Gene therapy is to be used for the first time in an attempt to improve the condition of heart failure patients. Subjects enrolled in the Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study will undergo a minimally invasive cardiac catheterization procedure designed to introduce a specially engineered gene that stimulates production of an enzyme necessary for the heart to pump more efficiently.
The multicenter national trial, which is funded and administered by the Celladon Corporation, will build on previous data suggesting that the treatment, called MYDICAR®, can lead to significant improvements in heart function without significant safety concerns in large-animal models of heart failure. This, however, is the first human trial of the technique.
Donna Mancini, the study’s principal investigator at New York Presbyterian Hospital/Columbia University Medical Center, is hopeful that gene therapy might be a suitable alternative in patients for whom conventional therapy is out of the question. “This new therapy seeks to replenish the levels of this enzyme by introducing the gene SERCA2a, which is depressed in these (heart failure) patients. If proven effective, this approach could be an alternative to heart transplant for patients without any other options,” she stated.
The trial will be divided into two parts, the first of which will measure the safety of the technique and the second of which will assess the ability of MYDICAR to improve heart function. Safety will be measured by the incidence and severity of adverse events: all-cause mortality, progression of heart failure leading to hospitalization, and/or intravenous inotrope, vasodilator, and/or diuretic administration.
The assessment of the efficacy of the technique will be based on changes from baseline to 3, 6, 9 and 12 months in VO2 max, a 6-min walk test, echocardiographic assessments, NT-proBNP level and NYHA Classification. Quality of Life will be measured by the Minnesota Living with Heart Failure Questionnaire.
We will have to wait until completion of the CUPID study in 2010 before we can assess whether the authors’ hypothesis that “increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life” is over-optimistic.
Source: www.celladon.net
Hedgehog antagonists may harm the adult heart
David Ornitz and his team at the Washington University school of Medicine (MO, USA) had previously shown that Hedgehog signaling is crucial for the growth of blood vessels in the developing mouse heart, but new research suggests that the adult heart might also depend on Hedgehog for its blood supply.
Ornitz and colleagues ablated endogenous hedgehog signaling in murine myocardial and perivascular smooth muscle cells, finding that hedgehog signaling was necessary for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of Hedgehog signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure and subsequent lethality.
This finding might bear particular relevance to cancer patients being treated with hedgehog antagonists, explained lead author Kory Lavine. “We’ve shown that small decreases in the hedgehog pathway in the setting of heart disease can lead to deleterious outcomes, and since a number of patients with cancer also have heart disease, this raises concern for those who might be treated with hedgehog antagonists,” he described.
Indeed Hedgehog antagonists are currently being used to treat a variety of cancers, including basal cell carcinoma, prostate cancer, pancreatic cancer, colorectal cancer and medulloblastoma.
However, whilst Ornitz has stated that “it could be very important to monitor patients,” the authors point out the possibility that the “therapeutic effects of hedgehog antagonists may be achieved at levels of inhibition that do not impair cardiac function”.
Source: Lavine KJ, Kovacs A, Ornitz DM. Hedgehog signaling is critical for maintenance of the adult coronary vThings are looking sunny for vitamin D in heart failure therapyasculature in mice. Clin Invest. 118(7), 2404–2414 (2008).
Things are looking sunny for vitamin D in heart failure therapy
A role for vitamin D in protecting against heart failure has been predicted by a number of investigators, but now Robert Simpson and colleagues at the University of Michigan have used a rat model of heart failure to show that activated vitamin D can prevent cardiac hypertrophy and increase cardiac output.
Spontaneously hypertensive heart failure rats were fed either a normal or a high-salt diet and half of each group was also treated with 1,25-dihydroxyvitamin D3 (activated vitamin D). After 13 weeks, Simpson and colleagues observed that 1,25-dihydroxyvitamin D3 treated rats fed a high-salt diet had a lower heart weight, lower myocardial collagen levels, smaller left ventricular diameter and lower cardiac output despite higher serum leptin levels.
“Our studies indicate that absence of vitamin D-mediated signal transduction and genomic activation results in cardiomyocytes overstimulation including increased contractility. These events ultimately lead to cardiomyocyte hypertrophy,” the authors explain.
Simpson et al. believe the results “suggest potential clinical utilization of 1,25-dihydroxyvitamin D3 as an adjunctive therapeutic agent in patients with LV hypertrophy, a strategy that has been used successfully to reduce posterior wall thickness in patients with renal failure.”
Source: Mancuso P, Rahman A, Hershey SD, Dandu L, Nibbelink KA, Simpson RU. 1,25-Dihydroxyvitamin-D3 treatment reduces cardiac hypertrophy and left ventricular diameter in spontaneously hypertensive heart failure-prone (cp/+) rats independent of changes in serum leptin. J. Cardiovasc. Pharmacol. 51(6), 559–564 (2008).
Thrombosis guidelines to be updated
An international panel of 90 experts has collaborated to develop the 8th Edition of the ACCP Antithrombotic and Thrombolytic Therapy Guidelines. According to Guidelines panel chair Jack Hirsh (Henderson Research Centre, Hamilton, ON, Canada) the new guidelines are a significant improvement over the previous effort. “We’ve markedly increased the number of non-North American participants, so the recommendations are more international. The process of evaluation has improved dramatically – it’s much more rigorous, with panelists for each chapter developing questions sent out to an evidenced-based center, which then performed a literature search. Tables of all the clinical trials that have been done for every single clinical condition are included. The review process has changed too, with each chapter and the manuscript as a whole reviewed by two independent people.”
As for any update, some things have changed greatly whereas others have changed little. While there is “not a lot that is new” according to Hirsh, for the management of anticoagulation therapy for atrial fibrillation, the new guidelines include a completely new chapter on perioperative management for patients on long-term antithrombotic therapy who require surgery or other invasive procedures. For example, the new recommendations suggest that those who are taking warfarin should alter their regimen according to the type and complexity of surgery. Thus, for a simple operation such as cataract surgery, the Warfarin dose should be lowered, but for more complex procedures, ceasing therapy around 5 days before surgery and instead using low-molecular-weight heparins could be an appropriate strategy.
There are a number of relevant chapters for cardiologists including: antithrombotic therapy for non-ST segment elevation acute coronary syndrome, acute ST segment elevation myocardial infarction, primary and secondary prevention of coronary artery disease, and valvular and structural heart disease.
Source: Hirsh J, Guyatt G, Albers GW et al. American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 133(6 Suppl.), 110S–968S (2008).
Machine at least as good as Man
An international study in 32 medical centers across Europe, involving more than 13,000 patients, has concluded that dosages of antianticoagulant drugs are as safe and reliable when calculated by a computer as they are when determined by a medical expert.
“The need for computer assistance arises from the massive demand for oral anticoagulants following their success at treating an increasing number of thrombotic and embolic conditions”, explains Professor Leon Poller, who coordinated the international team. Prescribing the correct oral dose of anticoagulant to patients can also be problematic, even for experienced medical staff: individuals differ greatly in response to a given dose and a single patient’s response can change over the period of an illness.
The percentage of manual tests to give the correct INR was 64.7%, compared to 65.9% for computer-assisted dosage. Time spent in the target INR range was significantly improved by computer assistance as compared with medical staff dosage in the majority of centers and the number of clinical events was lower.
“Our study confirms the clinical safety and effectiveness of computer-assisted dosage using the two systems we tested and should help to bring relief to overstretched medical professionals while providing r-eassurance to patients,” said Poller.
Source: Poller L, Keown M, Ibrahim S et al. An international multi-centre randomized study of computer-assisted oral anti-coagulant dosage vs. medical staff dosage. J. Thromb. Haemost. 6(6), 935–943 (2008).
A revolution in the treatment of stroke?
When it comes to the emergency treatment of ischemic stroke, tissue plasminogen activator (tPA) has been the drug of choice for over 10 years. Yet tPA is handicapped by concerns over hemorrhagic complications and the requirement that it be administered within 3 h of the onset of symptoms. Could a drug currently used to treat leukemia ameliorate these problems?
Researchers from the University of Michigan (MI, USA) and the Karolinska Institutet in Stockholm (Sweden), have collaborated to show that tPA increases the risk of bleeding and leakage of fluid within the brain because it can interact with a protein called PDGF-CC and the PDGF-α receptor that PDGF-CC binds to. This causes the blood–brain barrier to become porous, leading to leakage. However, the leukemia drug Gleevec® (imatinib) inhibits the PDGF-α receptor, thereby counteracting this unwanted effect of tPA.
First of all, the researchers demonstrated in non-stroke mice that tPA and PDGF-CC act on the same target, but they must both be injected into the brain side of the blood–brain barrier to cause leakage. Then, by observing the activation of the PDGF-α receptor on the side of the brain where a stroke had been induced, compared with the contralateral side, in both normal mice and mice that were deficient in natural tPA, the team deduced that the receptor is crucial to the blood–brain barrier permeability that is caused by tPA activation of PDGF-CC.
It followed that an agent capable of inhibiting the PFGF-α receptor might help to prevent leakage across the blood–brain barrier after stroke. Thus, 1 h after inducing stroke, one group of mice were administered a dose of imatinib. Mice that received the drug had 33% less leakage than those that did not, and 72 h later, the mice that received imatinib had 34% less damage to the brain than the control group.
As a pretreatment to tPA, imatinib also showed promise. When administered 1 h after the onset of stroke but 4 h before tPA treatment, mice that had received imatinib before tPA had 50% less hemoglobin than those that had not received pretreatment in the stroke affected side of the brain. This result is especially encouraging given that stroke diagnosis can often take hours.
Although the study was carried out in mice, senior author Daniel Lawrence is hopeful that these findings will have a real impact on the short-term treatment of ischemic stroke in humans: “Our findings may have immediate clinical relevance, and could be applied to find new treatments that will benefit stroke patients … By better understanding how the brain regulates the permeability of the blood–brain barrier, and how tPA acts upon that system, we hope to reduce the risks and increase the time window for stroke treatment”. Ulf Eriksson, leader of the team based at the Karolinska Institutet agrees: ‘Our research group identified the growth factor PDGF-CC 10 years ago and we are now very excited having unraveled a mechanism in the brain involving this factor, which potentially will be a revolution in the treatment of stroke.”
Source: Su E, Fredriksson L, Geyer M et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med. DOI: 10.1038/nm1787 (2008) (Epub ahead of print).
Drug-eluting may be better than bare metal for health of stent population
While most studies assessing the comparative merits of drug-eluting stents (DES) versus bare metal stents (BMS) have hinged on a comparison between outcomes in patients receiving either type, a recent study led by David Malenka of the Dartmouth-Hitchcock Medical Center employed a different tactic. “Another important aspect on the safety and effectiveness of DES could be obtained by assessing how the rapid adoption of DES use affected the health of the entire stented population,” he explained.
Malenka and colleagues compared the outcomes of Medicare patients who underwent non-emergent coronary stenting in the BMS era versus the DES era. A total of 38,917 patients who underwent surgery between October 2002 and March 2003, when only BMS were available, were compared with 28,086 similar patients who were operated on between September and December 2003, when 61.5% of patients received a DES and 38.5% received a BMS. The main outcome measures were coronary revascularization (percutaneous coronary intervention and coronary artery bypass surgery), ST-elevation myocardial infarction and survival through 2 years of follow-up.
The team found that patients treated in the DES era had significantly lower 2-year risks for repeat percutaneous coronary interventions (17.1 vs 20.0%; p < 0.001) and coronary artery bypass surgery (2.7 vs 4.2%; p < 0.01), even after risk adjustment. There was no difference in unadjusted mortality risks at 2 years (8.4 vs 8.4%; p = 0.98 ), but a small decrease in ST-elevation myocardial infarction existed (2.4 vs 2.0%; p < 0.001).
The authors conclude: “We speculate that whatever the increased risk of stent thrombosis associated with DES use is, it is more than offset by a decrease in the risk of developing restenosis and the attendant risk of a procedure to treat that restenosis.”
Source: Malenka DJ, Kaplan AV, Lucas FL, Sharp SM, Skinner JS. Outcomes following coronary stenting in the era of bare-metal vs the era of drug-eluting stents. JAMA 299(24), 2868–2876 (2008).