was a persistent decrease in LVSP and a persistent increase in -dP/dt after theophylline infusion, although increases in heart rate, +dP/dt and LVEDP were similar to those in the control rats. When K201 was infused along with theophylline in the magnesium-deficient rats, both the decrease in LVSP and increase in -dP/dt were suppressed. CONCLUSIONS: Theophylline impaired left ventricular function in the magnesium-deficient rats, and this was improved by K201. K201 may provide new insights regarding future strategies for heart failure treatment.

The wound healing response after implantation of a drug-eluting stent is impaired persistently in the long term.

A 70-year-old man underwent stent implantation for right coronary artery (RCA) lesions with a bare metal stent (BMS) and two sirolimus-eluting stents (SES). However, as both the BMS and SES stented sites developed restenosis after 13 months, he underwent target lesion revascularization using directional coronary atherectomy (DCA). On histopathology, the restenosis lesion at the SES-deployed site showed greater inflammation and less re-endothelialization than that at the BMS-deployed site. Three months later, the SES-deployed site developed a second restenosis, in which paclitaxel-eluting stents (PES) were implanted (PES-in-SES), while the BMS-deployed site was restenosis free. Five years later, restenosis was absent in these RCA lesions. However, by optical coherence tomography and/or coronary angioscopy, the PES-in-SES site in the RCA showed poor neointimal coverage over the stent struts and yellowish neointima, suggesting lipid-rich neoatheroma formation, whereas at the BMS site appropriate white neointima formation was observed. Drug-eluting stents still have problems of persistent inflammation, inappropriate neointima formation, and neoatherosclerosis. Although we are now in the era of second generation DESs in which better stent performance would be promising, we should remember that we are obliged to continue to follow-up all patients in whom first generation DESs such as SES or PES have been placed.

Comparison of the performance of zotarolimus- and everolimus-eluting stents by optical coherence tomography and coronary angioscopy.

Overall stent performance should be characterized by geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. The aim of this study was to compare the performance of zotarolimus-eluting stent (ZES), everolimus-eluting stent (EES) and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscopy. For 36 stented coronary lesions (BMS, 12 lesions; ZES, 11 lesions; EES, 13 lesions) in 27 patients, we calculated neointimal area and uncovered stent strut rate based on OCT findings at 10 months after stent placement. The grades of neointimal coverage and yellow color, both of which were classified from 0 to 3, were also assessed by coronary angioscopy. The plaque area of the ZES lesions was larger than that of the EES lesions (P < 0.05) but smaller than that of the BMS lesions (P < 0.05). The OCT-based uncovered rate of the ZES lesions was less than that of the EES lesions (P < 0.01), but similar to that of the BMS lesions. The stent coverage grade by angioscopy was higher in the ZES lesions than in the EES lesions (P < 0.05), but similar to the BMS lesions. The yellow grade was less in the ZES lesions than in the EES lesions (P < 0.01), but similar to the BMS lesions. ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as prevention of neoatheroma formation. ZES may have superior performance compared with EES.

The late-phase inflammatory response after drug-eluting stent implantation.

Recent advances in drug-eluting stent (DES) technology have succeeded in preventing restenosis. In addition to inhibiting smooth muscle cell proliferation, DES greatly inhibits the local inflammatory response in the acute phase after implantation, leading to prevention of restenosis. However, a unique issue in DES implantation is an impairment of reendothelialization, which may result in abnormal wound healing. Consequently, a late-phase inflammatory relapse could appear in the long term after DES implantation. In this study, we measured serum levels of inflammatory markers, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and myeloperoxidase, as well as high-sensitivity C-reactive protein at follow-up coronary angiography (mean 9 months) in 54 patients who received DES stenting who did not experience restenosis, and compared them with 51 patients receiving bare-metal stents (BMS) without restenosis. The level of IL-6 was over the measurement threshold (≥2.22 pg/ml) in 12 patients (21 %) in the DES group, but in only 2 patients (4 %) in the BMS group (P = 0.003). IL-8 was significantly higher in the DES group than in the BMS group (4.51 ± 2.40 vs 3.84 ± 1.34 pg/ml, P = 0.015). The levels of other biomarkers were similar between the two groups. DES showed an increase in inflammatory cytokines in the late phase after implantation in comparison with patients who received BMS, suggesting late-stage inflammation. Therefore, the wound-healing response after DES implantation might be different from that after BMS.

Transcatheter aortic valve-in-surgical aortic valve for a patient with repeated healed endocarditis: a case report.

BACKGROUND: Transcatheter valve replacement is contraindicated in patients with active infective endocarditis. However, few reports suggest that it could be beneficial for high-risk surgical patients with healed infective endocarditis. Here, we report a case of a surgical transcatheter aortic valve in a patient with healed repeated prosthetic valve endocarditis using a stentless valve. CASE PRESENTATION: A 79-year-old female who underwent the Bentall procedure using a stentless valve and coronary artery bypass grafting for annuloaortic ectasia 22 years ago was hospitalized for stage II bioprosthetic valve failure. The patient had a history of prosthetic valve endocarditis three times: the first and second prosthetic valve endocarditis occurred 15 years ago, and the third prosthetic valve endocarditis occurred 3 years ago. The causative organisms were Campylobacter fetus and Enterococcus faecalis. With appropriate antibiotic therapy, the lesion was localized and healed completely without valve destruction; however, the patient developed rapid aortic regurgitation. Based on a review of the patient's history of prosthetic valve endocarditis, the absence of signs of infection, and clinical findings of transesophageal echocardiography and computed tomography, a diagnosis of structural valve deterioration with healed infective endocarditis was made. Subsequently, a transcatheter aortic valve in a surgical aortic valve using a balloon-expandable type was performed, because the patient had a high surgical risk of 12.7%. The patient's postoperative course was uneventful. At the 1-year follow-up, there were no signs of infection or valve abnormalities. CONCLUSIONS: Transcatheter valve replacement can be a treatment option for high-risk surgical patients with healed limited lesions in infective endocarditis.

Relationship between the serum GDF-15 concentration and muscle function in female patients receiving aortic valve replacement (TAVR, SAVR): Comparison with healthy elderly female subjects.

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects. Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay. Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (ß = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement. Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.

Low-Intensity Resistance Training with Moderate Blood Flow Restriction Appears Safe and Increases Skeletal Muscle Strength and Size in Cardiovascular Surgery Patients: A Pilot Study.

We examined the safety and the effects of low-intensity resistance training (RT) with moderate blood flow restriction (KAATSU RT) on muscle strength and size in patients early after cardiac surgery. Cardiac patients (age 69.6 ± 12.6 years, n = 21, M = 18) were randomly assigned to the control (n = 10) and the KAATSU RT group (n = 11). All patients had received a standard aerobic cardiac rehabilitation program. The KAATSU RT group additionally executed low-intensity leg extension and leg press exercises with moderate blood flow restriction twice a week for 3 months. RT-intensity and volume were increased gradually. We evaluated the anterior mid-thigh thickness (MTH), skeletal muscle mass index (SMI), handgrip strength, knee extensor strength, and walking speed at baseline, 5-7 days after cardiac surgery, and after 3 months. A physician monitored the electrocardiogram, rate of perceived exertion, and the color of the lower limbs during KAATSU RT. Creatine phosphokinase (CPK) and D-dimer were measured at baseline and after 3 months. There were no side effects during KAATSU RT. CPK and D-dimer were normal after 3 months. MTH, SMI, walking speed, and knee extensor strength increased after 3 months with KAATSU RT compared with baseline. Relatively low vs. high physical functioning patients tended to increase physical function more after 3 months with KAATSU RT. Low-intensity KAATSU RT as an adjuvant to standard cardiac rehabilitation can safely increase skeletal muscle strength and size in cardiovascular surgery patients.

Mobilization of progenitor cells and vessel healing after implantation of SYNERGY in acute coronary syndrome.

This study was aimed to compare the vascular healing process of a SYNERGY stent with that of a PROMUS PREMIER stent in patients with acute coronary syndrome (ACS). In 71 patients with ACS, undergoing coronary stent implantation using the SYNERGY stent (n = 52) or PROMUS PREMIER stent (n = 19), we measured circulating CD34+/CD133+/CD45null cells and CD34+/KDR+ cells and observed vascular healing at the stented sites using optical coherence tomography (OCT) and coronary angioscopy. On the day 7, circulating CD34+/CD133+/CD45null cells increased in SYNERGY group (P < 0.0001), while it did not change in PROMUS group. The CD34+/KDR+ cells also increased in SYNERGY group (P < 0.0001) but less significantly in the PROMUS group (P < 0.05). The OCT-based neointimal thickness (P < 0.0005) and neointimal coverage rate (P < 0.05) at 12 months were greater in SYNERGY group, compared with PROMUS group. The coronary angioscopy-based neointimal coverage grade at 12 months was also greater in SYNERGY group (P < 0.001). In overall patients, the change in CD34+/KDR+ cells on the day 7 correlated with the OCT-based neointimal thickness at 12 months (R = 0.288, P < 0.05). SYNERGY stent seems to have potential advantages over PROMUS PREMIER stent for ACS patients in terms of vascular healing process at the stented sites.

Neointimal tissue characterization after implantation of drug-eluting stents by optical coherence tomography: quantitative analysis of optical density.

Normalized optical density (NOD) measured by optical coherence tomography represents neointimal maturity after coronary stent implantation and is correlated with morphologic information provided by both light and electron microscopy. We aimed to test the hypothesis that even second generation drug-eluting stents (DESs) are problematic in terms of neointimal maturity. We implanted bare-metal stents (BMS: n = 14), everolimus-eluting stents (EESs: n = 15) or zotarolimus-eluting stents (ZESs: n = 12) at 41 sites in 32 patients with stable coronary artery disease. OCT was performed at up to 12 months of follow-up, and the average optical density of neointima covering struts was evaluated. NOD was calculated as the optical density of stent-strut covering tissue divided by the optical density of the struts. We also measured circulating CD34+ /CD133+ /CD45low cells, and serum levels of stromal cell-derived factor (SDF)-1, interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 at baseline and follow-up. NOD was lower in the EES (0.70 ± 0.06) group than in the BMS (0.76 ± 0.07, P < 0.05) and ZES (0.76 ± 0.06, P < 0.05) groups. The mean neointimal area (R = 0.33, P < 0.05) and mean neointimal thickness (R = 0.37, P < 0.05) were correlated with NOD. Although NOD was not correlated with percent changes in circulating endothelial progenitor cells, and the levels of SDF-1 and IL-8, it was negatively correlated with the change in MMP-9 level (R = - 0.51, P < 0.01). Neointimal maturity might be lower at EES sites than BMS or ZES sites. This might lead to impaired neointimal tissue growth and matrix degradation. These results suggest a specific pathophysiology after DES implantation.

Mobilization of progenitor cells and assessment of vessel healing after second generation drug-eluting stenting by optical coherence tomography.

BACKGROUND: Bone marrow-derived progenitor cells likely contribute to both endothelial- and smooth muscle cell-dependent healing responses in stent-injured vessel sites. This study aimed to assess mobilization of progenitor cells and vessel healing after zotarolimus-eluting (ZES) and everolimus-eluting (EES) stents. METHODS AND RESULTS: In 63 patients undergoing coronary stent implantation, we measured circulating CD34 + CD133 + CD45low cells and serum levels of biomarkers relevant to stem cell mobilization. In 31 patients of them, we assessed vessel healing within the stented segment using optical coherence tomography (OCT) imaging. The CD34 + CD133 + CD45low cells increased 68 ± 59% 7 days after bare metal stent (BMS), 10 ± 53% after ZES (P < 0.01 vs BMS), 3 ± 49% after EES (P < 0.001 vs BMS), compared with baseline. Percent change in CD34 + CD133 + CD45low cells was positively correlated with that in stromal cell-derived factor (SDF)-1α (R = 0.29, P = 0.034). Percentage of uncovered struts was higher in the EES group (14.4 ± 17.3%), compared with the BMS (0.7 ± 1.3, P < 0.01) and ZES (0.4 ± 0.5, P < 0.01) groups. The change in CD34 + CD133 + CD45low cells showed positive correlation with OCT-quantified mean neointimal area (R = 0.48, P < 0.01). Finally, circulating mononuclear cells obtained from 5 healthy volunteers were isolated to determine the effect of sirolimus, zotarolimus and everolimus on vascular cell differentiation. The differentiation of mononuclear cells into endothelial-like cells was dose-dependently suppressed by sirolimus, zotarolimus, and everolimus. CONCLUSIONS: Mobilization of progenitor cells was suppressed, and differentiation of mononuclear cells into endothelial-like cells was inhibited, in association with increased number of uncovered stent struts, even after second generation drug-eluting stenting. These data suggest that new approaches are necessary to enhance stent healing.

The different features of angiographic peri-stent contrast staining after implantation of sirolimus-eluting stents.

If we had a case with angiographic peri-stent contrast staining(PSS)s after the first-generation sirolimus-eluting stent, we need a further observation using coronary imaging modalities to evaluate the risk of very late stent thrombosis due to PSSs and to continue or to resume the dual antiplatelet therapy if necessary.

Which has the stronger impact on coronary artery disease, eicosapentaenoic acid or docosahexaenoic acid?

It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27±0.19 vs. 0.44±0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78±0.27 vs. 0.79±0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00-0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98-1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD.

Clinical features of spontaneous coronary artery dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an infrequent but increasingly recognized cause of acute coronary syndrome (ACS). Previous case reports demonstrated that this condition occurs in young females with a low atherosclerotic risk factor burden and may be associated with peripartum or postpartum status. The purpose of this study was to review patients with angiographically confirmed SCAD to provide additional insight into the diagnosis and treatment of this condition. METHODS AND RESULTS: We screened medical records of all patients with ACS from March 2001 to November 2012. From these patients, we selected patients with SCAD based on coronary angiographic review. Of a total of 1159 ACS patients, 10 patients (0.86%) were diagnosed with SCAD. The mean age of these patients was 46 years, and 9 were female. ST-elevation myocardial infarction (STEMI) was observed in 9 patients and 5 patients had no coronary risk factors. One patient was treated conservatively with medication alone and 3 patients underwent thrombectomy. Balloon angioplasty was performed in 2 patients, and a bare metal stent was placed in one of these patients later. In the remaining 4 patients, bare metal stents were implanted emergently. Follow-up coronary angiography showed appropriate repair of SCAD in all 10 patients. CONCLUSIONS: In our experience, the clinical features of SCAD appear to be similar to those reported previously. SCAD appears to be rare, but it should be considered in ACS patients, especially in younger females.