scientificsessions.org
Saturday, November 8
Post Edition
Saturday, November 8
Sunday, November 9
Monday, November 10
Tuesday, November 11
Wednesday, November 12
Mild renal insufficiency induces cardiac fibrosis, diastolic dysfunction
Four Late-Breaking Clinical Trial results presented
Central sleep apnea increases erythropoietin in HF patients
MicroRNAs may determine cardiac cell differentiation, apoptosis
People with high HDL-C, low LCAT still prone to ischemic heart disease
Mild renal insufficiency induces cardiac fibrosis, diastolic dysfunction
Mild experimental renal insufficiency produced by unilateral nephrectomy affects cardiac structure and function in rodents, a Mayo Clinic researcher said Monday in an abstract oral presentation.Researchers assessed cardiorenal function and structure in Wistar rats at four weeks and again at 16 weeks post-nephrectomy (one kidney), Fernando Martin, M.D., said during his presentation, “The Heart-Kidney Interface — New Insights into the Kidney-Heart Connection.”
At four weeks, researchers observed post-nephrectomy collagen changes in the left ventricle of these animals. Removing one kidney appears to increase myocardial collagen content.
In a detailed analysis using genome-wide microarray studies of the cardiac left ventricle, researchers observed that after nephrectomy, 278 genes changed their expression.
“It is true that these changes could be either protective or deleterious; however, the fact that these changes are accompanied by cardiac structural changes as well makes us think that the scale tips to the negative side,” said Martin, a scientist in the Cardiorenal Research Laboratory at the Mayo Clinic in Rochester, Minn.
Results of the study showed no neurohumoral activation of the renin angiotensin aldosterone system or the natriuretic peptide system. Researchers also found no difference in blood pressure between the control animals and the nephrectomized group.
“Regular echocardiographic studies showed no change in ejection fraction, LV mass or end systolic diameters; however, more sensitive echocardiographic analysis using the speckle tracking strain method resulted in diastolic functioning in nephrectomized rats,” Martin said.
At the end of the 16-week study, the rodents continued to show increased collagen in the left ventricle of the heart and diastolic dysfunction.
“Most importantly, at 16 weeks we also observed the presence of a systolic impairment as well, accompanied by LV hypertrophy,” he said.
Martin said current literature increasingly shows that renal insufficiency or even mild renal impairment contributes to cardiovascular disease as a risk factor, and renal insufficiency increases cardiovascular morbidity and mortality in humans, Martin said.
But, he said, “larger studies will be needed to assess in detail the influence of renal function in cardiovascular disease. The fact that removing only one kidney from a rat can generate such changes in cardiac structure and function is an important observation.”
back to top
back to today's issue
Four Late-Breaking Clinical Trial results presented
For patients with non-ST segment elevation acute coronary syndromes (ACS), early intervention within the first 24 hours is safe and may provide benefit over delayed intervention (after 36 hours), particularly in the highest-risk patients, according to results of the international randomized Trial of Intervention in patients with Acute Coronary Syndromes (TIMACS) study.
Investigators reported a nonsignificant improvement in the primary outcome, a composite of the rates of death, new myocardial infarction (MI), or stroke at 6 months, with early vs. delayed intervention (9.7 percent vs. 11.4 percent) among the 3,031 patients evaluated. A composite of the rates of death, MI or refractory ischemia did show a significant benefit with early vs. delayed intervention (9.6 percent vs. 13.1 percent). Moreover, early intervention was associated with a significant 70 percent reduction in the rate of refractory ischemia (1.0 percent vs. 3.3 percent).The investigators reported no significant differences in major bleeding or other safety outcomes between the two strategies.
All patients were suitable for revascularization but were high-risk, defined as meeting two of the three following factors: older than 60 years of age, ischemic EKG change, or elevated biomarkers. In the one-third of patients with a high Global Registry of Acute Coronary Events (GRACE) Risk score (> 140), there was a significant 35 percent improvement in the primary outcome (death, new MI or stroke) with early vs. delayed intervention (14.1 percent vs. 21.6 percent).
These findings show that “there is no detriment to going to the catheterization lab early,” said Shamir R. Mehta, M.D., associate professor, Department of Medicine, McMaster University, Ontario, Canada. “In fact, it may have a benefit for patients with high risk.” He added that the practical application of such an early intervention strategy would clearly have implications for the healthcare system.
New oral anti-coagulant effective after ACS
The new oral direct Factor Xa inhibitor rivaroxaban may reduce the risk of death, myocardial infarction (MI), or stroke after 6 months in patients with recent ACS, according to results of a phase II randomized, multicenter, international, placebo-controlled, dose-escalation study of 3,491 patients.
Patients were stratified based on their usual care at home of aspirin alone (760 patients) or aspirin plus thienopyradine (2,731 patients) then randomized to also receive either placebo or one of four daily doses of the Factor Xa inhibitor on a once- or twice-a-day schedule.
The primary study endpoint, a safety analysis of bleeding risk, revealed a dose-dependent increase in the incidence of clinically significant bleeding (TIMI Major, TIMI Minor and bleeding requiring medical attention) with rivaroxaban vs. placebo, with rates ranging from 6.1 percent in patients receiving 5 mg of the drug each day to 15.3 percent in those receiving 20 mg daily, compared to 3.3 percent in patients receiving placebo.
However, overall, 82 percent of all bleeding incidents fell in the mildest, non-TIMI tier of severity, said C. Michael Gibson, M.D., M.S., chair of the ATLAS ACS-TIMI 46 study, director of the Thrombolysis in Myocardial Infarction (TIMI) data coordinating center at Brigham and Women’s Hospital, and chief of clinical research at the Beth Israel Deaconess Medical Center in Boston. Moreover, rivaroxaban was not associated with liver function test abnormalities.
The primary efficacy endpoint, a composite of the rate of death, MI, stroke or severe ischemia requiring revascularization, showed a nonsignificant trend toward a benefit with rivaroxaban vs. placebo (7.0 percent vs. 5.6 percent). A secondary efficacy analysis did note a significant 31 percent reduction in the risk of endpoint, incidence of death, MI or stroke with rivaroxaban vs. placebo (5.5 percent vs. 3.9 percent).
The researchers found a trend for twice-a-day dosing to be safer and more effective than once-a-day dosing. Based on the safety and efficacy outcomes, two low doses—2.5 mg and 5 mg twice-daily—will be evaluated in a phase III trial.
Drug-eluting stents beat bare metal stents in treating diabetics
For patients with diabetes, drug-eluting stents (DES) may reduce the need for repeat revascularization procedures compared with bare metal stents (BMS) and are safe, suggest results of the observational Drug-eluting and Bare Metal Stenting in Patients with Diabetes Mellitus (Mass-DAC) registry.
This first real-world comparison of the two approaches in this population analyzed outcomes in 5,051 diabetic patients undergoing percutaneous coronary interventions (PCI) at acute-care, non-federal hospitals between April 2003 and September 2004 who were enrolled in a mandatory state database in Massachusetts.
In a propensity-score matched analysis of 1,476 DES patients and 1,476 BMS patients, DES was significantly superior to BMS after three years in terms of risk-adjusted mortality rate (17.5 percent vs. 20.7 percent), myocardial infarction rate (13.8 percent vs. 16.9 percent) and target vessel revascularization rate (18.4 percent vs. 23.7 percent).
“As a result, we can say that these stents appear to be safe in diabetic patients, whose diabetes puts them at higher risk of mortality and heart attack than the general population,” said Laura Mauri, M.D., M.Sc., principal investigator of the study and assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.
Diabetic patients make up about a third of all patients undergoing PCI. Patients in the registry were about twice as likely to receive DES compared with BMS (66.1 percent vs. 33.9 percent).
Tailored drugs reduce adverse effects after angioplasty, stenting
Individually tailoring the loading dose of the anti-clotting drug clopidogrel significantly cuts the rate of adverse events after angioplasty and stenting, according to the multicenter, prospective, randomized Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Prevent Stent Thrombosis Study.
The study enrolled 429 patients undergoing PCI who had a low response (VASP = 50%) to an initial 600 mg clopidogrel loading dose. The VASP index has previously been shown to be highly specific at measuring a patient’s anti-platelet response to clopidogrel. Patients were randomized to receive the usual single administration of one 600-mg dose of clopidogrel or up to three additional 600-mg clopidogrel doses to obtain a predefined adequate antiplatelet response (VASP index < 50%).
In his presentation, Franck Paganelli, M.D., Ph.D., professor of medicine in the division of cardiology at Hôpital Nord (North Hospital), University of Marseille, School of Medicine, in Marseille, France noted that patients with coronary artery disease vary widely in their responses to clopidogrel, and responses to clopidogrel are unpredictable.
The individualized approach was associated with a significant improvement in the rate of early definite stent thrombosis, defined as a total blockage originating in or within 5 mm of the stent and associated with a symptom of cardiovascular distress within 48 hours that occurred within a month of stent placement (0.5 percent vs. 4.2 percent with standard clopidogrel dosing). Paganelli pointed out that all early thromboses occurred within the first week.
The rate of major adverse cardiovascular events (MACE), including myocardial infarction, cardiovascular death, or urgent revascularization, was also significantly lower with individualized vs. standard treatment (0.5 percent vs. 8.9 percent).
Paganelli noted that the tailored approach significantly lowered the primary and secondary event endpoints without significantly increasing bleeding events, including major or minor bleeding. Moreover, no intra-cerebral bleeding or fatal bleeding events occurred. However, 8 percent of the patients in the test group remained low responders despite receiving the trial’s highest dose — 2400 mg of clopidogrel over three days.
back to top
back to today's issue
Central sleep apnea increases erythropoietin in HF patients
Nocturnal hypoxemia due to central sleep apnea promotes an increase in circulating endogenous erythropoietin in heart failure patients that is associated with an adverse prognosis, according to a study presented Monday in a moderated ePoster session on “Insights into the Pathophysiology of Anemia in Heart Failure.”
“Central sleep apnea, or CSA, affects up to 40 percent of heart failure patients,” said Andrew D. Calvin, M.D., M.P.H., an internal medicine resident at Mayo Clinic, Rochester, Minn. “CSA is also associated with hypoxemia. This hypoxemia causes neurohormonal activation and triggers erythropoietin production.”Erythropoietin, in turn, promotes increased neurohumoral activation, Calvin said. Elevated concentrations of endogenous erythropoietin in heart failure are associated with severity of the disease and increased mortality.
To prove the hypothesis that elevated erythropoietin levels are due to hypoxemia associated with CSA, Calvin and his colleagues used polysomnography to evaluate 29 ambulatory, non-anemic heart failure patients who had left-ventricular ejection fraction (LVEF) less than 45 percent and 18 healthy controls. They also measured erythropoietin concentrations.
The researchers defined CSA as an apnea-hypopnea index greater than 15 per hour, with more than 50 percent of sleep apnea events deemed central. They excluded patients with obstructive sleep apnea. Hypoxemia was quantified both as mean nocturnal oxygen (O2) saturation and percent of time spent with arterial O2 saturation less than 90 percent (T90).
“Forty-two percent of our heart failure subjects were found to have central sleep apnea. This finding is concordant with previous studies. Furthermore, men were much more likely to have central sleep apnea,” Calvin said. In addition, the heart failure patients were found to have higher levels of hypoxemia.
When the investigators looked at T90 levels after adjusting for potential confounding factors, such as age, gender, LVEF, renal function and hemoglobin, they found that the T90 levels correlated with erythropoietin levels. Patients with advanced heart failure (New York Heart Association class III-IV) had significantly higher levels of erythropoietin than non-advanced heart failure patients (NYHA I-II). This finding persisted after adjusting for hypoxemia.
back to top
back to today's issue
MicroRNAs may determine cardiac cell differentiation, apoptosis
MicroRNAs (miRs) may determine how cardiac cells respond to ischemic insults, according to data presented Monday during two Oral Abstract Sessions—one on “The Multipotency of Progenitor Cells into Myocytes” and the other on “Molecular Modulation of Autophagy and Apoptosis.”MiRs are small RNA molecules that can inhibit the translation of a gene by binding to a complementary sequence in its mRNA. Specifically, MiR-499 may be an important modulator that translocates to cardiac progenitor cells (CPCs) via gap junctions and differentiates them into cardiomyocytes. This observation may be significant for myocardial regeneration and partial recovery of the infarcted heart, said Toru Hosoda, M.D., Ph.D., Brigham and Women’s Hospital in Boston, Mass.
Hosoda and colleagues showed that MiR-499 is expressed more in mature myocytes than in CPCs. When murine cells were forced to overexpress MiR-499 and co-cultured with CPCs, the MiR-499 was able to migrate into CPCs—as determined from in situ immunofluorescence. The formation of gap junctions between the two cells was shown by immunostaining for connexin 43, a gap junction molecule. The involvement of gap junction was implicated when gap junction inhibitors prevented MiR-499 from crossing into CPCs.
In separate cell culture assays, MiR-499 prevented the expression of Sox6 and Rod1, two genes that may be involved in the transcriptional regulation of CPCs.
“The new biological process of translocation of MiR from one cell to another (called ‘mircrine’) may be significant for myocardial recovery of the infarcted heart,” Hosoda said.
It may be possible to inject the infarcted heart with CPCs overexpressing MiR-499, he said. This will help in the maturation of CPCs into cardiomyocytes.
In a second presentation, Shweta Rane, a graduate student at the University of Medicine and Dentistry of New Jersey in Newark, showed that MiR-199a is important in cardiac hypertrophy and its depletion may explain why cardiac myocyte apoptosis occurs during cardiac ischemia.
Rane showed an acute and complete elimination of MiR-199a in the heart and cardiac myocytes upon oxygen deprivation, a situation synonymous with cardiac ischemia. The depletion in MiR-199a correlated with an increase in hypoxia-inducible factor-1 alpha (HIF-1a) during hypoxia, which may be a direct target of miR-199a, followed by cardiac cell apoptosis.
Furthermore, hypoxia-induced apoptosis occurred by HIF-1a–mediated stabilization of p53, a gene that regulates apoptosis, Rane said. When MiR-199a was replenished during hypoxia, the expression of molecules directly involved in cell death — the caspases — was inhibited and cardiac myocyte apoptosis was significantly retarded.
In ongoing studies, Rane showed that under conditions that mimicked ischemia preconditioning, depleting cardiac myocytes of MiR-199a is associated with an upregulation of both HIF-1a and sirtuin 1, a longevity and anti-apoptotic molecule. HIF-1a, and by extension MiR-199a, can thus regulate both apoptosis and anti-apoptotic processes.
Ischemia preconditioning is the most effective approach known in protecting the heart against ischemic damage, but unfortunately relies on predicting the onset of an ischemic episode. Engineering reagents, such as miR-199a antagonists, that can induce miR-199a knockdown and, thus, mimic preconditioning, can be used as a preemptive strategy in ischemic heart disease, Rane said.
back to top
back to today's issue
People with high HDL-C, low LCAT still prone to ischemic heart disease
People with high HDL cholesterol (HDL-C) and low lecithin-cholesterol acyltransferase (LCAT) levels are as prone to coronary heart disease (CHD) as
those with low HDL-C and low LCAT activity, a National Institutes of Health researcher said Monday in an oral abstract session.In the session, “Modification of HDL and Risk,” Amar Sethi, M.D., Ph.D., a researcher from the Lipoprotein Metabolism Section, the National Heart, Lung, and Blood Institute (NHLBI), said these findings are contrary to current clinical belief that individuals with high levels of HDL-C are protected from cardiovascular morbidity.
The hypothesis tested was that patients with high HDL-C and cardiovascular disease have dysfunctional HDL, which may be due to the compositional difference of the HDL particle.
In data presented from the Copenhagen City Heart Study, groups of patients with high HDL-C (n=58) and low HDL-C (n=47) with CHD were age and gender matched with subjects with high HDL-C (n=58) and low HDL-C (n=55) without CHD. All participants had normal low-density lipoprotein and triglyceride levels and were not receiving lipid-lowering medications.
Initial analysis of the composition of the lipid and apolipoprotein fractions did not show significant differences between the patient and control populations.
Sethi and colleagues then checked to see if differences in reverse cholesterol transport — a way the body removes bad cholesterol — might provide an explanation. Using isolated HDL particles, they first noticed that pre-beta HDL levels were significantly high in all patients with CHD, regardless of whether they had low (p=0.001) or high HDL-C (p<0.0001) compared with control subjects.
Since pre-beta HDL accumulation with maturation of HDL is an issue, Sethi and colleagues determined if enzymes involved in the maturation of HDL contributed to the accumulation of pre-beta HDL. Using commercially available kits, they found that activity of LCAT, more than other enzymes, was significantly low in patients with CHD having high HDL-C (p=0.002) and low HDL-C (p=0.03) compared with the matched controls. In addition, based on receiver operator curves, a graphical method for determining sensitivity and accuracy, high HDL-C and low LCAT activity together correctly classified 92 percent of patients with CHD.
“Measuring pre-beta HDL-C and LCAT activity are feasible diagnostic tests that can be implemented to identify most patients at increased risk for cardiovascular morbidity,” Sethi said.
Based on current treatment guidelines, about 30 percent of the U.S. population with low HDL-C and no risk factors for cardiovascular morbidity receive no treatment to alleviate cardiovascular risks.
“These individuals may benefit from testing for pre-beta HDL-C and LCAT activity,” Sethi said.
back to top
back to today's issue
PAID ADVERTISEMENT
