[Show abstract][Hide abstract] ABSTRACT: Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistent arterial hypertension; however, structured pre-clinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the pre-clinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria toward standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, periarterial nerves, and associated periadventitial tissues. The pre-clinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (e.g., necrosis) of the periarterial tissues and its relationship (i.e., location and distance) and the effect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (e.g., tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (i.e., on the arterial wall) as well as tissues at a distance (e.g., soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable us to proceed to optimize the development and assessment of these emerging technologies.
[Show abstract][Hide abstract] ABSTRACT: Background
Although renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly understood.
The aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries.
Bilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti–tyrosine hydroxylase and anti–calcitonin gene–related peptide.
A total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene–related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients.
The density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures.
Journal of the American College of Cardiology 08/2014; 64(7):635–643. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months.
[Show abstract][Hide abstract] ABSTRACT: Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.
The Journal of cardiovascular surgery 06/2014; 55(3):307-23. · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The perioperative risk of non-cardiac surgery (NCS) in the patients on antiplatelet therapy after percutaneous coronary intervention (PCI) remains unclear.
This study was a retrospective and single center study. Between January 2008 and December 2011, 198 patients who had already received PCI underwent NCS in our hospital. Among them, 63 patients underwent surgery on dual antiplatelet therapy (DAPT group) and 88 patients on single antiplatelet therapy (SAPT group). We compared bleeding events and cardiovascular events during perioperative period between the two groups.
There was no stent thrombosis in either group. The bleeding events in the DAPT group were significantly higher than that in the SAPT group (9.5% vs 2.3%, p=0.049). There was no difference in events between with or without heparin-bridge in the SAPT group.
The frequency of bleeding events was higher in the DAPT group. Both bleeding and cardiovascular events with aspirin alone were low in our study. It may be safe to undergo NCS with SAPT after PCI.
Journal of Cardiology 05/2014; · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute coronary syndrome is the leading cause of death worldwide and plaque rupture is the most common underlying mechanism of coronary thrombosis. During the last 2 decades the understanding of atherosclerotic plaque progression advanced dramatically and pathology studies provided fundamental insights of underlying plaque morphology, which paved the way for invasive imaging modalities, which bring a new area of atherosclerotic plaque characterization in vivo. The development of intravascular ultrasound (IVUS) allowed the field to evaluate the principles of vascular anatomy, which is often underestimated by coronary angiography. Furthermore, IVUS image technologies were developed to obtain improved characterization of plaque composition. However, since spatial resolution of IVUS is insufficient to distinguish details of plaque morphology, a broad adoption of this technology in clinical practice was missing. Optical coherence tomography is a light-based imaging modality with higher spatial resolution compared to IVUS, which enables the assessment of vascular anatomy with great detail.
[Show abstract][Hide abstract] ABSTRACT: Dipeptidyl peptidase-4 (DPP4) is an integral membrane glycoprotein that modulates the pathological state of diabetes mellitus (DM), and DPP4 inhibitors are a new class of anti-type-2 DM drugs. Recent preclinical studies have associated DPP4 inhibition with improved myocardial systolic and diastolic function. Based on preclinical findings, we investigated associations between the administration of DPP4 inhibitors and cardiac function after acute myocardial infarction (AMI) in a clinical setting. We enrolled 34 patients with diabetes who were treated for acute myocardial infarction at our hospital between January 2010 and December 2012. We retrospectively compared changes in cardiac parameters determined by trans-thoracic echocardiography between patients treated with (DPP4-I group; n = 13) or without (non-DPP4-I group; n = 21) a DPP4 inhibitor during follow-up. The values of E/e' and of e'/a' significantly decreased and increased, respectively, in the DPP4-I, compared with the non-DPP4-I group (-2.53 ± 5.53 vs. 2.58 ± 5.68, p = 0.038 and 0.08 ± 0.23 vs. -0.12 ± 0.21, p = 0.036, respectively). We concluded that DPP4 inhibitors could improve E/e' and e'/a' in patients with DM and AMI and thus might be effective for treating left ventricular diastolic failure.
[Show abstract][Hide abstract] ABSTRACT: We interrogated our autopsy registry to investigate the histopathologic features of early stent thrombosis (ST) in patients presenting with acute coronary syndrome (ACS).
The occurrence of early ST following percutaneous coronary intervention (PCI) for ACS remains a clinical problem despite advances in stent technology in both bare metal and drug-eluting stents.
- Sixty-seven stented coronary lesions from 59 patients who presented with ACS and died within 30 days were included. Stented segments were cross-sectioned at 3-4 mm intervals, evaluated by light microscopy, and morphometric analysis was performed.
Early ST (<30 days of PCI) was identified in 34 (58%) of the 59 patients. Early ST was dependent on the underlying plaque morphology and underlying thrombus burden: presence of necrotic core prolapse was more frequent in thrombosed lesions compared with patent lesions (70% vs. 43%, p=0.045) and maximum underlying thrombus thickness was significantly greater in thrombosed versus patent lesions. All 3 patients with false lumen stenting had ST. Detailed analysis revealed that the percentage of necrotic core prolapse, medial tear, or incomplete apposition was significantly greater in the early ST compared with patent group (28% vs.11%, p<0.001, 27% vs. 15% p=0.004, and 34% vs. 18% p =0.008, respectively). Multivariate analysis revealed that maximum depth of strut penetration, % strut with medial tear, and % struts with incomplete apposition were the primary indicators of early ST.
- The current autopsy study highlights the impact of thrombus burden and suboptimal stent implantation in unstable lesions as a trigger of early ST, suggesting that improvement in implantation technique and refinement of stent design may improve clinical outcomes of ACS patients.
Journal of the American College of Cardiology 04/2014; · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postprandial hyperglycemia is a risk factor for cardiovascular disease and mortality. Serum 1,5-anhydroglucitol (1,5-AG) level is an useful clinical marker of glucose metabolism which reflects postprandial hyperglycemia more robustly compared to hemoglobin A1c (HbA1c). Relationship between serum 1,5-AG level and cardiovascular disease has been reported; however, comparison between HbA1c and 1,5-AG as markers of cardiovascular disease was not performed. We included 227 consecutive patients who underwent coronary angiography meeting the following inclusion criteria: (1) patients who had no history of coronary artery disease (CAD); (2) patients without acute coronary syndrome; (3) patients without poorly controlled diabetes mellitus; (4) patients without anemia, liver dysfunction, acute, and chronic renal failure and malnutrition; and (5) patients without adhibition of acarbose or Chinese herbal medicine. We measured HbA1c, glycoalbumin, and 1,5-AG. Serum 1,5-AG was significantly lower in patients with CAD (16.6 ± 8.50 vs. 21.1 ± 7.97 μg/ml, P < 0.001). Multivariable logistic regression analysis showed decrease in serum 1,5-AG was independently associated with the presence of denovo CAD (0.93, 95 % CI 0.88-0.98, P = 0.006). Serum 1,5-AG was also independently associated with the presence of denovo CAD in patients without diabetes mellitus (0.94, 95 % CI 0.88-0.99, P = 0.046). In conclusion, lower serum 1,5-AG was associated with the presence of denovo CAD. Serum 1,5-AG may identify high cardiovascular risk patients for denovo CAD in both diabetic and non-diabetic patients.
[Show abstract][Hide abstract] ABSTRACT: Coronary artery calcification is a well-established predictor of future cardiac events; however, it is not a predictor of unstable plaque. The intimal calcification of the atherosclerotic plaques may begin with smooth muscle cell apoptosis and release of matrix vesicles and is almost always seen microscopically in pathological intimal thickening, which appears as microcalcification (≥0.5 μm, typically <15 μm in diameter). Calcification increases with macrophage infiltration into the lipid pool in early fibroatheroma where they undergo apoptosis and release matrix vesicles. The confluence of calcified areas involves extracellular matrix and the necrotic core, which can be identified by radiography as speckled (≤2 mm) or fragmented (>2, <5 mm) calcification. The calcification in thin-cap fibroatheromas and plaque rupture is generally less than what is observed in stable plaques and is usually speckled or fragmented. Fragmented calcification spreads into the surrounding collagen-rich matrix forming calcified sheets, the hallmarks of fibrocalcific plaques. The calcified sheets may break into nodules with fibrin deposition, and when accompanied by luminal protrusion, it is associated with thrombosis. Calcification is highest in fibrocalcific plaques followed by healed plaque rupture and is the least in erosion and pathological intimal thickening. The extent of calcification is greater in men than in women especially in the premenopausal period and is also greater in whites compared with blacks. The mechanisms of intimal calcification remain poorly understood in man. Calcification often occurs in the presence of apoptosis of smooth muscle cells and macrophages with matrix vesicles accompanied by expression of osteogenic markers within the vessel wall.
Arteriosclerosis Thrombosis and Vascular Biology 02/2014; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Left atrial appendage (LAA) electrical isolation is reported to improve atrial fibrillation ablation outcomes. However, loss of mechanical function may increase thromboembolic risk.
To evaluate the feasibility and safety of LAA occlusion following electrical isolation in a canine model.
Nine canines underwent LAA isolation with irrigated radiofrequency ablation following pulmonary vein (PV) isolation. Entrance and exit block were confirmed with intravenous adenosine after 30min. The LAA was then occluded with a Watchman device. Device position was assessed at 10-days by transthoracic echocardiography (TTE). At 45-days, LAA isolation was assessed epicardially. Hearts were then examined macroscopically and histologically.
All 36 PVs and 8/9 (89%) LAAs were electrically isolated. Acute LAA reconnection occurred in 4/8 (50%). All were re-isolated. Mean ablation time was 51±19 min, including 24±18 min for LAA isolation. LAA occlusion was successful in all cases. One animal died at 36hrs post-procedure from a primary intracranial bleed due to anticoagulant hypersensitivity. TTE at 10-days confirmed satisfactory device positions and no pericardial effusion. At 45-days, 7/8 (88%) had persistent LAA electrical isolation. All devices were stable without evidence of erosion. Microscopy revealed complete device-tissue apposition and a mature connective tissue layer overlying the device surface in all cases.
LAA electrical isolation and mechanical occlusion can be performed concomitantly in this animal model, with no displacement or mechanical erosion of the appendage at 45-days.
This technique can potentially improve success rates and obviate the need for chronic anticoagulation. Future studies should address efficacy, safety and feasibility in humans.
[Show abstract][Hide abstract] ABSTRACT: Since drug-eluting stents (DESs) appeared in Japan, coronary artery bypass grafting (CABG) has been indicated for more severe lesions. To understand the implications of this trend, we compared SYNTAX scores in two groups of patients treated with CABG before and after DESs approval.
Consecutive CABG patients during January 2001-July 2003 (pre-DES era patients, n = 160) and January 2008-July 2010 (DES era patients, n = 103) were included. The SYNTAX scores of both groups were compared and a cardiologist retrospectively re-evaluated coronary angiograms to determine whether CABG or percutaneous coronary intervention (PCI) would be recommended under current standards.
SYNTAX scores were significantly higher in DES era group compared with pre-DES era group (33.3 ± 10.6 vs. 28.1 ± 10.6, p < 0.01). Percutaneous coronary intervention would be the preferred treatment option in 66 (41 %) of pre-DES patients, whose SYNTAX scores were significantly lower than those of patients who were considered good candidates for CABG (21.9 ± 9.3 vs. 32.5 ± 9.1, p < 0.01).
Although CABG is now being performed in intermediate-to-highly complex cases, DES era outcomes, including operative mortality and early graft failure, have not worsened in comparison to the pre-DES era.
General Thoracic and Cardiovascular Surgery 12/2013;
[Show abstract][Hide abstract] ABSTRACT: Clinical trials have demonstrated that second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to first-generation paclitaxel-eluting stent (PES) and is non-inferior or superior to sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from SES and PES, since the pathology of CoCr-EES has not been described in humans.
A total of 204 lesions (SES=73, PES=85, CoCr-EES=46) from 149 autopsy cases with duration of implant >30 days and ≤3 years were pathologically analyzed, where comparison of vascular responses was corrected for duration of implant. The observed frequency of late and very late stent thrombosis (LST/VLST) was less in CoCr-EES (4%) versus SES (21%, p=0.029) and PES (26%, p=0.008). Neointimal thickness was comparable among the groups, while the percent uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%, p<0.0005) and PES (18.7%, p<0.0005). CoCr-EES showed less inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%, SES=35%, PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%, SES=40%, PES=19%; p=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%, SES=5.5%, PES=1.2%).
CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less LST/VLST as compared to SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathologic events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to investigate chronic total occlusion (CTO) in human coronary arteries to clarify the difference between CTO with prior coronary artery bypass graft (CABG) and those without prior CABG.
A total of 95 CTO lesions from 82 patients (61.6 ± 14.0 years, male 87.8%) were divided into the following three groups: CTO with CABG (n = 34) (CTO+CABG), CTO without CABG-of long-duration (n = 49) (LD-CTO) and short-duration (n = 12) (SD-CTO). A histopathological comparison of the plaque characteristics of CTO, proximal and distal lumen morphology, and negative remodelling between groups was performed. A total of 1127 sections were evaluated. Differences in plaque characteristics were observed between groups as follows: necrotic core area was highest in SD-CTO (18.6%) (LD-CTO: 7.8%; CTO+CABG: 4.5%; P = 0.02); calcified area was greatest in CTO+CABG (29.2%) (LD-CTO: 16.8%; SD-CTO: 12.1%; P = 0.009); and negative remodelling was least in SD-CTO [remodelling index (RI) 0.86] [CTO+CABG (RI): 0.72 and LD-CTO (RI): 0.68; P < 0.001]. Approximately 50% of proximal lumens showed characteristics of abrupt closure, whereas the majority of distal lumen patterns were tapered (79%) (P < 0.0001).
These pathological differences in calcification, negative remodelling, and presence of necrotic core along with proximal and distal tapering, which has been associated with greater success, help explain the differences in success rates of percutaneous coronary intervention in CTO patients with and without CABG.
European Heart Journal 10/2013; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The circumstances surrounding infective endocarditis (IE) are under constant change due to an increase in drug-resistant organisms, a decrease in rheumatic valve disease, progress in surgical treatment, and aging society. The purpose of this study was to compare clinical features of IE between the 1990s and 2000s and to elucidate the determinants of death or clinical event.
All hospital admission records between January 1990 and December 2009 were retrospectively analyzed. The definition of IE was based on modified Duke criteria. Clinical presentation, blood culture, laboratory results, and echocardiography findings were compared between the 1990s and 2000s.
There were 112 patients with definite or probable IE according to modified Duke criteria. The most frequent organism causing IE was Streptococcus viridians both in the 1990s and 2000s. The determinants of in-hospital death were hemodialysis and congestive heart failure. The in-hospital mortality of IE was 5.4% in the 1990s and 13.3% in the 2000s. Composite events of in-hospital death and central nervous system disorders were significantly higher in the 2000s compared with the 1990s.
The most frequent causative organism of IE was S. viridians, both in the 1990s and 2000s. Independent predictors of in-hospital mortality in IE were hemodialysis and congestive heart failure.
Journal of Cardiology 07/2013; · 2.30 Impact Factor