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1192 Correspondence JACC Vol. 54, No. 13, 2009September 22, 2009:1190–4

. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009expert consensus document on pulmonary hypertension: a report ofthe American College of Cardiology Foundation Task Force onExpert Consensus Documents and the American Heart Association,developed in collaboration with the American College of ChestPhysicians; American Thoracic Society, Inc.; and the PulmonaryHypertension Association. J Am Coll Cardiol 2009;53:1573– 619.

. Enriquez-Sarano M, Rossi A, Seward J, Bailey K, Tajik J. Determinantsof pulmonary hypertension in left ventricular dysfunction. J Am CollCardiol 1997;29:153–9.

. Tumminello G, Lancellotti P, Lempereur M, D’Orio V, Pierard LA.Determinants of pulmonary artery hypertension at rest and duringexercise in patients with heart failure. Eur Heart J 2007;28:569 –74.

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e appreciate these insightful comments on our paper (1) andully agree that mitral regurgitation can importantly contribute tohe development of pulmonary hypertension in left-sided heartailure. As demonstrated in heart failure with reduced ejectionraction (2,3), hemodynamically significant mitral regurgitationan cause left atrial volume and pressure overload with resultantncreases in pulmonary artery systolic pressure independent of leftentricular filling pressures. As noted in the Methods section (1),n our sample of heart failure with preserved ejection fractionHFpEF), patients with hemodynamically significant (greater thanoderate) mitral regurgitation were excluded in accordance withmerican College of Cardiology/American Heart Association

uidelines for the diagnosis of HFpEF (4). In our hypertensiveontrol group from the general community, clinically significantitral valve disease was exceedingly rare (n � 2, 0.4%). Thus, we

onclude that mitral regurgitation at rest did not contribute to theevelopment of pulmonary hypertension in our sample.

One could speculate that hemodynamic stress during periods ofypertension or exercise could produce intermittent mitral regurgita-ion and contribute to the development of pulmonary hypertension.

owever, we excluded patients with intrinsic valve disease (mitralalve prolapse, and so on) who would be susceptible to stress-inducedorsening of mitral regurgitation. Further, in contrast to heart failureith reduced ejection fraction, the lack of ventricular dilation inFpEF would make it unlikely for significant “functional” mitral

egurgitation to develop. We did not exclude patients with coronaryrtery disease, which could cause ischemic mitral regurgitation withtress. Hence, while we agree that mitral regurgitation can contributeo pulmonary hypertension in heart failure patients, it would seemnlikely to be a major contributor in this cohort.

arolyn S. P. Lam, MBBSMargaret M. Redfield, MD

Mayo Clinic and Foundationardiovascular Research00 First Street SWochester, Minnesota 55905-mail: redfield.margaret@mayo.edu

doi:10.1016/j.jacc.2009.05.057

EFERENCES

. Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT,Redfield MM. Pulmonary hypertension in heart failure with pre-

served ejection fraction: a community-based study. J Am CollCardiol 2009;53:1119 –23. d

. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ.Determinants of pulmonary hypertension in left ventricular dysfunction.J Am Coll Cardiol 1997;29:153–9.

. Tumminello G, Lancellotti P, Lempereur M, D’Orio V, Pierard LA.Determinants of pulmonary artery hypertension at rest and duringexercise in patients with heart failure. Eur Heart J 2007;28:569–74.

. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused updateincorporated into the ACC/AHA 2005 guidelines for the diagnosis andmanagement of heart failure in adults: a report of the American Collegeof Cardiology Foundation/American Heart Association Task Force onPractice Guidelines. J Am Coll Cardiol 2009;53:e1–90.

enal Protectiveffects and Prevention ofontrast-Induced Nephropathyy Atrial Natriuretic Peptidean It Work?

e congratulate Morikawa et al. (1) on this important paper onherapeutic prevention of contrast-induced nephropathy, andhen (2) for his editorial comment putting this research intoerspective. The editorial comment already mentioned manyositive aspects of the study.

Contrast-induced nephropathy frequently complicates primaryercutaneous coronary intervention (3). In the present study,orikawa et al. (1) chose an intermediate dose of atrial natriuretic

eptide (ANP) at 0.042 �g/kg/min to prevent contrast-inducedephropathy and found—corresponding with the physiologicalffect of “natriuretic” peptide—increased diuresis associated with atatistically significant but clinically perhaps not meaningfulhange of glomerular markers (serum creatinine, estimated glo-erular filtration rate, cystatin C) at 1 month after the procedure

ompared with control, for example, a reduced loss of estimatedlomerular filtration rate �1 ml/min/1.73 m2. The relevance ofhis finding is further questioned by the lack of an effect of ANPn markers of tubular damage (urinary microglobulin and-acetyl-D-glucosaminidase), although contrast-induced ne-

hropathy has been described involving tubular damage.A previous randomized controlled trial using nesiritide pre-

ented during the Congress of the American Society of Nephrol-gy 2008 (4) showed an absolute reduction in the incidence ofcute kidney injury after cardiac surgery similar to that of theresent study (1), but although powered for it, the former studyould not demonstrate a reduced need for dialysis and wasiscontinued after an interim analysis (4).

It would strengthen the message further to discuss why, in thetudy by Morikawa et al. (1), N-acetylcysteine has not been usedor nephroprotection although N-acetylcysteine has been shown toeduce the incidence of contrast-induced nephropathy and theortality associated with it (5,6). N-acetylcysteine does not arti-

cially reduce serum creatinine concentration (7), which was arevious concern (8), and its use is current clinical practice foratients undergoing angiography who present with chronic kidney

isease at many European centers.

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1193JACC Vol. 54, No. 13, 2009 CorrespondenceSeptember 22, 2009:1190–4

Last, patients of the present study were hospitalized for at least8 h after the procedure, which deviates from clinical practice, ateast in the U.S. and in Europe—the additional potential risksthrombosis, infection) and costs need to be considered.

We hope that the authors can further elucidate the issue of 272atients assessed for eligibility, with only 4 patients who did not fulfillhe inclusion criteria (serum creatinine �1.3 mg/dl), suggesting thatlmost all patients presenting for angiography at this hospital havehronic renal impairment with an average estimated glomerularltration rate of 30 ml/min/1.73 m2. Additional comment on this

ssue may provide more complete insight into the local patientopulation.

Michael Haase, MDnja Haase-Fielitz, PharmDirk Habedank, MD

tefan D. Anker, MD, PhD

Department of Nephrology and Intensive Careharité, Campus Virchow-Klinikumugustenburger Platz 1-13353 Berlinermany-mail: michael.haase@charite.de

doi:10.1016/j.jacc.2009.05.058

EFERENCES

. Morikawa S, Sono T, Tsuboi H, et al. Renal protective effects and theprevention of contrast-induced nephropathy by atrial natriuretic pep-tide. J Am Coll Cardiol 2009;53:1040–6.

. Chen HH. Atrial natriuretic peptide for the prevention of contrast-induced nephropathy: what’s old is new but at the right dose andduration of therapy! J Am Coll Cardiol 2009;53:1047–9.

. Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathyin patients undergoing primary angioplasty for acute myocardial infarc-tion. J Am Coll Cardiol 2004;44:1780–5.

. Ejaz AA, Martin TD, Johnson RJ, et al. Decreased incidence of acutekidney injury associated with prophylactic use of nesiritide in cardiacsurgery patients. Paper presented at: Congress of the American Societyof Nephrology; November 4, 2008; Philadelphia, PA.

. Baker CS, Wragg A, Kumar S, et al. A rapid protocol for the preventionof contrast-induced renal dysfunction: the RAPPID study. J Am CollCardiol 2003;41:2114–8.

. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:2773–82.

. Haase M, Haase-Fielitz A, Ratnaike S, et al. N-acetylcysteine does notartifactually lower plasma creatinine concentration. Nephrol DialTransplant 2008;23:1581–7.

. Hoffmann U, Fischereder M, Krüger B, et al. The value ofN-acetylcysteine in the prevention of radiocontrast agent-inducednephropathy seems questionable. J Am Soc Nephrol 2004;15:407–10.

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ontrast-induced nephropathy (CIN) involves both glomerular fil-ration failure and tubular dysfunction. However, CIN is defined onlysing the value of serum creatinine, or estimated glomerular filtrationate (eGFR) calculated from serum creatinine (1). Creatinine andystatin C are endogenous markers of glomerular filtration, and all ofhem are contained in blood. By contrast, tubular dysfunctionarkers such as N-acetyl-�-D-glucosaminidase (NAG) and � -

1

nd �2-microglobulin are collected from urine. A few reports

egarding CIN estimated NAG and microglobulin (2). Theseeports showed that the markers of glomerular filtration failureeem to be more appropriate as CIN markers than tubularysfunction markers, even if they were expressed after beingdjusted by dividing by urine creatinine. We could not adjust thealues of NAG and microglobulin by urine creatinine (3). Thisay be the reason that we detected no significant difference inAG and �2-microglobulin. In our results, �2-microglobulin was

ignificantly higher at 24 h from baseline in both atrial natriureticeptide (ANP) and control groups (both p � 0.0001). In allatients combined, the decrease in eGFR was �1 ml/min/1.73 m2

s pointed out, but the decrease in 19 patients with CIN was 9.1l/min/1.73 m2 at 48 h.In our study, only 1 patient in the control group required

emporary dialysis. The long-term prognosis with treatmentith ANP or nesiritide (B-type natriuretic peptide) should be

stimated in a large, controlled multicenter study. In an integrateddvanced algorithm for the management of CIN, treatment with-acetylcysteine or ascorbic acid as an antioxidant is recom-ended in the case of eGFR in the range of 30 to 59 ml/min (1),

ut an analysis of studies using N-acetylcysteine demonstrated thatignificant benefits were observed in only one-half of the studies inatients with chronic renal insufficiency (4). As the algorithmays, adjunctive medications do not require all patients tondergo angiography— only the subjects already with renalnsufficiency. If the number of patients with CIN were reducedo one-fourth by ANP as demonstrated in our study, the costould be negligible.We used Ringer solution containing 28 mEq for hydration

ithout bicarbonate because volume supplementation with eitherntravenous normal saline or bicarbonate remains a better regimenor preventing CIN in moderate- to high-risk patients (1,5). Wehould pay more attention to high-risk patients with renal insuf-ciency during angiography. We recruited 272 patients withreatinine levels of �1.3 and �6 mg/dl, but excluded 11 beforereatment was assigned, and 4 of them showed creatinine levelsutside of the acceptable range.

Finally, we suggest again that in addition to hydration, treat-ent with a dose of ANP infusion that is calibrated so as not to

educe blood pressure too greatly helps to prevent CIN.

Kenji Okumura, MDakahito Sone, MDhuji Morikawa, MDideyuki Tsuboi, MDiroaki Mukawa, MD

tsuro Morishima, MDichitaka Uesugi, MD

asuhiro Morita, MDasushi Numaguchi, MDoyoaki Murohara, MD

Cardiovascular Research Medicineagoya University School of Medicineagoya, Aichi 466-8550

apan-mail: kenji@med.nagoya-u.ac.jp

doi:10.1016/j.jacc.2009.05.059