circulation2010-05-25

(Circulation. 2010;121:2162-2168.)
© 2010 American Heart Association, Inc.

Abstract 1 of 7

Epidemiology and Prevention
Whole-Grain, Cereal Fiber, Bran, and Germ Intake and the Risks of All-Cause and Cardiovascular Disease–Specific Mortality Among Women With Type 2 Diabetes Mellitus
Meian He, MD, PhD; Rob M. van Dam, PhD; Eric Rimm, ScD; Frank B. Hu, MD, PhD; Lu Qi, MD, PhD
From the Departments of Nutrition (M.H., R.M.v.D., E.R., F.B.H., L.Q.) and Epidemiology (R.M.v.D., E.R., F.B.H.), Harvard School of Public Health, Boston, Mass; Institute of Occupational Medicine, School of Public Health, and Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (M.H.); and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (R.M.v.D., E.R., F.B.H., L.Q.).
Reprint requests to Dr Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail nhlqi@channing.harvard.edu
Received September 4, 2009; accepted March 1, 2010.
Background— Although whole-grain consumption has been associated with a lower risk of cardiovascular diseases (CVD) and mortality in the general population, the association of whole grain with mortality in diabetic patients remains to be determined. This study investigated whole grain and its components cereal fiber, bran, and germ in relation to all-cause and CVD-specific mortality in patients with type 2 diabetes mellitus.
Methods and Results— We followed 7822 US women with type 2 diabetes mellitus in the Nurses’ Health Study. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. We documented 852 all-cause deaths and 295 CVD deaths during up to 26 years of follow-up. After adjustment for age, the highest versus the lowest fifths of intakes of whole grain, cereal fiber, bran, and germ were associated with 16% to 31% lower all-cause mortality. After further adjustment for lifestyle and dietary risk factors, only the association for bran intake remained significant (P for trend=0.01). The multivariate relative risks across the fifths of bran intake were 1.0 (reference), 0.94 (0.75 to 1.18), 0.80 (0.64 to 1.01), 0.82 (0.65 to 1.04), and 0.72 (0.56 to 0.92). Similarly, bran intake was inversely associated with CVD-specific mortality (P for trend=0.04). The relative risks across the fifths of bran intake were 1.0 (reference), 0.95 (0.66 to 1.38), 0.80 (0.55 to 1.16), 0.76 (0.51 to 1.14), and 0.65 (0.43 to 0.99). Similar results were observed for added bran alone.
Conclusions— Whole-grain and bran intakes were associated with reduced all-cause and CVD-specific mortality in women with diabetes mellitus. These findings suggest a potential benefit of whole-grain intake in reducing mortality and cardiovascular risk in diabetic patients.

Abstract 2 of 7

Heart Failure
Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy
Karin Y. van Spaendonck-Zwarts, MD; J. Peter van Tintelen, MD, PhD; Dirk J. van Veldhuisen, MD, PhD; Rik van der Werf, MD; Jan D.H. Jongbloed, PhD; Walter J. Paulus, MD, PhD; Dennis Dooijes, PhD; Maarten P. van den Berg, MD, PhD
From the Departments of Genetics (K.Y.v.S.-Z., J.P.v.T., J.D.H.J.) and Cardiology (D.J.v.V., R.v.d.W., M.P.v.d.B.), University Medical Centre Groningen, University of Groningen, Groningen; Department of Physiology, Free University Medical Centre, Amsterdam (W.J.P.); and Department of Genetics, Erasmus Medical Centre, Rotterdam (D.D.), the Netherlands.
Correspondence to K.Y. van Spaendonck-Zwarts, MD, Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands. E-mail k.y.spaendonck@medgen.umcg.nl
Received December 9, 2009; accepted March 13, 2010.
Background— Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period.
Methods and Results— We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case.
Conclusions— Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families.

Abstract 3 of 7

Heart Failure
Rare Variant Mutations in Pregnancy-Associated or Peripartum Cardiomyopathy
Ana Morales, MS, CGC; Thomas Painter, BS; Ran Li, BS; Jill D. Siegfried, MS, CGC; Duanxiang Li, MD, MS; Nadine Norton, PhD; Ray E. Hershberger, MD
From the Cardiovascular Division, University of Miami Miller School of Medicine, Miami, Fla.
Correspondence to Ray E. Hershberger, MD, Biomedical Research Building (R-125), Room 811, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Miami, FL 33136. E-mail rhershberger@med.miami.edu
Received December 11, 2009; accepted March 24, 2010.
Background— The term peripartum cardiomyopathy (PPCM) describes dilated cardiomyopathy (DCM) without known cause that occurs during the last month of pregnancy to 5 months postpartum. A related term, pregnancy-associated cardiomyopathy (PACM), refers to DCM onset earlier in pregnancy. Multiple studies have focused on inflammatory, immunologic, and environmental causes. An alternative hypothesis is that PPCM and PACM result, in part, from a genetic cause. In this study, we sought to test the hypothesis that rare DCM-associated mutations underlie a proportion of PACM or PPCM cases.
Methods and Results— A systematic search of our DCM database designed for family-based genetic studies was undertaken for cases associated with pregnancy and the postpartum period; in the identified cases, clinical and molecular genetic data, including exonic and near intron/exon boundaries of DCM genes, were analyzed. Of 4110 women from 520 pedigrees in the Familial Dilated Cardiomyopathy Research Project database, we identified 45 cases of PPCM/PACM. Evidence of familial clustering with DCM was present in 23 unrelated cases. Of the 45 cases, 19 had been resequenced for known DCM genes, and 6 carried mutations. Five had PPCM, of which 3 were familial with mutations found in MYH7, SCN5A, and PSEN2, and 2 were sporadic with mutations in MYH6 and TNNT2. One case had PACM and carried a mutation in MYBPC3.
Conclusions— These findings suggest that a proportion of PPCM/PACM cases results from a genetic cause.

Abstract 4 of 7

Hypertension
Acute Kidney Injury and Cardiovascular Outcomes in Acute Severe Hypertension
Lynda A. Szczech, MD, MSCE; Christopher B. Granger, MD; Joseph F. Dasta, MSc, FCCM; Alpesh Amin, MD; W. Frank Peacock, MD; Peter A. McCullough, MD, MPH; John W. Devlin, PharmD; Matthew R. Weir, MD, MS; Jason N. Katz, MD; Frederick A. Anderson, Jr, PhD; Allison Wyman, MS; Joseph Varon, MD, for the Studying the Treatment of Acute Hypertension Investigators
From the Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, NC (L.A.S.); Duke Clinical Research Institute, Durham, NC (C.B.G.); College of Pharmacy, University of Texas, Round Rock (J.F.D.); UCIMC, Orange, Calif (A.A.); Emergency Department, The Cleveland Clinic, Cleveland, Ohio (W.F.P.); William Beaumont Hospital, Royal Oak, Mich (P.A.M.); School of Pharmacy, Northeastern University School of Pharmacy, Boston, Mass (J.W.D.); Division of Nephrology, University of Maryland School of Medicine, Baltimore (M.R.W.); Divisions of Cardiology and Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill (J.N.K.); Center for Outcomes Research, University of Massachusetts Medical School, Worcester (F.A.A., A.W.); and University of Texas Health Science Center and St Luke’s Episcopal Hospital, Houston (J.V.).
Correspondence to Lynda Anne Szczech, MD, MSCE, Duke University Medical Center, Box 3646, Durham, NC 27710. E-mail szcze001@mc.duke.edu
Received July 24, 2009; accepted March 23, 2010.
Background— Little is known about the association of kidney dysfunction and outcome in acute severe hypertension. This study aimed to measure the association between baseline chronic kidney disease (estimated glomerular filtration rate), acute kidney injury (AKI, decrease in estimated glomerular filtration rate 25% from baseline) and outcome in patients hospitalized with acute severe hypertension.
Methods and Results— The Studying the Treatment of Acute Hypertension (STAT) registry enrolled patients with acute severe hypertension, defined as 1 blood pressure measurement >180 mm Hg systolic and/or >110 mm Hg diastolic and treated with intravenous antihypertensive therapy. Data were compared across groups categorized by admission estimated glomerular filtration rate and AKI during admission. On admission, 79% of the cohort (n=1566) had at least mild chronic kidney disease (estimated glomerular filtration rate <60 mL/min in 46%, <30 mL/min in 22%). Chronic kidney disease patients were more likely to develop heart failure (P<0.0001), non–ST-elevation myocardial infarction (P=0.003), and AKI (P<0.007). AKI patients were at greater risk of heart failure and cardiac arrest (P 0.0001 for both). Subjects with AKI experienced higher mortality at 90 days (P=0.003). Any acute loss of estimated glomerular filtration rate during hospitalization was independently associated with an increased risk of death (odds ratio, 1.05; P=0.03 per 10-mL/min decline). Other independent predictors of mortality included increasing age (P<0.0001), male gender (P=0.016), white versus black race (P=0.003), and worse baseline kidney function (P=0.003).
Conclusions— Chronic kidney disease is a common comorbidity among patients admitted with acute severe hypertension, and AKI is a frequent form of acute target organ dysfunction, particularly in those with baseline chronic kidney disease. Any degree of AKI is associated with a greater risk of morbidity and mortality.

Abstract 5 of 7

Molecular Cardiology
Smooth Muscle Cells Orchestrate the Endothelial Cell Response to Flow and Injury
Mercedes Balcells, PhD; Jordi Martorell, MS; Carla Olivé, MS; Marina Santacana, MS; Vipul Chitalia, MD, PhD; Angelo A. Cardoso, MD, PhD; Elazer R. Edelman, MD, PhD
From the Harvard–MIT Division of Health Sciences and Technology, Cambridge, Mass (M.B., J.M., C.O., M.S., V.C., E.R.E.); Institut Químic de Sarrià, Ramon Llull University, Barcelona, Spain (M.B., J.M., C.O., M.S.); Boston University School of Medicine, Boston, Mass (V.C.); Indiana University Simon Cancer Center, Indianapolis, Ind (A.A.C.); and Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (E.R.E.).
Correspondence to Mercedes Balcells, PhD, MIT, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail merche@mit.edu
Received May 4, 2009; accepted February 23, 2010.
Background— Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs.
Methods and Results— SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution.
Conclusions— The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets.

Abstract 6 of 7

Molecular Cardiology
Prelamin A Acts to Accelerate Smooth Muscle Cell Senescence and Is a Novel Biomarker of Human Vascular Aging
Cassandra D. Ragnauth, PhD*; Derek T. Warren, PhD*; Yiwen Liu, PhD; Rosamund McNair; Tamara Tajsic, MD; Nichola Figg; Rukshana Shroff, MD, PhD; Jeremy Skepper, PhD; Catherine M. Shanahan, PhD
From the British Heart Foundation Centre, Division of Cardiovascular Medicine, Kings College London (C.D.R., D.T.W., Y.L., T.T., C.M.S.), and Nephrology Unit (R.S.), Great Ormond Street Hospital, London, UK; Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK (R.M., N.F.); and Imaging Centre, Department of Anatomy, University of Cambridge, Cambridge, UK (J.S.). Dr Ragnauth is currently affiliated with the Genomics CoreLab, University of Cambridge Metabolic Research Laboratories, Addenbrooke’s Hospital, Cambridge, UK.
Correspondence to Catherine M. Shanahan, PhD, Division of Cardiovascular Medicine, Kings College London, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK. E-mail cathy.shanahan@kcl.ac.uk
Received August 13, 2009; accepted March 1, 2010.
Background— Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition.
Methods and Results— To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs. In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects, and these defects were reversible by treatment with farnesylation inhibitors and statins. In human arteries, prelamin A accumulation was not observed in young healthy vessels but was prevalent in medial VSMCs from aged individuals and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. Prelamin A accumulation correlated with downregulation of the lamin A processing enzyme Zmpste24/FACE1, and FACE1 mRNA and protein levels were reduced in response to oxidative stress. Small interfering RNA knockdown of FACE1 reiterated the prelamin A–induced nuclear morphology defects characteristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence. We show that prelamin A acts to disrupt mitosis and induce DNA damage in VSMCs, leading to mitotic failure, genomic instability, and premature senescence.
Conclusions— This study shows that prelamin A is a novel biomarker of VSMC aging and disease that acts to accelerate senescence. It therefore represents a novel target to ameliorate the effects of age-induced vascular dysfunction.


Abstract 7 of 7

Molecular Cardiology
Mobilized Human Hematopoietic Stem/Progenitor Cells Promote Kidney Repair After Ischemia/Reperfusion Injury
Bing Li, MD, PhD; Amy Cohen, MT; Thomas E. Hudson, BA; Delara Motlagh, PhD; David L. Amrani, PhD, FAHA; Jeremy S. Duffield, MD, PhD
From the Laboratory of Inflammation Research, Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (B.L., T.E.H., J.S.D.); Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People’s Republic of China (B.L.); Regenerative Medicine, Cellular Therapies R&D, Baxter Healthcare, Deerfield, Ill (A.C., D.M., D.L.A.); and Harvard Stem Cell Institute, Harvard University, Cambridge, Mass (J.S.D.).
Correspondence to Jeremy S. Duffield, MD, PhD, Laboratory of Inflammation Research, Fifth Floor, Renal Division, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. E-mail jduffield@rics.bwh.harvard.edu
Received December 6, 2009; accepted March 24, 2010.
Background— Understanding the mechanisms of repair and regeneration of the kidney after injury is of great interest because there are currently no therapies that promote repair, and kidneys frequently do not repair adequately. We studied the capacity of human CD34+ hematopoietic stem/progenitor cells (HSPCs) to promote kidney repair and regeneration using an established ischemia/reperfusion injury model in mice, with particular focus on the microvasculature.
Methods and Results— Human HSPCs administered systemically 24 hours after kidney injury were selectively recruited to injured kidneys of immunodeficient mice (Jackson Labs, Bar Harbor, Me) and localized prominently in and around vasculature. This recruitment was associated with enhanced repair of the kidney microvasculature, tubule epithelial cells, enhanced functional recovery, and increased survival. HSPCs recruited to kidney expressed markers consistent with circulating endothelial progenitors and synthesized high levels of proangiogenic cytokines, which promoted proliferation of both endothelial and epithelial cells. Although purified HSPCs acquired endothelial progenitor markers once recruited to the kidney, engraftment of human endothelial cells in the mouse capillary walls was an extremely rare event, indicating that human stem cell mediated renal repair is by paracrine mechanisms rather than replacement of vasculature.
Conclusions— These studies advance human HSPCs as a promising therapeutic strategy for promoting renal repair after injury.