Hideo Kanemitsu

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.

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.

Left ventricle restoration in patients with non-ischemic dilated cardiomyopathy: risk factors and predictors of outcome and change of mid-term ventricular function

OBJECTIVE The partial left ventriculectomy (PLV) for end-stage dilated cardiomyopathy (DCM) which worked in some patients has been reported, although the hospital mortality is high. To reduce hospital mortality, we selected operative procedures of left ventricular (LV) restoration to improve the operative results. We analyzed the risk factors and predictors of outcome, and the mid-term changes of the LV function were determined. PATIENTS AND METHODS Between December 1996 and September 2000, 74 patients with non-ischemic DCM received LV restoration. The age ranged from 14 to 76 years (mean, 49.0+/-14.0 years), and there were 63 men and 11 women. The etiology of the DCM was idiopathic DCM in 49 patients, and dilated hypertrophic cardiomyopathy in seven patients and others in 18. The preoperative New York Heart Association (NYHA) functional class was 29 in class III and 45 in class IV, in which 32 patients depended on inotropic support. PLV or septal anterior ventricular exclusion (SAVE) was selected depending on the akinetic lesion of the LV based on the intraoperative echo-test. Fifty-six patients received elective operations, and emergency operations were performed in 18 patients. The risk factors and predictors of outcome were analyzed in 74 patients, and in 35 patients who survived more than 1 year after receiving LV restoration, the mid-term cardiac function was examined by cardiac echogram and catheterization. RESULTS PLV was performed in 62 patients and SAVE in 12 patients. Concomitant mitral surgery was performed in 66 patients (89%) and tricuspid annuloplasty in 42 patients (57%). There were 15 hospital deaths and 13 patients died after discharge from the hospital (cardiac deaths in nine and non-cardiac deaths in four). In the 46 late survivors, the NYHA class was I or II in 42 patients and III in four patients. Selection of the procedure of LV restoration (P<0.01), elective operation (P<0.05), and the preoperative volume of LV (endodiastolic volume index of <180 ml/m(2); P<0.05) were risk factors and predictors influencing hospital and late death. After the operation, the LV function improved significantly and the improvement was maintained at the mid-term period; the LV ejection fraction was 31.8+/-7.9% (P<0.01) at 1 year from 23.0+/-7.3% preoperatively, left ventricular diastolic diameter was 62.8+/-10.9 (P<0.01) from 81.7+/-8.2 mm and the LV endosystolic volume index was 88.5+/-45.8 (P<0.05) from 162.6+/-41.6 ml/m(2). CONCLUSIONS The operative results improved with the selection of the procedures, with elective operation, and mitral plasty for less cardiac dilatation. The mid-term results of clinical status and LV function showed the effectiveness of the operation.

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.

Spironolactone alleviates late cardiac remodeling after left ventricular restoration surgery

OBJECTIVE Although left ventricular restoration is effective for treating ischemic cardiomyopathy caused by left ventricular remodeling and redilation, the initial improvement in left ventricular function is not always sustained. We have reported that the inhibition of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is effective in preventing late remodeling after left ventricular restoration. However, the effects of spironolactone--an aldosterone blocker--after left ventricular restoration have not been elucidated. METHODS Myocardial infarction was induced by ligating the left anterior descending artery. The rats developed left ventricular aneurysms and underwent left ventricular restoration by the plication of the left ventricular aneurysm 4 weeks after the ligation. Thereafter, the rats were randomized into a left ventricular restoration (vehicle) group and left ventricular restoration with spironolactone (100 mg/kg/d, by mouth) group. RESULTS Echocardiography revealed that in the left ventricular restoration with spironolactone group, late cardiac redilation was significantly attenuated (left ventricular end-diastolic area: 0.51 +/- 0.03 cm(2) vs 0.63 +/- 0.03 cm(2), P < .05) and late left ventricular function was preserved (fractional area change: 48.8% +/- 3.0% vs 35.8% +/- 2.4%, P < .01). Hemodynamically, rats in the left ventricular restoration with spironolactone group exhibited improved systolic function (maximal end-systolic pressure-volume relationship: 0.38 +/- 0.03 mm Hg/microL vs 0.11 +/- 0.04 mm Hg/microL, P < .01) and diastolic function (tau: 18.5 +/- 1.5 sec vs 23.1 +/- 1.4 sec, P < .05) than those in the LVR group. Histologically, interstitial fibrosis in the remote area was significantly reduced (5.6% +/- 1.3% vs 12% +/- 1.0%, P < .01), and fibrosis around the pledgets (near area) was also attenuated in the left ventricular restoration with spironolactone group. The myocardial messenger ribonucleic acid expressions of transforming growth factor-beta1 and brain natriuretic peptide measured using the real-time polymerase chain reaction were lower in the left ventricular restoration with spironolactone group (transforming growth factor-beta1: 0.13 +/- 0.02 vs 0.28 +/- 0.02, P < .01; brain natriuretic peptide: 0.99 +/- 0.14 vs 1.54 +/- 0.18, P < .05). The systemic blood pressure and heart rate did not differ between the 2 groups. CONCLUSION Spironolactone reduced the gene expression of transforming growth factor-beta1 and brain natriuretic peptide and alleviated not only cardiac redilation but also the deterioration of left ventricular function late after left ventricular restoration without inducing hypotension, a major side effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blocker. Spironolactone is a promising therapeutic option for alleviating remodeling after left ventricular restoration.

The Impact of Preoperative and Postoperative Pulmonary Hypertension on Long-Term Surgical Outcome after Mitral Valve Repair for Degenerative Mitral Regurgitation

PURPOSE The aim of this study is to elucidate the impact of preoperative and postoperative pulmonary hypertension (PH) on long-term clinical outcomes after mitral valve repair for degenerative mitral regurgitation. METHODS A total of 654 patients who underwent mitral valve repair for degenerative mitral regurgitation between 1991 and 2010 were retrospectively reviewed. Patients were divided into PH(+) group (137 patients) and PH(-) group (517 patients). Follow-up was complete in 99.0%. The median follow-up duration was 7.5 years. RESULTS Patients in PH(+) group were older, more symptomatic and had higher tricuspid regurgitation grade. Thirty-day mortality was not different between 2 groups (p = 0.975). Long-term survival rate was lower in PH(+) group; 10-year survival rate after the operation was 85.2% ± 4.0% in PH(+) group and 89.7% ± 1.8% in PH(-) group (Log-rank, p = 0.019). The incidence of late cardiac events were not different between groups, however, the recurrence of PH was more frequent in PH(+) group. The recurrence of PH had an adverse impact on survival rate, late cardiac events and symptoms. Univariate analysis showed age and preoperative tricuspid regurgitation grade were the predictors of PH recurrence. CONCLUSION Early surgical indication should be advocated for degenerative mitral regurgitation before the progression of pulmonary hypertension and tricuspid regurgitation.

Long-Term Outcomes of Tricuspid Annuloplasty for Functional Tricuspid Regurgitation Associated with Degenerative Mitral Regurgitation: Suture Annuloplasty Versus Ring Annuloplasty Using a Flexible Band

PURPOSE We investigated the long-term outcomes of suture/ring tricuspid valve annuloplasty for functional tricuspid regurgitation associated with degenerative mitral regurgitation. METHODS We retrospectively reviewed patients who underwent flexible ring tricuspid valve annuloplasty (n = 120) or suture tricuspid valve annuloplasty (n = 42) for functional tricuspid regurgitation concomitant with surgery for degenerative mitral regurgitation (mean follow-up duration, 5.3 ± 5.1 years). RESULTS The mean age of patients was 62.5 ± 13.1 years. Thirty-day mortality was zero in the suture group, and 0.8% in the ring group. Tricuspid regurgitation grade at discharge was lower in the ring group ( p = 0.002). No difference was observed between survival and freedom from major cardiac/cerebrovascular adverse events between the groups. However, freedom from ≥moderate tricuspid regurgitation was higher in the ring group (Log-rank p = 0.003). From univariate analysis, the risk factors for ≥moderate TR were suture annuloplasty and preoperative tricuspid regurgitation grade. No reoperation for recurrent tricuspid regurgitation occurred in either group because symptoms experienced by patients with recurrent tricuspid regurgitation were relatively insignificant. CONCLUSION Concomitant tricuspid annuloplasty using flexible bands offered improved durability than suture annuloplasty for preventing postoperative tricuspid regurgitation progression.

Impact of tricuspid regurgitation after redo valvular surgery on survival in patients with previous mitral valve replacement

OBJECTIVE The impact on survival of tricuspid regurgitation (TR) after redo valvular surgery in patients with previous mitral valve replacement (MVR) is unclear. METHODS We retrospectively analyzed 118 consecutive patients undergoing redo valvular surgery after MVR over a 20-year period. We determined the impact of TR after redo valvular surgery on survival and clinical factors that were associated with TR of 2+ or higher. The mean follow-up period was 7.1±6.5 years. RESULTS Overall hospital mortality was 8.5% (10 of 118). Logistic regression analysis revealed that cardiopulmonary bypass duration (odds ratio, 1.025; P=.0270) was an independent risk factor for hospital death. There were 25 late deaths. Survival after 5, 10, and 15 years was 77.5%±4.2%, 68.5%±5.1%, and 58.8%±6.3%, respectively. Multivariate Cox regression analysis showed that TR less than 2+ at discharge was a predictor of late survival (hazard ratio, 0.043; P<.0382), whereas age, female sex, left ventricular end-diastolic dimension, and cardiopulmonary bypass duration were predictors of late death. Survival for patients with TR less than 2+ versus 2+ or higher after redo surgery were 91.4%±3.4% versus 59.5%±11.9% at 5 years and 81.1%±5.3% versus 52.1%±12.5% at 10 years, respectively (log-rank P=.0285). Logistic regression analysis indicated that preoperative TR (odds ratio, 3.718; P=.0044) and chronic obstructive pulmonary disease (odds ratio, 28.576; P=.0154) were independent risk factors for TR of 2+ or higher after redo surgery. CONCLUSIONS Survival in patients with TR of 2+ or higher after redo valvular surgery was poor. The results of this study suggest that it is important to maintain a postoperative TR less than 2+ to improve long-term survival.

Midterm Outcomes of Chordal Cutting in Combination with Downsized Ring Annuloplasty for Ischemic Mitral Regurgitation

PURPOSE We describe midterm outcomes after division of secondary chords (chordal cutting) combined with downsized ring annuloplasty for ischemic mitral regurgitation (IMR). METHODS We compared the clinical outcomes in patients who underwent chordal cutting with downsized ring annuloplasty (CC-group, n = 15) and those who underwent conventional ring annuloplasty only (Conventional-group, n = 35) for IMR. Follow-up was complete in all patients. The median follow-up time was 4.1 years. RESULTS Thirty-day mortality was 0% in CC-group and 20% in Conventional-group. The overall survival rate at 5-year was 80.8% ± 12.6% in CC-group and 61.7% ± 8.4% in Conventional-group (Log-rank, p = 0.145). The freedom rate from valve-related events at 5 year was 84.6% ± 10.0% in CC-group and 65.3% ± 10.1% in Conventional-group (Log-rank, p = 0.213). Recurrence of severe mitral regurgitation was revealed in 3 patients of CC-group. Preoperative tenting height was the significant predictor of mitral regurgitation recurrence. In CC-group, the mean left ventricular ejection fraction was 38.0% ± 14.0%, which was similar to the preoperative value of 40.0% ± 13.2% (p = 0.349). CONCLUSIONS Chordal cutting with downsized ring annuloplasty for IMR is a simple method and provides satisfactory early outcomes. However, it carries with high recurrence of MR especially for patients with high tenting height.

Prolonged Antegrade Cerebral Perfusion via Right Axillary Artery (≥60 min) Does Not Affect Early Outcomes in a Repair of Type A Acute Aortic Dissection

PURPOSE We aim to investigate whether the duration of antegrade cerebral perfusion (ACP) via right axillary artery with an 8-mm prosthetic graft affects early outcomes in a repair of type A acute aortic dissection (AAD). METHODS Over the 24 months from April 2010, a repair of AAD under ACP via the right axillary artery and mild hypothermic circulatory arrest (rectum temperature, 28-30°C) was performed in 34 patients. Mean age was 64.5 ± 13.7 years of age.Preoperative shock status was in three due to cardiac tamponade. Organ malperfusion occurred in 11 patients preoperatively. Mean follow-up period was 9.6 ± 8.4 months and follow-up rate was 100%. RESULTS Hospital mortality rate was 8.8%. No newly required hemodialysis and new onset of temporary or permanent neurologic deficits were present in survivors.There were no statistically significant differences of mortality rate, new onset of permanent or temporary neurologic deficits and distal organ dysfunction between ACP duration <60 min and ≥60 min. The 12-month survival was 84.4% ± 6.4%. And, freedom from aorta-related events at 12 and 18 months were 100% ± 0.0% and 88.9% ± 10.5%, respectively. CONCLUSIONS The duration of ACP via right axillary artery does not affect early outcomes following a repair of AAD.