Hiroshi Tsuneyoshi

Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats

Human chymase activates not only angiotensin II but also transforming growth factor-β, a major stimulator of myocardial fibrosis, while rat chymase activates transforming growth factor-β, but not angiotensin II. To clarify the role of chymase-dependent transforming growth factor-β activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats. Myocardial infarction was induced by ligation of the left anterior descending coronary artery. One day after the ligation, rats were randomized into 2 groups: 1) a chymase-treated group that received 10 mg/kg per day of the chymase inhibitor NK3201 orally for 4 weeks; and 2) a vehicle group of non-treated rats with myocardial infarction. We also included a control group who underwent sham-operation and no treatment. Four weeks after ligation, echocardiography revealed that chymase inhibitor treatment reduced the akinetic area and increased fractional area change but did not significantly change left ventricular end-diastolic area. Chymase inhibition significantly reduced left ventricular end-diastolic pressure, increased the maximal end-systolic pressure–volume relationship and decreased the time constant of left ventricular relaxation. Chymase activity in the non-infarcted myocardium was significantly increased in the vehicle group, but it was significantly reduced by chymase inhibitor treatment. The fibrotic area in the cardiac tissues and the mRNA levels of collagen I and collagen III were also significantly lower in the chymase inhibitor-treated group than in the vehicle group. Therefore, the pathway forming chymase-dependent transforming growth factor-β may play an important role in myocardial fibrosis and cardiac dysfunction rather than left ventricular dilatation after myocardial infarction.

Multislice Computed Tomography Accurately Quantifies Left Atrial Size and Function After the MAZE Procedure

Background— Although the MAZE procedure allows for the recovery of sinus rhythm and left atrial (LA) mechanical function in the great majority of patients with chronic atrial fibrillation (AF), the effects of MAZE on the precise LA geometry and wall motion remain to be elucidated. We hypothesized that LA size and mechanical function in patients with chronic AF and mitral valvular disease are well restored after MAZE. Methods and Results— We studied 14 patients (MAZE group: mean±SD age, 63.9±8.6 years; 8 men and 6 women) who underwent MAZE for chronic AF and mitral valve surgery and 10 patients with sinus rhythm (coronary artery bypass graft [CABG] group: age, 70.0±7.9 years; 5 men and 5 women) who underwent CABG at Takeda Hospital between February 2002 and September 2005. MAZE was conducted by the endocardial application of radiofrequency ablation with a temperature-controlled multipolar radiofrequency catheter. LA volume and booster function were quantitatively evaluated by multislice computed tomography at 17.9±10.0 months (MAZE group) and 15.3±13.6 months (CABG group) postoperatively. All patients with MAZE were free of AF and other atrial arrhythmias during the follow-up period. In the CABG group, LA maximal and minimal volumes and ejection fraction were 109±12 mL, 82±11 mL, and 26±10%, respectively. In the MAZE group, LA maximal volume was 139±17 mL (P=0.187 versus CABG), and LA minimal volume was 121±16 mL (P=0.082 versus CABG), with an ejection fraction of 15±7% (P=0.004 versus CABG). In both groups, all parts of the LA wall contracted toward the geometric center of the LA. The extent of wall motion was significantly worse in the MAZE group compared with the CABG group. In both groups, LA booster function was inversely correlated with LA maximal volume. Conclusions— MAZE with radiofrequency ablation is safe and effective for the restoration of sinus rhythm in patients with chronic AF and mitral valve disease. However, chronic AF associated with mitral valve disease deteriorates LA mechanical function diffusely throughout the LA wall. Further studies with the use of multislice computed tomography are needed to sequentially evaluate LA function after MAZE in patients with and without mitral valve surgery.

Atrial Natriuretic Peptide Helps Prevent Late Remodeling After Left Ventricular Aneurysm Repair

Background—Left ventricular aneurysm repair (LVR) reduces LV wall stress and improves LV function. However, as we reported previously, the initial improvement of LVR was short-term because of LV remodeling but could be maintained longer with postoperative use of an angiotensin-converting enzyme (ACE) inhibitor. Atrial natriuretic peptide (ANP) has been used to treat patients with heart failure by natriuretic and vasodilatory actions. Recent reports have suggested that ANP inhibits the rennin-angiotensin system. In this study, the effects of ANP after LVR were evaluated. Methods and Results—Rats that had an LV aneurysm 4 weeks after left anterior descending artery ligation underwent LVR by plicating the LV aneurysm and were randomized into 2 groups: LVR+A group was intravenously administrated with 10 &mgr;g/h of carperitide, recombinant &agr;-hANP, by osmotic-pump for 4 weeks, and the LVR group was given normal saline. Echocardiography revealed better LV remodeling and function in LVR+A group than in LVR group. Four weeks after LVR, left ventricular end diastolic pressure (LVEDP) and Tau were significantly lower in LVR+A group (LVEDP: 10±4 in LVR+A group versus 18±6 mm Hg in LVR group, Tau: 13±2 versus 17±2ms). End-systolic elastance (Ees) was higher in LVR+A group (Ees: 0.34±0.2 versus 0.19±0.11 mm Hg/&mgr;L). The levels of myocardial ACE activity in LVR+A group was significantly lower than in LVR group. The mRNA expressions of brain natriuretic peptide and transforming growth factor &bgr;1 inducing fibrosis significantly decreased in LV myocardium in LVR+A group. Histologically, myocardial fibrosis was significantly reduced in LVR+A group. Conclusions—Intravenous administration of ANP had beneficial effects on LV remodeling, function, and fibrosis after LVR. ANP could be a useful intravenous infusion drug for postoperative management after LV repair surgery.

Does the β2-Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading?

Objective—Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a β2-adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, β2-AR stimulation is reported to improve Ca2+ handling and contribute to antiapoptosis. However, there is little information on the effects of clenbuterol during LV unloading. Methods and Results—We investigated LV atrophy and function after LV unloading produced by heterotopic heart transplantation in isogenic rats. After transplantation, rats were randomized to 1o f 2 groups (n=10 each). The clenbuterol group received 2 mg·kg−1·d−1 of the drug for 2 weeks; the control group received normal saline. The weight of unloaded control hearts was 48% less than that of host hearts after 2 weeks of unloading. Clenbuterol significantly increased the weight of the host hearts but did not prevent unloading-induced LV atrophy. Papillary muscles were isolated and stimulated, and there was no difference in developed tension between the 2 groups. However, the inotropic response to the β-AR agonist isoproterenol significantly improved in the clenbuterol group. The mRNA expression of myocardial sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) and fetal gene shift (myosin heavy chain [MHC] mRNA isozyme) was also significantly improved by clenbuterol treatment. There was no difference in β1-AR mRNA expression between the 2 groups. In contrast, β2-AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate β2-ARs. In the evaluation of apoptosis, mRNA expression of caspase-3, which is the central pathway for apoptosis, tended to be better in the clenbuterol group. Conclusions—During complete LV unloading, clenbuterol did not prevent myocardial atrophy but improved gene expression (SERCA2a, β-MHC) and β-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of β2-ARs.

Accuracy of Aortic Annulus Diameter Measurement: Comparison of Multi-Detector CT, Two- and Three-Dimensional Echocardiography.

Accurate preprocedural quantification of the aortic annulus diameter is crucial for the operative success of the aortic valve surgery and especially transcatheter aortic valve replacement (TAVR). We conducted a prospective study to compare the accuracy of preoperative aortic annulus measurements using different imaging methods and direct measurements for aortic valve surgery.

Effects of two inhibitors of renin-angiotensin system on attenuation of postoperative remodeling after left ventricular aneurysm repair in rats.

Abstract We reported that the initial beneficial effects of left ventricular repair (LVR) surgery for LV aneurysm after myocardial infarction (MI) did not persist because of postoperative LV remodeling in a rat model. The renin‐angiotensin system (RAS) plays an important role in postinfarction LV remodeling. Inhibition of RAS may be useful to preserve LV function by preventing remodeling. We studied the effects of two inhibitors of RAS in an attempt to improve the operative results of LVR. LV aneurysms were created in rats after ligating the left anterior descending artery. These rats underwent LVR by plicating the LV aneurysm and were treated by three methods: no treatment, treatment with angiotensin‐converting enzyme inhibitor (ACE‐I) (lisinopril 10 mg/kg per day), and treatment with angiotensin II receptor blocker (ARB) (candesartan 5 mg/kg per day). One week after LVR, echocardiography revealed smaller LV size and better LV motion than before surgery. Four weeks after LVR, LV size returned to the preoperative value in the untreated group, but not as much in the treated groups. Cardiac catheterization revealed lower LV end‐diastolic pressure and higher E‐max in the treated groups. There was no difference between ACE‐I and ARB groups except for systolic blood pressure. LVR decreased LV size and improved systolic function only in the early phase. Adjuvant therapy of ACE‐I or ARB‐attenuated LV remodeling and maintained LV function at the same level after LVR. This probably indicates that tissue RAS is associated with postoperative remodeling. Concomitant use of RAS inhibitors may make LVR a longer‐lasting procedure for LV aneurysm. (J CARD SURG 2003;18 (Suppl 2):S61‐S68)

Fate of uncomplicated acute type B aortic dissection and impact of concurrent aortic dilatation on remote aortic events

Objective: This study aimed to describe the reliable prognostic factors of mortality and subsequent aortic events during the follow‐up of uncomplicated type B acute aortic dissection. Methods: From January 2004 to December 2014, 255 patients with uncomplicated type B acute aortic dissection were admitted to our hospital. Cox proportional hazards analysis was performed to identify risk factors for all‐cause mortality, aorta‐related mortality, and aortic events. Results: In‐hospital mortality was observed in 7 patients (2.7%). The rates of 5‐year freedom from all‐cause mortality, aorta‐related mortality, and aortic events were 79.4% ± 2.9%, 93.3% ± 2.0%, and 71.7% ± 3.4%, respectively. The rate of 5‐year freedom from aortic events was significantly lower among those with a patent false lumen (P = .006). Age and descending aorta diameter were independent risk factors of all‐cause and aorta‐related mortality (hazard ratio [HR], 1.08 and 1.13; 95% confidence interval [CI], 1.04‐1.10 and 1.03‐1.24; P = .0001 and .007, respectively). Independent risk factors for aortic events were descending aorta diameter, false lumen thickness, and dilatation of abdominal aorta (HR, 1.06; 95% CI, 1.02‐1.12; P = .006; HR, 1.07; 95% CI, 1.04‐1.11; P = .00002; HR, 2.01; CI, 1.20‐3.38; P = .008). Conclusions: In uncomplicated type B acute aortic dissection, the age and dilatation of the thoracic aorta were associated with a higher risk of death, whereas false lumen thickness and concurrent abdominal aortic dilatation augment the risk for aortic events.

Coronary artery bypass surgery is superior to second generation drug-eluting stents in three-vessel coronary artery disease: a propensity score matched analysis

OBJECTIVES Compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) appears to be a promising revascularization strategy for multivessel coronary disease. Trials comparing these treatments have not used second‐generation drug‐eluting stents (2nd DES). We conducted a retrospective evaluation of both treatments using a propensity score‐matched analysis (PSMA). METHODS A total of 537 patients with three‐vessel with/without left‐main‐trunk coronary artery disease underwent CABG (n = 239) or primary PCI using 2nd DES (298) at a single institution. PSMA resulted in 168 matched pairs. For both treatments, Kaplan‐Meier analysis and Cox regression were used to compare all‐cause mortality, cardiac death, myocardial infarction (MI), stroke rates and target‐vessel revascularization (TVR). RESULTS The CABG group included sicker patients with renal dysfunction, peripheral vascular disease, low ejection fraction and current smokers than those in the PCI group. After PSMA, both groups were well matched in all parameters. Mean follow‐up (months) was 32 in CABG and 35 in PCI. In the unmatched patient population, there was no difference in the incidence of all‐cause death, cardiac death, MI, or stroke but the incidence of TVR was significantly higher in the PCI group [hazard ratio (HR) 4.63; 95% confidence interval (95% CI) 2.43‐8.82; P < 0.001] and, after PSMA, the incidence of all‐cause death (HR 2.71; 95% CI 1.14‐6.46; P = 0.019) and TVR (HR 9.0; 95% CI 2.73‐29.67; P < 0.001) was significantly higher in the PCI group than in the CABG group. CONCLUSIONS In patients with three‐vessel coronary artery disease, CABG is associated with better survival and less revascularization than PCI using 2nd DES at mid‐term results.

Physician Modification to Shorten a TAG Thoracic Endoprosthesis for Treatment of a Pseudoaneurysm in the Ascending Aorta

Purpose:To report initial use of a physician-modified Gore TAG Thoracic Endoprosthesis for the treatment of pseudoaneurysm in the ascending aorta. Technique: This technique is demonstrated in a 42-year-old man with a pseudoaneurysm of the ascending aorta after a Bentall operation. The treatable length extending from the sinotubular junction to the anastomotic aneurysm edge was only 5 cm. A 45×100-mm TAG endograft for the pseudoaneurysm was modified on a back table to shorten its length. The delivery shaft was incised, and the 2 threads that fasten the top and bottom portions of the stent-graft to the sleeve were pulled out. The unfolded half of the stent-graft was cut back after pulling out the strand for the back half. Next, this custom-made graft was deployed via a transcarotid approach with cardiopulmonary bypass; no endoleak was observed. Postoperative computed tomography showed a minute type Ib endoleak. The patient was doing well at postoperative month 6. Conclusion: Physician modification of a TAG endograft facilitated effective management of this ascending aortic lesion by shortening the length of aortic coverage.

Update on mitral valve surgery.

Recently, the outcome for patients with mitral valve disease has significantly improved. This may be due to concomitant advances in many fields. In particular, the development of surgical techniques has contributed to this improvement, and many surgical techniques and topics are introduced in this article. After the evaluation of results in mitral valve surgery and exploration of the relationship between the mitral valve and the mitral subvalvular apparatus, it is currently accepted that mitral valve repair is superior to replacement and that replacement with preservation of the mitral subvalvular apparatus is preferable to replacement alone. Another current topic is mitral repair in dilated cardiomyopathy. Mitral regurgitation is a known complication of end-stage cardiomyopathy and is associated with a poor prognosis because of progressive mitral annular dilatation. Recently, to solve this problem, undersized mitral annuloplasty or cardiomyoplasty has been advocated. In the future, mitral valve surgery may be performed off-pump or by a percutaneous approach. Several groups are investigating the use of new devices and new techniques that avoid cardiopulmonary bypass in experimental studies. In this article, we review current topics and discuss our experiences in mitral valve surgery.