BNP in mitral valve restrictive annuloplasty for ischemic mitral regurgitation

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BNP in mitral valve restrictive annuloplasty for ischemic mitral regurgitation Domenico Paparella a,⁎, Pietro Giorgio Malvindi a , Roberta Romito b , Massimo Iacoviello c , Giuseppe Visicchio a , Francesca Di Serio d , Stefano Favale c , Luigi de Luca Tupputi Schinosa a a

Division of Cardiac Surgery, Department of Emergency and Organ Transplant. University of Bari, Italy b Division of Emergency Cardiology, Policlinico Hospital, Bari, Italy c Division of Cardiology, Department of Emergency and Organ Transplant. University of Bari, Italy d Department of Clinical Pathology, Policlinico Hospital, Bari, Italy Received 20 January 2008; Accepted 26 April 2008 Available online 26 July 2008

Abstract Restrictive annuloplasty with undersized mitral rings is used to correct functional mitral regurgitation (MR) in patients with ischemic left ventricular dysfunction. Seventeen patients with severe coronary artery disease, previous myocardial infarction, moderate/severe functional MR and heart failure symptoms were prospectively evaluated. All patients received CABG associated with restrictive annuloplasty. Preoperatively and 6 months after the operation, clinical evaluation, echocardiography and blood sampling for BNP measurement were performed. Operative mortality occurred in 1 patient. MR degree decreased from 3.8 ± 0.3 to 1.0 ± 0.7 (p b 0.01), LVEF increased from 36 ± 11% to 43 ± 8% (p b 0.05), left ventricular end diastolic diameters changed from 54.7 ± 5.2 mm to 51.5 ± 5.8 mm (p = 0.51). NYHA class improved from 2.94 ± 1.02 to 1.21 ± 0.42 (p b 0.01). Mean plasma BNP levels decreased from 471 ± 248 pmol/l to 55.6 ± 52.8 pmol/l (p b 0.05). Restrictive mitral annuloplasty is a safe procedure to be associated to CABG operation. We demonstrated mid-term reduction of BNP plasma values after MR correction thus suggesting the effectiveness of surgical treatment in modifying natural history of the disease. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Congestive heart failure; Coronary disease; Myocardial infarction; Valve disease; Functional mitral regurgitation; Brain natriuretic peptide

Increasing degrees of mitral regurgitation (MR) developed after acute myocardial infarction (AMI) independently and unfavorably affects five years survival [1]. In both degenerative [2] and functional [3] MR, different degree of regurgitation and associated symptoms are correlated with increasing plasma levels of brain natriuretic peptide (BNP), a prognostic marker [4] generally considered to reflect neurohormonal activation. Presence of MR influences also short and long-term prognosis of patients requiring coronary artery revascularization [5]. Restrictive annuloplasty with undersized mitral rings has been recently suggested as a tool to correct functional mitral regurgitation in patients with ischemic LV dysfunction [6,7]. To evaluate the potential benefit of restrictive annuloplasty, plasma BNP levels were measured in patients with ischemic cardiomyopathy and symptoms of heart failure undergoing coronary artery bypass grafting (CABG) and mitral restrictive annuloplasty. ⁎ Corresponding author. Division of Cardiac Surgery, Dipartimento d’Emergenza e Trapianti d’Organo (D.E.T.O.), University of Bari, Piazza Giulio Cesare 11, 70100 Bari, Italy. Tel.: +390805595075. E-mail address: [email protected] (D. Paparella).

1. Methods Seventeen patients (12 men and 5 women, mean age 68.6 ± 8.7 years) with severe coronary artery disease, previous MI, moderate/severe to severe functional MR and heart failure symptoms were prospectively enrolled in this study. The local ethic committee approved the study protocol, individual consent was obtained. Functional MR was diagnosed in the absence of any valvular and annular structural deterioration and in the presence of wall motion abnormality as a consequence of previous myocardial infarction. The operations were performed using cardiopulmonary bypass and cardioplegic arrest. The left atrium was opened and restrictive annuloplasty performed applying a partial and flexible ring in the first 9 cases and a complete and partially rigid ring in the following cases. Ring sizes were only 26 and 28. Surgical revascularization was performed in all patients. A transthoracic echocardiogram (TTE) was performed within 3 days before surgery, before discharge and 6 months after the operation. The severity of mitral regurgitation was graded semiquantitatively from color-flow Doppler in the conventional parasternal long-axis and apical 4-chamber

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images. Mitral regurgitation was characterized as: mild, 1_ (jet area/left atrial area _10%); moderate, 2_ (jet area/left atrial area 10% to 20%); moderately severe, 3_ (jet area/left atrial area 20% to 45%); and severe, 4_ (jet area/left atrial area_45%). The following parameters were calculated: maximal velocity of early (E) and late (A) diastolic filling, deceleration time (DT) of early diastolic filling and the ratio of maximal early to maximal late diastolic filling velocities (E/A). Mitral flow pattern was classified as restrictive when E/A was N 1 and DT was b 130, and 2) nonrestrictive when E/A was b 1 or E/A was N1 and DT was N130. Blood samples were obtained from all patients the day before the operation and 6 months after. Plasma BNP was measured by means of ADVIA Centaur® system (ADVIA Centaur® Bayer Diagnostics division of Bayer HealthCare). 2. Results Patients had compromised left ventricular function and functional status (Table 1). Intra-operative TEE showed significant reduction of mitral regurgitation in all cases

(MR = 0.9 ± 0.8; p b 0.01 compared to preoperative) and in no case a second mitral valve procedure (repair correction or replacement) was required. One patient died 28 days after the operation for low cardiac output syndrome, multi-organ failure and sepsis. Two patients experienced acute renal failure and were treated with continuous veno-venous hemodialysis. Echocardiography evaluation 1 week after operations showed improvement in degree (+/++++) of mitral regurgitation (from 3.8 ± 0.3 to 0.9 ± 0.8; p b 0.01) and a modest increase in LVEF (from 36 ± 11% to 40 ± 10%; p = 0.17). Six months after, mitral regurgitation decreased from 3.8 ± 0.3 to 1.0 ± 0.7 (p b 0.01), LVEF increased from 36 ± 11% to 43 ± 8% (p b 0.05), left ventricular end diastolic diameters changed from 54.7 ± 5.2 mm to 51.5 ± 5.8 mm (p = 0.51). NYHA class improved from 2.94 ± 1.02 to 1.21 ± 0.42 (p b 0.01) (Fig. 1). Mean plasma BNP levels decreased from 471 ± 248 pmol/l to 55.6 ± 52.8 pmol/l (p b 0.05) (Fig. 1). Preoperatively mitral flow pattern was considered restrictive in 52.9% of the patients and nonrestrictive in the remaining 47.1%. Six months after the operation, mitral flow pattern was restrictive in 37.5% of the surviving patients and non-restrictive in the remaining 62.5%. 3. Discussion

Table 1 Preoperative clinical status and intra-operative variables. Characteristic Patients Age (years) mean ± SD Male Systemic hypertension Diabetes Hypercholesterolemia Nicotine abuse Previous CVA PVD CRF Chronic AF Preoperative IABP EF (%) mean ± SD Mitral regrugitation degree NYHA class Mean ± SD II III IV Euroscore mean ± SD Preoperative cTnI (ng/ml) Ring Partial flexible Complet rigid Ring size 26 28 Anastomoses/patient mean ± SD CPB time (min) mean ± SD Cross-clump time (min) mean ± SD

17 68.6 ± 8.7 12 11 11 8 5 1 5 1 2 3 36 ± 11 3.8 ± 0.3 3.05 ± 0.89 6 4 7 11.1 ± 2.6 2.6 ± 3.9 11 6 6 11 3.4 ± 0.9 181 ± 24 118 ± 18

Abbreviations: CVA = cerebral vascular accident; PVD = peripheral vascular disease; CRF = chronic renal failure; AF = atrial fibrillation; IABP = intraaortic balloon pump; EF = ejection fraction. cTnI = cardiac troponin I; CPB = cardiopulmonary bypass.

This study demonstrates that in patients with ischemic cardiomyopathy, moderate/severe–severe MR and heart failure symptoms a restrictive mitral valve annuloplasty is a safe procedure to be associated to CABG operation; it provides satisfactory operative results also in high risk situations such those encountered by heart failure patients. This operation induces a significant mid-term improvement in terms of functional, hemodynamical and neurohormonal status. Annuloplasty reduces septo-lateral distance and restores the intertrigonal distance of mitral valve but does not affect subvalvular pathological components that lead to ischemic mitral regurgitation. The role of ventricular factors and the tethering phenomenon in the pathogenesis of ischemic mitral regurgitation, the impact of left ventricular dysfunction and the recurrence of mitral regurgitation after annuloplasty indicate that annuloplasty alone address only few components of the complex pathophysiology of functional MR [8]. Despite of these limitations, good results have been reported in terms of hospital mortality, long-term survival and freedom from repair failure in patients who underwent mitral valve restrictive annuloplasty [6,7]. Undersizing the mitral annulus with a prosthetic ring has shown to promote a left ventricular reverse-remodeling process in patients with end-stage cardiomyopathy and severe functional mitral regurgitation with improvement in sphericity index, ejection fraction, cardiac output and regurgitant fraction [9]. However, whether annuloplasty should always be performed is still a matter of debate: no randomized controlled trial have been produced this far to verify clinical benefit of the association of CABG with mitral

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Fig. 1. Brain natriuretic peptide (BNP) levels and NYHA class variations between preoperative (Preop) and six months follow-up (FU) evaluations.

annuloplasty versus CABG alone in patients with significant functional MR undergoing surgery and no longterm survival benefit were demonstrated in 2 propensity matched retrospective studies [10,11]. In our study we found not only a significant improvement in terms of hemodynamic and functional status, but also a significant reduction of BNP plasma values. It has been shown that BNP concentrations are strictly associated with hemodynamic status in heart failure patients [12]. The presence of high plasma BNP levels is associated with an increased risk of death or hospitalisation due to heart failure progression [13]. In patients with MR it has been demonstrated that BNP is a biomarker of MR severity and poor clinical outcome, as well as of ventricular remodelling [4]. In our study we demonstrated mid-term reduction of BNP plasma values after MR correction thus suggesting the effectiveness of surgical treatment in modifying natural history of the disease. Patients having severely compromised left ventricular function and heart failure symptoms are those whose long-term prognosis result mostly affected by

presence of MR [5], they are probably those who benefit most from mitral annuloplasty associated to CABG. References [1] Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative doppler assessment. Circulation 2001;103:1759–64. [2] Sutton TM, Stewart RA, Gerber IL, West TM, et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol 2003;41:2280–7. [3] Detaint D, Messika-Zeitoun D, Chen HH, et al. Association of Btype natriuretic peptide activation to left ventricular end-systolic remodeling in organic and functional mitral regurgitation. Am J Cardiol 2006;97:1029–34. [4] Hartmann F, Packer M, Coats Aj, et al. Prognostic Impact of Plasma NTerminal Pro-Brain Natriuretic Peptide in Severe Chronic Congestive Heart Failure A Substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Trial. Circulation 2004;110:1780–6. [5] Paparella D, Mickleborough LL, Carson S, Ivanov J. Mild to moderate mitral regurgitation in patients undergoing coronary bypass grafting: effects on operative mortality and long-term significance. Ann Thorac Surg 2003;76:1094–100.

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[6] Bax JJ, Braun J, Somer ST, et al. Restrictive annuloplasty and coronary revascularization in ischemic mitral regurgitation results in reverse left ventricular remodeling. Circulation 2004;110(11 suppl I):II103–8. [7] Geidel S, Lass M, Schneider, et al. Downsizing of the mitral valve and coronary revascularization in severe ischemic mitral regurgitation results in reverse left ventricular and left atrial remodeling. Eur J Cardio-thorac Surg 2005;27:1011–6. [8] Tibayan FA, Rodriguez F, Langer F, et al. Annular or subvalvular approach to chronic ischemic mitral regurgitation. J Thorac Cardiovasc Surg 2005;129:1266–75. [9] Bolling SF, Pagani FD, Deeb GM, Bach DS. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381–8. [10] Diodato MO, Moon MR, Pasque MK, et al. Repair of ischemic mitral regurgitation does not increase mortality or improve long-term survival

in patients undergoing coronary artery revascularization: a propensity analysis. Ann Thorac Surg 2004;78:794–9. [11] Mihaljevic T, Lam BK, Rajeswaran J, et al. Impact of mitral valve annuloplasty combined with revascularization in patients with functional ischemic mitral regurgitation. J Am Coll Cardiol 2007;49:2191–201. [12] Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647–54. [13] Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509–16.

0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.04.090

Manifestations of the mitochondrial A3243G mutation Josef Finsterer ⁎ Krankenanstalt Rudolfstiftung, Vienna, Austria Received 21 January 2008; Accepted 26 April 2008 Available online 26 July 2008

Abstract The tRNA(Leu) A3243G mutation is one of the most frequently observed mutations of mitochondrial DNA genes. Eighty percent of the patients with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) syndrome carry the mutation. Nevertheless, MELAS is genetically heterogeneous and presents with a wide range of phenotypic features. One of the organs most frequently affected is the heart. Cardiac abnormalities manifest as impulse generation or conduction abnormalities or abnormalities of the left ventricular myocardium. To recognize cardiac disease in MELAS thorough and comprehensive investigations are a prerequisite. Early detection of cardiac involvement is essential to punctually treat cardiac disease in MELAS and to prevent sudden cardiac death. Additionally, drugs toxic to the respiratory chain or oxidative phosphorylation need to be avoided. Cardiac affection in MELAS requires special attention since patients may survive malignant rhythm abnormalities or hard failure if detected and treated early. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Mitochondrial disorder; Cardiac involvement; Genetics; Cardiomyopathy

With interest we read the article by Takahashi et al. about a 36-year-old male with markedly thickened left ventricular myocardium. The patient carried the mitochondrial A3243G mutation and cardiac manifestations were interpreted as cardiac involvement in a mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) syndrome [1].

⁎ Postfach 20, 1180 Vienna, Austria, Europe. Tel.: +43 1 71165 92085; fax: +43 1 4781711. E-mail address: [email protected].

The findings, analysis, and discussion evoked the following concerns: A hallmark of MELAS syndrome, in addition to myopathy, encephalopathy, hypacusis, cardiomyopathy, and diabetes, are stroke-like episodes (SLEs). Obviously, however, the patient never experienced one so far. Also renal failure is not a key feature. Furthermore, the mitochondrial A3243G mutation does not necessarily imply MELAS, since it may cause a broad variety of other phenotypes, such as MELAS/myoclonic epilepsy and ragged red fibers (MERRF) overlap syndrome, chronic progressive external ophthalmoplegia (CPEO),