Showing papers by "Cardiovascular Institute of the South published in 2011"

EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease

Abstract: The introduction of devices for transcatheter aortic valve implantation, mitral repair, and closure of prosthetic paravalvular leaks has led to a greatly expanded armamentarium of catheter-based approaches to patients with regurgitant as well as stenotic valvular disease. Echocardiography plays an essential role in identifying patients suitable for these interventions and in providing intra-procedural monitoring. Moreover, echocardiography is the primary modality for post-procedure follow-up. The echocardiographic assessment of patients undergoing transcatheter interventions places demands on echocardiographers that differ from those of the routine evaluation of patients with native or prosthetic valvular disease. Consequently, the European Association of Echocardiography in partnership with the American Society of Echocardiography has developed the recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. It is intended that this document will serve as a reference for echocardiographers participating in any or all stages of new transcatheter treatments for patients with valvular heart disease.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

Abstract: CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Relation of brachial and digital measures of vascular function in the community: the Framingham heart study.

Abstract: Impaired vascular function contributes to the development of clinical cardiovascular disease The relation between vasodilator function assessed noninvasively in the brachial and digital arteries remains incompletely defined In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow-mediated dilation (FMD; n = 7031; age 48 ± 13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n = 4352; 55 ± 16 years; age range, 19 to 90 years; 51% women) Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high-density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function In participants who had concurrent testing (n = 1843), PAT ratio was not significantly associated with FMD in multivariable models In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels

Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention.

Abstract: Objectives The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy. Background Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. Methods The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. Results The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p Conclusions Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%.

Association of Myocardial Enzyme Elevation and Survival Following Coronary Artery Bypass Graft Surgery

Abstract: confidenceinterval[CI],0.36%-1.02%)for0to1,0.86%(95%CI,0.49%-1.40%)for 1t o2, 0.95% (95% CI, 0.72%-1.22%) for 2 to 5, 2.09% (95% CI, 1.69%-2.57%) for5to10,2.78%(95%CI,2.12%-3.58%)for10to20,and7.06%(95%CI,5.46%8.96%) for 20 to 40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (

Frequency and Predictors of Stent Thrombosis After Percutaneous Coronary Intervention in Acute Myocardial Infarction

Abstract: Background—Concerns persist regarding the risk of stent thrombosis in the setting of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Methods and Results—T...

Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus.

Abstract: Background: Myocardial extravascular extracellular volume fraction (Ve) measures quantify diffuse fibrosis not readily detectable by conventional late gadolinium (Gd) enhancement (LGE). Ve measurement requires steady state equilibrium between plasma and interstitial Gd contrast. While a constant infusion produces steady state, it is unclear whether a simple bolus can do the same. Given the relatively slow clearance of Gd, we hypothesized that a bolus technique accurately measures Ve, thus facilitating integration of myocardial fibrosis quantification into cardiovascular magnetic resonance (CMR) workflow routines. Assuming equivalence between techniques, we further hypothesized that Ve measures would be reproducible across scans. Methods: In 10 volunteers (ages 20-81, median 33 yr, 3 females), we compared serial Ve measures from a single short axis slice from two scans: first, during a constant infusion, and second, 12-50 min after a bolus (0.2 mmol/kg gadoteridol) on another day. Steady state during infusion was defined when serial blood and myocardial T1 data varied <5%. We measured T1 on a 1.5 T Siemens scanner using a single-shot modified Look Locker inversion recovery sequence (MOLLI) with balanced SSFP. To shorten breath hold times, T1 values were measured with a shorter sampling scheme that was validated with spin echo relaxometry (TR = 15 sec) in CuSO4-Agar phantoms. Serial infusion vs. bolus Ve measures (n = 205) from the 10 subjects were compared with generalized estimating equations (GEE) with exchangeable correlation matrices. LGE images were also acquired 12-30 minutes after the bolus. Results: No subject exhibited LGE near the short axis slices where Ve was measured. The Ve range was 19.3-29.2% and 18.4-29.1% by constant infusion and bolus, respectively. In GEE models, serial Ve measures by constant infusion and bolus did not differ significantly (difference = 0.1%, p = 0.38). For both techniques, Ve was strongly related to age (p < 0.01 for both) in GEE models, even after adjusting for heart rate. Both techniques identically sorted older individuals with higher mean Ve values.

Present Status of Anticoagulation Treatment in Japanese Patients With Atrial Fibrillation : A Report From the J-RHYTHM Registry

Abstract: Background: Underuse and an inadequate range for the international normalized ratio (INR) for warfarin use are still problems in the management of the patients with atrial fibrillation (AF) in Japan. Methods and Results: From January to July 2009, a total of 7,937 AF patients [5,468 men (68.6±10.0 years) and 2,469 women (72.2±9.0 years)] were registered from 158 institutions for the J-RHYTHM Registry. Overall, 34.2% of the patients were over the age of 75. The associated cardiovascular diagnoses were hypertension in 59.1%, coronary artery disease in 10.1%, cardiomyopathy in 8.3%, valvular heart disease in 13.7% and artificial cardiac valves in 3.1% of the patients. The type of AF was paroxysmal in 37.1%, persistent in 14.4%, and permanent in 48.5%. Overall, 87.3% of patients were taking warfarin (2.9±1.2mg/day), of whom 66.0% had an INR between 1.6 and 2.6, and 35.4% were in the INR range from 2.0 to 3.0 at the time of registration. Aspirin was prescribed in 22.3% of cases. The CHADS2 score was 0 in 15.7% of patients, 1 in 34.0%, and ≥2 in 50.3%. Conclusions: At present, warfarin is used extensively in patients with AF whose stroke risk is relatively low (ie, in Japan) and half of them had CHADS2 scores of 0 to 1 (UMIN Clinical Trials Registry UMIN000001569). (Circ J 2011; 75: 1328-1333)

Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection

Abstract: Percutaneous coronary intervention (PCI) has become the predominant procedure for coronary revascularization in patients with both stable and unstable coronary artery disease (CAD). Over the past two decades, technical advances in PCI have resulted in a better and safer therapeutic procedure with minimal procedural complications. However, about 30% of patients undergoing elective PCI sustain myocardial injury arising from the procedure itself, the extent of which is significant enough to carry prognostic importance. The peri-procedural injury which accompanies PCI might therefore reduce some of the beneficial effects of coronary revascularization. The availability of more sensitive serum biomarkers of myocardial injury such as creatine phosphokinase MB isoenzyme (CK-MB), Troponin T, and Troponin I has enabled the quantification of previously undetectable myocardial injury. Peri-procedural myocardial injury (PMI) can also be visualized by cardiac magnetic resonance imaging, a technique which allows the detection and quantification of myocardial necrosis following PCI. The identification of CAD patients at greatest risk of sustaining PMI during PCI would allow targeted treatment with novel therapies capable of limiting the extent of PMI or reducing the number of patients experiencing PMI.

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.

Abstract: Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis

Abstract: Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial.

Abstract: Aims Major guidelines recommend lowering systolic blood pressure (SBP) to <140 mmHg in all hypertensives, but evidence is missing whether this is beneficial in (i) uncomplicated hypertensives, (ii) grade 1 hypertensives, and (iii) elderly hypertensives. Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives. Methods and results Felodipine Event Reduction (FEVER) was a double-blind, randomized trial on 9711 Chinese hypertensives, in whom cardiovascular outcomes were significantly reduced by more intense therapy (low-dose hydrochlorothiazide and low-dose felodipine) achieving a mean of 138 mmHg SBP compared with less-intense therapy (low-dose hydrochlorothiazide and placebo) achieving a mean of 142 mmHg. FEVER included older and younger patients, and patients with and without diabetes or cardiovascular disease. In the analyses here reported, Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics. Significant reductions in stroke were found in uncomplicated hypertensives (−39%, P = 0.002), in hypertensives with randomization SBP <153 mmHg (−29%, P = 0.03), and in elderly hypertensives (−44%, P < 0.001), when their SBP was lowered by more intense treatment. Significant reductions (between −29 and −47%, P = 0.02 to <0.001) were also found in all cardiovascular events and all deaths. Achieving mean SBP values <140 mmHg by adding a small dose of a generic drug prevented 2.1 (uncomplicated hypertensives) and 5.2 (elderly) cardiovascular events every 100 patients treated for 3.3 years. Conclusions These analyses provide strong support, missing so far, to guidelines recommending goal SBP <140 mmHg in uncomplicated hypertensives, individuals with moderately elevated BP and elderly hypertensives. The FEVER trial has been registered on [www.clinicaltrials.gov][1], n. [NCT01136863][2] [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01136863&atom=%2Fehj%2Fearly%2F2011%2F02%2F22%2Feurheartj.ehr039.atom

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility

Abstract: Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) 5 1.48, 95% confidence interval (CI) 1.23, 1.78; P 5 2.52 3 10 25 ] compared with controls, while the association with rs755383 persisted (per allele OR 5 1.26, 95% CI 1.08, 1.47, P 5 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR 5 14.1, 95% CI 5.12, 38.6; P 5 2.98 3 10 27 ) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

Relation of Left Ventricular Ejection Fraction to Cognitive Aging (from the Framingham Heart Study)

Abstract: Heart failure is a risk factor for Alzheimer's disease and cerebrovascular disease. In the absence of heart failure, it was hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected from 1,114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (aged 40 to 89 years, mean age 67 ± 9 years, 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI–assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p values >0.15). However, LVEF quintile analyses yielded several U-shaped associations. Compared to the referent (quintile 2 to 4), the lowest quintile (quintile 1) LVEF was associated with lower mean cognitive performance, including Visual Reproduction Delayed Recall (β = −0.27, p

Saphenous Vein Graft Intervention

Abstract: Saphenous vein grafts are commonly used conduits for surgical revascularization of coronary arteries but are associated with poor long-term patency rates. Percutaneous revascularization of saphenous vein grafts is associated with worse clinical outcomes including higher rates of in-stent restenosis, target vessel revascularization, myocardial infarction, and death compared with percutaneous coronary intervention of native coronary arteries. Use of embolic protection devices is a Class I indication according to the American College of Cardiology/American Heart Association guidelines to decrease the risk of distal embolization, no-reflow, and periprocedural myocardial infarction. Nonetheless, these devices are underused in clinical practice. Various pharmacological agents are available that may also reduce the risk of or mitigate the consequences of no-reflow. Covered stents do not decrease the rates of periprocedural myocardial infarction and restenosis. Most available evidence supports treatment with drug-eluting stents in this high-risk lesion subset to reduce angiographic and clinical restenosis, although large, randomized trials comparing drug-eluting stents and bare-metal stents are needed.

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

Abstract: Factors secreted by the heart, referred to as “cardiokines,” have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure. The aim of this study was to investigate the role of cardiac Fstl1 in the remodeling response to pressure overload. Cardiac myocyte-specific Fstl1-KO mice were constructed and subjected to pressure overload induced by transverse aortic constriction (TAC). Although Fstl1-KO mice displayed no detectable baseline phenotype, TAC led to enhanced cardiac hypertrophic growth and a pronounced loss in ventricular performance by 4 wk compared with control mice. Conversely, mice that acutely or chronically overexpressed Fstl1 were resistant to pressure overload-induced hypertrophy and cardiac failure. Fstl1-deficient mice displayed a reduction in TAC-induced AMP-activated protein kinase (AMPK) activation in heart, whereas Fstl1 overexpression led to increased myocardial AMPK activation under these conditions. In cultured neonatal cardiomyocytes, administration of Fstl1 promoted AMPK activation and antagonized phenylephrine-induced hypertrophy. Inhibition of AMPK attenuated the antihypertrophic effect of Fstl1 treatment. These results document that cardiac Fstl1 functions as an autocrine/paracrine regulatory factor that antagonizes myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload, possibly through a mechanism involving the activation of the AMPK signaling axis.

Usefulness of a New Miniaturized Echocardiographic System in Outpatient Cardiology Consultations as an Extension of Physical Examination

Abstract: Background The aim of this study was to assess the usefulness of a new miniaturized echocardiographic system (MS) to perform bedside echocardiography in initial outpatient cardiology consultations, in addition to physical examination. Methods One hundred eighty-nine patients referred for initial cardiology outpatient consultations at two tertiary hospitals in two countries were studied. Each patient was submitted to physical examination followed by MS assessment. Scanning time, the number of examinations with abnormal results after physical examination and the MS, and the information obtained by physical examination alone and followed by the MS (in terms of its importance in reaching a diagnosis, in the necessity of performing routine echocardiography, and in the decision to release the patient from the outpatient clinic) were assessed. Results The scanning time with the MS was 180 ± 86 seconds. Its use after physical examination led to diagnoses in 141 patients (74.6%) and to an additional 37 patients (19.6%) being released from the outpatient clinic. After physical examination followed by MS assessment, only 64 patients (33.9%) were sent to the echocardiography lab. The MS modified the decision of whether to send a patient to the echocardiography lab, with referral determined by the MS in 27 patients (14.3%) and no referral determined by the MS in 58 patients (30.7%). Conclusions The new MS caused a negligible increase in the duration of consultations. It showed additive clinical value over physical examination, increasing the number of diagnoses, reducing the use of unnecessary routine echocardiography, increasing the number of adequate echocardiographic studies, and determining a large number of releases from the outpatient clinic.

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study).

Abstract: Aims Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. Methods and results The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group ( P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. Conclusions In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

Abstract: Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 μg/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1–200 μM). ARVM hypertrophy was measured by [3H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg−1·day−1 for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H2O2-induced p-ERK activity and NF-κB activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-κB activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS-induced cardiac remodeling.

The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study.

Abstract: Background One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors. Methods and Findings We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10−8≤p≤5.21×10−7). A significant interaction (p = 4.0×10−4) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10−7), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10−3) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10−4, and HR = 1.35, p = 4.1×10−3, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10−9) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026). Conclusions The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors' Summary