Speciality
Spotlight

 




 


Cardiology


 


   





  • Minal
    Chande

    Sulindac prevents restenosis after angioplasty
    in rodents


    The Lancet, vol.356, Oct.14, 200, pg.1333

        


    New research in rodents suggests that sulindac, a
    non-steroidal anti-inflammatory drug, may be
    effective in preventing vascular restenosis after
    angioplasty and related procedures.

        


    The research team from the Mount Sinai School of
    Medicine (New York, NY USA) used a mouse model of
    arterial injury, recognised to have essential
    similarities to human cardiovascular disorders, to
    assess the effects of aspirin and sulindac on
    neointimal formation. They report that sulindac
    reduced neointimal formation by as much as 70% in
    normolipidaemic and hyperlipidaemic mice.
    Treatment with aspirin did not significantly
    reduce neointimal formation.

       


    “The clinical implications are that a drug
    that has proven safe and effective in human beings
    may have the potential to reduce the rate of
    restenosis, but this remains to be proven in a
    clinical trial”, says lead author, Edward
    Fisher. 

       

  • Michael
    Bristow

    Etomoxir: a new approach to treatment of
    chronic heart failure.


    The Lancet, vol.356, Nov.11, 2000, pg.1621.

       


    Etomoxir, a compound once developed for the
    treatment of diabetes mellitus, has recently been
    shown to have promise as a novel form of therapy
    for heart failure.

       


    Etomoxir is an oxirane carboxylic acid derivative
    that is an inhibitor (Ki of 8mM) of carnitine
    palmitoyltransferase-I (CPT-1). CPT-1 is a
    mitochondrial enzyme that plays a key role in the
    transport of long-chain acyl-CoA compounds into
    the mitochondria, so etomoxir inhibits fatty-acid
    metabolism but promotes that of glucose.

       


    Rats made diabetic with streptozotocin develop
    myocardial molecular or biochemical abnormalities
    that resemble chronic myocardial failure in human
    beings. The abnormalities include those of
    b-receptor signal transduction and induction of
    the “fetal” gene programme.

      


    The concept of the fetal gene programme is that
    pathological hypertrophy is produced by both
    qualitative and quantitative change is to a
    ventricular expression of genes which contribute
    to the increase in myocardial mass. The
    qualitative change is to a ventricular expression
    pattern ordinarily observed only during fetal
    life. The fetal gene programme includes atrial
    natriuretic peptide and brain natriuretic peptide,
    two counter regulatory proteins considered to be
    molecular markers of hypertrophy. Other members of
    the fetal gene programme are the contractile
    proteins b-myosin heavy chain (b-MyHC), atrial
    light chain-1, and the a-skeletal actin, all of
    which demonstrate increased expression in humans
    and/or rodent models of pathological hypertrophy
    and myocardial failure. Associated with the
    increased expression of these contractile protein
    fetal isoforms, at least in rodent models, is a
    down-regulation in sarcoplasmic reticulum Ca
    ATPase (SERCA2), a key enzyme in regulating
    systolic and diastolic function.

        


    In diabetic rats etomoxir attenuates these
    molecular abnormalities. Moreover, when rats are
    subjected to pressure overload, etomoxir also
    prevents induction of the fetal gene programme,
    preserves myocardial contractile function and
    prevents dilatation of the left ventricule.

       


    The observation make it logical to evaluate
    etomoxir as a treatment for chronic heart failure.

       


    These investigators evaluated the effects of
    etomoxir on haemodynamics and myocardial function
    acutely in vitro and in vivo, and chronically
    (over 3 months) in patients with heart failure.
    Etomoxir produced no acute effects in isolated
    preparations of human heart or in patients with
    heart failure. However, when etomoxir was given
    over 3 months to patients with Class II or III
    symptoms , systolic function improved. Evidence of
    this improvement included substantial increase in
    stroke volume at rest and improved cardiac output
    with exercise, a decrease in pulmonary wedge mean
    pressure and an increase in LVEF. However, a
    single dose of etomoxir did not decrease systemic
    vascular resistance over the next 4 h, and the
    investigators offer the oblique argument that the
    improvement in myocardial function was due to a
    direct, time-dependent effect of etomoxir on
    myocardial gene expression. 

       


    They speculate that an up-regulation of SERCA2
    accounted for the improvement in myocardial
    function. If they turn out to be right, etomoxir
    could be a pharmacological agent for reversing
    abnormal myocardial gene expression in patients
    with chronic heart failure. As such, etomoxir
    would join b-blocking agents as a compound that
    improves SERCA2 expression and other aspects of
    fetal gene expression in chronic heart failure, as
    well as improving myocardial contractile function
    in a time dependent, biological fashion.
    b-blocking agents are also CPT-1 inhibitors.
    However, the precise mechanisms by which etomoxir
    or b-blockers reverse fetal gene induction is not
    well understood.

       

  • Scott Gottlieb

    News : b Blockers Improve Bypass Surgery Survival Rates

    BMJ, 11 May, 02, Vol.324, pg.1118

      

    Patients who take b blockers before coronary artery bypass surgery can increase their odds of surviving, a new study says.

     

    The study found that 2.8% of patients who took b blockers before surgery died within a month, compared with 3.4% of patients who did not take the drugs.

       

  • James A. De Lemos, David A. Morrow, et al

    The Prognostic Value of B-Type Natriuretic Peptide in Patients with Acute Coronary Syndromes

    New Eng J Med. Vol.345, Oct.4, 2001, pg.1014-21

      

    Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation.

      

    The authors measured B-type natriuretic peptide in plasma specimens obtained a mean (+SD) of 40+ 20 hours after the onset of ischemic symptoms in 2525 patients.

     

    A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides predictive information for use in risk stratification across the spectrum of acute coronary syndromes. Cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes.

       

  • LeRoy E. Rabbani

    Acute Coronary Syndromes Beyond Myocyte Necrosis

    New Eng J Med. Vol.345, Oct.4, 2001, pg.1057-59

       

    The acute coronary syndromes, which comprise unstable angina, myocardial infarction without ST-segment elevation, and myocardial infarction with ST-segment elevation, continue to be a major health problem.

      

    A typical approach to the acute coronary syndromes includes multiple treatment options: aspirin, beta-blockers, nitrates, unfractionated heparin, low-molecualr-weight heparin, intravenous glycoprotein IIb/IIIa receptor inhibitors, clopidogrel, coronary stenting, thrombolytic agents, statins, and angiotensin-converting-enzyme (ACE) inhibitors.

       

    Use of the clinical characteristics of the patient, the electrocardiographic findings, and the levels of traditional serum markers of myocyte necrosis, such as the creatine kinase MB fraction and troponin I, is only partially successful in risk stratification. In patients who have unstable angina or myocardial infarction without ST-segment elevation, an elevated troponin level confers an increased short-term risk of death.

      

    De Lemos and colleagues measured plasma levels of brain (B-type) natriuretic peptide, a natriuretic and vasodilative peptide regulated by ventricular wall tension and stored mainly in the ventricular myocardium, in 2525 patients with acute coronary syndromes.

      

    A single measurement of B-type natriuretic peptide obtained a median of 40 hours after the onset of ischemic symptoms predicted the risk of death in patients who had myocardial infarction with ST-segment elevation, myocardial infarction without ST-segment elevation, or unstable angina, as well as the risk of new or progressive congestive heart failure and new or recurrent myocardial infarction.

      

    Moreover, the relation between the long-term risk of death and the B-type natriuretic peptide level was independent of electrocardiographic changes, troponin I levels, renal function, and the presence or absence of clinical evidence of congestive heart failure.

      

    The observation that B-type natriuretic peptide, a marker of neurohormonal activation, is a prognostic factor in acute coronary syndromes is intriguing, given the importance of neurohormonal activation in acute myocardial infarction. Beta-blockers and ACE inhibitors, both of which counter neurohormonal activation, are crucial for the secondary prevention of myocardial infarction.

      

    In contrast to the long-standing knowledge that neurohormonal activation is deleterious in the acute coronary syndromes, the realization that inflammation has a critical role in the pathogenesis of these syndromes has occurred relatively recently. Inflammation contributes on several levels to the rupture of vulnerable atherosclerotic plaques or to the superficial intimal erosion, both of which may be followed by coronary thrombosis.

      

    Bayes-Genis and colleagues present histologic evidence that pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase and an activator of proatherogenic insulin-like growth factor I (that was first identified in pregnant women), is expressed in ruptured and eroded plaques but not stable plaques.

      

    Circulating PAPP-A levels were significantly elevated in patients with acute coronary syndromes. Elevated PAPP-A levels appeared to identify patients with unstable angina in the absence of elevations in either troponin I or C-reactive protein. Therefore, this inflammatory marker may have the ability to detect at-risk patients with rupture or erosion of plaques before and independent of the advent of myocyte necrosis.

      

    Tests for both neurohormonal activation, reflected by an elevation in B-type natriuretic peptide, and inflammation, reflected by the release of PAPP-A, may augment the ability to identify patients with acute coronary syndromes who are at risk for adverse events.

      

    The use of these markers could thus potentially augment the ability to reserve the most expensive and aggressive therapies for patients who have the highest risk. Finally, these insights may also stimulate the development of drugs, such as antiinflammatory and antineurohormonal agents, that will further improve the outcomes of patients with acute coronary syndromes.

         

  • Michael S. Lauer

    Aspirin for Primary Prevention of Coronary Events

    New Eng J Med. Vol.346, May 9, 2002, pg.1468-74

      

    Suggested Algorithm for Making Decisions about the Use of Aspirin for Primary Prevention of Coronary Heart Disease

      



      

    Aspirin use probably reduces the risk of myocardial infarction in men over the age of 50 years. For individual patients, the decision to initiate aspirin therapy should be based on a careful assessment of absolute risk. The absolute risk of major coronary events should be calculated as the Framingham risk score.

      

    This can easily be done in the physician’s office with the use of an on-line or downloaded version of the scoring system (for example, that available at http://www.nhlbi.nih.gov/atpiii/calculator.asp? usertype=prof). A suggested algorithm for making decisions about the use of aspirin therapy on the basis of predictions of absolute risk is presented in the figure.

           

  • Richard O. Cannon

    Perspective: Restenosis After Angioplasty

    New Eng J Med. Vol.346, April 18, 2002, pg.1182-83

      

    The success of percutaneous coronary intervention has been due largely to an explosion in technology development, with the introduction of a broad array of balloon catheters, atherectomy devices, lasers, and stents. The impetus for the development of such devices has been the occurrence – noted soon after the introduction of balloon angioplasty – of intimal tears, arterial recoil, and ingrowth of tissue in response to balloon expansion within the diseased arterial segment.

      

    The result is abrupt closure or restenosis after a period of weeks or months. The introduction of balloon-expandable stents has increased the success of percutaneous coronary intervention by allowing intimal flaps and dissections to be tacked to the arterial wall and by preventing recoil, but these stents did not eliminate the proliferation of fibrous and smooth-muscle tissue within and around the wire mesh of the
    stent.

       

    Cognizant of the inhibitory effects of radiation on cellular proliferation, investigators have approached the problem of restenosis by using radiation within the restenosed arterial segment (brachytherapy), generally after repeated balloon angioplasty, atherectomy, or stenting. In 2000, on the basis of data from randomized clinical trials, the FDA approved two brachytherapy devices for the treatment of restenosis within stents implanted during a prior percutaneous coronary intervention. One device has a beta-particle-emitting source, and the other a gamma-ray-emitting source.

      

    Waksman and coworkers report on the use of the latter device to address a particularly difficult problem for interventionists: the treatment of in-stent restenosis within saphenous-vein grafts in patients who have previously undergone coronary-artery bypasss surgery.

      

    At 12 months, significantly fewer radiation-treated patients required rehospitalization for angina, and the need for repeated treatment of restenosis in this group was reduced by 70 percent – important findings from a clinical perspective.

       

    Sousa and coworkers implanted stents coated with sirolimus (previously called rapamycin) in diseased coronary arteries in 45 patients in Brazil and the Netherlands. None of the patients had restenosis, as assessed by coronary angiography and intravascular ultrasonography, one year after treatment.

       

  • Christine M. Albert, Hannia Campos, et al

    Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death

    New Eng J Med. Vol.346, April 11, 2002, pg.1113-8

      

    Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown.

      

    The authors conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians’ Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status.

       

    The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.

       

  • Irwin H. Rosenberg

    Fish – Food to Calm the Heart

    New Eng J Med. Vol.346, April 11, 2002, pg.1102-03

        

    By 1930, it was clear that some fatty acids not only were sources of energy (as a result of oxidation), but also were essential in the diet – thus, the term “essential fatty acids.”

      

    The author’s focus is on long-chain n-3 fatty acids, which are characterized by the presence of a double bond three carbons from the n end of the molecule. Two such acids – docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – derived largely from marine species, especially fatty fish (salmon, bluefish, mackerel, arctic char, and sword- fish), are mainly responsible for the protective effects of this group of substances, although they can be made from shorter-chain a-linolenic acid, which is present in some vegetable oils, nuts, and seeds.

       

    The result of the protective action of n-3 fatty acids in blood (these substances are really markers of dietary patterns, as the authors point out), but rather the effect of diet on the fatty-acid content of phospholipids in heart-cell membranes in the functionally critical SN2 position.

      

    In the event of severe physiological stress, such as that caused by the loss of blood supply to a portion of the heart early in an ischemic attack, the DHA or EPA occupying the SN2 position in phospholipids is released and protects the heart cell locally participating in the genesis and propagation of ventricular tachycardia, which can result in cardiac arrest and sudden death.

      

    This protective effect, which is absent if other fatty acids derived from the diet occupy the SN2 position, depends on the unique ability of these n-3 fatty acids to stabilize all contractile heart cells electrically and thus protect against sudden death from arrhythmias.

      

    The mechanism underlying the prevention of sudden death from cardiac causes differs from that of prevention of atherosclerotic heart disease, and n-3 fatty acids play a critical part. It is both safe and prudent to eat, as recommended by the American Heart Association, at least two servings of fish per week, especially fatty fish. There are also likely to be other beneficial effects of the intake of n-3 fatty acids including those on blood triglyceride levels, the immune system, the developing central nervous system (by the transmission of fatty acids through breast milk).

        

  • N T Mulvihill, and J B Foley

    Review: Inflammation in Acute Coronary Syndromes

    Heart Vol.87(3), March 2002, pg.201-204

      

    There is substantial evidence implicating an inflammatory process in the pathogenesis of acute coronary syndromes. Local inflammatory cells can generate and release cytokines that have the potential to activate the endothelium, transforming its natural antiadhesive and anticoagulant properties.

      

    Furthermore, inflammatory cytokines may reduce matrix synthesis and increase its degradation, favouring plaque rupture. Finally, cytokines may enhance synthesis of endothelin in endothelial cells and macrophages, resulting in increased smooth muscle cell reactivity to local vasoconstrictors. The evidence supporting this hypothesis that inflammation is critical in the pathogenesis of acute coronary syndromes comes from a variety of sources.

      

    Histological analysis of atherosclerotic coronary arteries taken from patients who died of acute coronary syndromes has shown that unstable or ruptured atherosclerotic plaques are characterised by the presence of foam cells, macrophages, lymphocytes, and mast cells. Macrophages and to a lesser extent T lymphocytes were the dominant cell type at the site of plaque rupture or erosion. These inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption.

      

    Activated mast cells are abundant in the adventitial layer of infarct related coronary vessels and, interestingly, mast cell densities were twofold higher in normal segments of the infarct related artery, suggesting that the entire adventitial layer of the vessel is involved in an inflammatory process. When activated, the mast cells can release histamine as well as other endogenous vasoconstrictors and the resultant coronary spasm can contribute to the clinical syndrome.

      

    It may be concluded that, there is extensive evidence to support a pathogenic role for both local and systemic inflammation in acute coronary syndromes. There is also evidence that increased concentrations of inflammatory markers at presentation can identify patients at high risk of future ischaemic events, suggesting that the intensity of the inflammatory response influences clinical outcome in acute coronary syndromes.

      

    It remains to be elucidated whether the inflammatory process observed is a precursor or a consequence of coronary plaque rupture; the emerging data suggest that the inflammatory process is indeed a precursor of the clinical event.

       

  • Y Fukuda, H Teragawa, et al

    Tetrahydrobiopterin Restores Endothelial Function of Coronary Arteries in Patients with Hypercholesterolaemia

    Heart Vol.87(3), March 2002, pg.264-269

      

    The objective of this study was to examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients.

      

    Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine
    (ACh).

      

    ACh was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 before and after infusion of
    L-NG-monomethyl-L-arginine (L-NMMA).

      

    The conclusion of the study was that intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients.

      

  • M Komajda

    Editorial: Are Angiotensin II Receptor Blockers Indicated in Chronic Heart failure?

    Heart Vol.87(1), January 2002, pg.1-2

      

    Chronic heart failure is one of the most serious cardiac problems encountered in clinical practice. Modulation of the renin angiotensin system is a key element in the treatment of this syndrome. There is overwhelming evidence in favour of the benefit of angiotensin converting enzyme (ACE) inhibitors on morbidity and mortality in mild to severe heart failure and in heart failure or left ventricular dysfunction following acute myocardial infarction.

      

    It is not known, however, whether the benefit of ACE inhibition is solely attributable to blockade of angiotensin II production or also related to bradykinin accumulation. Morevover, bradykinin accumulation has been implicated in the adverse effects observed with ACE inhibitors such as cough and might result in prejunctional noradrenaline (norepinephrine) release.

      

    The development of orally active, non-peptide angiotensin II type I receptor blockers (ARBs) has raised hopes for a new generation of modulators of the renin angiotensin system better tolerated and potentially more powerful. Since ARBs block directly the binding of angiotensin II to the receptor which mediates harmful biological actions such as vasoconstriction, aldosterone synthesis, and trophic effects, one potential advantage is to avoid the ACE independent pathway generation to angiotensin II.

      

    ARBs might be a useful alternative agent to block the renin angiotensin system in patients who do not tolerate ACE inhibitors.

      

    The results of Val-HeFT trial demonstrate a modest benefit for ARBs over ACE inhibitors in morbidity and mortality.

      

    The dual combination ACE inhibitor-b blocker is so powerful in reducing morbidity and mortality that the addition of a third neuromodulator, valsartan, does not result in any benefit because of a “plateau” effect.

       

  • Eugene Crystal, Stuart J Connolly

    Evolution of the Implantable Cardioverter Defibrillator

    Lancet Vol. 359, April 20, 2002, Pg. 1362-63

      

    Ventricular fibrillation is a leading cause of preventable death in patients with heart disease, and use of the implantable cardioverter defibrillator (ICD) is key in reducing mortality from this cause. Either spontaneous or inducible sustained ventricular fibrillation or tachycardia is a leading indication for an
    ICD.

      

    The ICD is evolving from an instrument for stopping ventricular fibrillation to one for the management of heart failure. The convergence of technology for defibrillation and for biventricular pacing is another step on this path. More and more, myocardial dysfunction, with or without overt arrhythmia, will become the prime indication for
    ICD.

       

  • Arthur J. Moss, Wojciech Zareba, et al for the Multicenter Automatic Defibrillator Implantation Trial II Investigators

    Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction

    N Engl J Med Vol. 346, March 21, 2002, Pg. 877-83

      

    In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy.

       

  • Paul Dorian, Dan Cass, et al

    Amiodarone As Compared With Lidocaine for Shock-Resistant Ventricular Fibrillation

    N Engl J Med Vol. 346, March 21, 2002, Pg. 884-90

      

    As compared with lidocaine, amiodarone leads to substantially higher rates of survival to hospital admission in patients with shock-resistant out-of-hospital ventricular fibrillation.

        


BACK




 

 

Speciality Spotlight

 

   

  • Minal Chande
    Sulindac prevents restenosis after angioplasty in rodents
    The Lancet, vol.356, Oct.14, 200, pg.1333
        
    New research in rodents suggests that sulindac, a non-steroidal anti-inflammatory drug, may be effective in preventing vascular restenosis after angioplasty and related procedures.
        
    The research team from the Mount Sinai School of Medicine (New York, NY USA) used a mouse model of arterial injury, recognised to have essential similarities to human cardiovascular disorders, to assess the effects of aspirin and sulindac on neointimal formation. They report that sulindac reduced neointimal formation by as much as 70% in normolipidaemic and hyperlipidaemic mice. Treatment with aspirin did not significantly reduce neointimal formation.
       
    “The clinical implications are that a drug that has proven safe and effective in human beings may have the potential to reduce the rate of restenosis, but this remains to be proven in a clinical trial”, says lead author, Edward Fisher. 
       

  • Michael Bristow
    Etomoxir: a new approach to treatment of chronic heart failure.
    The Lancet, vol.356, Nov.11, 2000, pg.1621.
       
    Etomoxir, a compound once developed for the treatment of diabetes mellitus, has recently been shown to have promise as a novel form of therapy for heart failure.
       
    Etomoxir is an oxirane carboxylic acid derivative that is an inhibitor (Ki of 8mM) of carnitine palmitoyltransferase-I (CPT-1). CPT-1 is a mitochondrial enzyme that plays a key role in the transport of long-chain acyl-CoA compounds into the mitochondria, so etomoxir inhibits fatty-acid metabolism but promotes that of glucose.
       
    Rats made diabetic with streptozotocin develop myocardial molecular or biochemical abnormalities that resemble chronic myocardial failure in human beings. The abnormalities include those of b-receptor signal transduction and induction of the “fetal” gene programme.
      
    The concept of the fetal gene programme is that pathological hypertrophy is produced by both qualitative and quantitative change is to a ventricular expression of genes which contribute to the increase in myocardial mass. The qualitative change is to a ventricular expression pattern ordinarily observed only during fetal life. The fetal gene programme includes atrial natriuretic peptide and brain natriuretic peptide, two counter regulatory proteins considered to be molecular markers of hypertrophy. Other members of the fetal gene programme are the contractile proteins b-myosin heavy chain (b-MyHC), atrial light chain-1, and the a-skeletal actin, all of which demonstrate increased expression in humans and/or rodent models of pathological hypertrophy and myocardial failure. Associated with the increased expression of these contractile protein fetal isoforms, at least in rodent models, is a down-regulation in sarcoplasmic reticulum Ca ATPase (SERCA2), a key enzyme in regulating systolic and diastolic function.
        
    In diabetic rats etomoxir attenuates these molecular abnormalities. Moreover, when rats are subjected to pressure overload, etomoxir also prevents induction of the fetal gene programme, preserves myocardial contractile function and prevents dilatation of the left ventricule.
       
    The observation make it logical to evaluate etomoxir as a treatment for chronic heart failure.
       
    These investigators evaluated the effects of etomoxir on haemodynamics and myocardial function acutely in vitro and in vivo, and chronically (over 3 months) in patients with heart failure. Etomoxir produced no acute effects in isolated preparations of human heart or in patients with heart failure. However, when etomoxir was given over 3 months to patients with Class II or III symptoms , systolic function improved. Evidence of this improvement included substantial increase in stroke volume at rest and improved cardiac output with exercise, a decrease in pulmonary wedge mean pressure and an increase in LVEF. However, a single dose of etomoxir did not decrease systemic vascular resistance over the next 4 h, and the investigators offer the oblique argument that the improvement in myocardial function was due to a direct, time-dependent effect of etomoxir on myocardial gene expression. 
       
    They speculate that an up-regulation of SERCA2 accounted for the improvement in myocardial function. If they turn out to be right, etomoxir could be a pharmacological agent for reversing abnormal myocardial gene expression in patients with chronic heart failure. As such, etomoxir would join b-blocking agents as a compound that improves SERCA2 expression and other aspects of fetal gene expression in chronic heart failure, as well as improving myocardial contractile function in a time dependent, biological fashion. b-blocking agents are also CPT-1 inhibitors. However, the precise mechanisms by which etomoxir or b-blockers reverse fetal gene induction is not well understood.
       

  • Scott Gottlieb
    News : b Blockers Improve Bypass Surgery Survival Rates
    BMJ, 11 May, 02, Vol.324, pg.1118
      
    Patients who take b blockers before coronary artery bypass surgery can increase their odds of surviving, a new study says.
     
    The study found that 2.8% of patients who took b blockers before surgery died within a month, compared with 3.4% of patients who did not take the drugs.
       

  • James A. De Lemos, David A. Morrow, et al
    The Prognostic Value of B-Type Natriuretic Peptide in Patients with Acute Coronary Syndromes
    New Eng J Med. Vol.345, Oct.4, 2001, pg.1014-21
      
    Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation.
      
    The authors measured B-type natriuretic peptide in plasma specimens obtained a mean (+SD) of 40+ 20 hours after the onset of ischemic symptoms in 2525 patients.
     
    A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides predictive information for use in risk stratification across the spectrum of acute coronary syndromes. Cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes.
       

  • LeRoy E. Rabbani
    Acute Coronary Syndromes Beyond Myocyte Necrosis
    New Eng J Med. Vol.345, Oct.4, 2001, pg.1057-59
       
    The acute coronary syndromes, which comprise unstable angina, myocardial infarction without ST-segment elevation, and myocardial infarction with ST-segment elevation, continue to be a major health problem.
      
    A typical approach to the acute coronary syndromes includes multiple treatment options: aspirin, beta-blockers, nitrates, unfractionated heparin, low-molecualr-weight heparin, intravenous glycoprotein IIb/IIIa receptor inhibitors, clopidogrel, coronary stenting, thrombolytic agents, statins, and angiotensin-converting-enzyme (ACE) inhibitors.
       
    Use of the clinical characteristics of the patient, the electrocardiographic findings, and the levels of traditional serum markers of myocyte necrosis, such as the creatine kinase MB fraction and troponin I, is only partially successful in risk stratification. In patients who have unstable angina or myocardial infarction without ST-segment elevation, an elevated troponin level confers an increased short-term risk of death.
      
    De Lemos and colleagues measured plasma levels of brain (B-type) natriuretic peptide, a natriuretic and vasodilative peptide regulated by ventricular wall tension and stored mainly in the ventricular myocardium, in 2525 patients with acute coronary syndromes.
      
    A single measurement of B-type natriuretic peptide obtained a median of 40 hours after the onset of ischemic symptoms predicted the risk of death in patients who had myocardial infarction with ST-segment elevation, myocardial infarction without ST-segment elevation, or unstable angina, as well as the risk of new or progressive congestive heart failure and new or recurrent myocardial infarction.
      
    Moreover, the relation between the long-term risk of death and the B-type natriuretic peptide level was independent of electrocardiographic changes, troponin I levels, renal function, and the presence or absence of clinical evidence of congestive heart failure.
      
    The observation that B-type natriuretic peptide, a marker of neurohormonal activation, is a prognostic factor in acute coronary syndromes is intriguing, given the importance of neurohormonal activation in acute myocardial infarction. Beta-blockers and ACE inhibitors, both of which counter neurohormonal activation, are crucial for the secondary prevention of myocardial infarction.
      
    In contrast to the long-standing knowledge that neurohormonal activation is deleterious in the acute coronary syndromes, the realization that inflammation has a critical role in the pathogenesis of these syndromes has occurred relatively recently. Inflammation contributes on several levels to the rupture of vulnerable atherosclerotic plaques or to the superficial intimal erosion, both of which may be followed by coronary thrombosis.
      
    Bayes-Genis and colleagues present histologic evidence that pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase and an activator of proatherogenic insulin-like growth factor I (that was first identified in pregnant women), is expressed in ruptured and eroded plaques but not stable plaques.
      
    Circulating PAPP-A levels were significantly elevated in patients with acute coronary syndromes. Elevated PAPP-A levels appeared to identify patients with unstable angina in the absence of elevations in either troponin I or C-reactive protein. Therefore, this inflammatory marker may have the ability to detect at-risk patients with rupture or erosion of plaques before and independent of the advent of myocyte necrosis.
      
    Tests for both neurohormonal activation, reflected by an elevation in B-type natriuretic peptide, and inflammation, reflected by the release of PAPP-A, may augment the ability to identify patients with acute coronary syndromes who are at risk for adverse events.
      
    The use of these markers could thus potentially augment the ability to reserve the most expensive and aggressive therapies for patients who have the highest risk. Finally, these insights may also stimulate the development of drugs, such as antiinflammatory and antineurohormonal agents, that will further improve the outcomes of patients with acute coronary syndromes.
         

  • Michael S. Lauer
    Aspirin for Primary Prevention of Coronary Events
    New Eng J Med. Vol.346, May 9, 2002, pg.1468-74
      
    Suggested Algorithm for Making Decisions about the Use of Aspirin for Primary Prevention of Coronary Heart Disease
      

      
    Aspirin use probably reduces the risk of myocardial infarction in men over the age of 50 years. For individual patients, the decision to initiate aspirin therapy should be based on a careful assessment of absolute risk. The absolute risk of major coronary events should be calculated as the Framingham risk score.
      
    This can easily be done in the physician’s office with the use of an on-line or downloaded version of the scoring system (for example, that available at http://www.nhlbi.nih.gov/atpiii/calculator.asp? usertype=prof). A suggested algorithm for making decisions about the use of aspirin therapy on the basis of predictions of absolute risk is presented in the figure.
           

  • Richard O. Cannon
    Perspective: Restenosis After Angioplasty
    New Eng J Med. Vol.346, April 18, 2002, pg.1182-83
      
    The success of percutaneous coronary intervention has been due largely to an explosion in technology development, with the introduction of a broad array of balloon catheters, atherectomy devices, lasers, and stents. The impetus for the development of such devices has been the occurrence – noted soon after the introduction of balloon angioplasty – of intimal tears, arterial recoil, and ingrowth of tissue in response to balloon expansion within the diseased arterial segment.
      
    The result is abrupt closure or restenosis after a period of weeks or months. The introduction of balloon-expandable stents has increased the success of percutaneous coronary intervention by allowing intimal flaps and dissections to be tacked to the arterial wall and by preventing recoil, but these stents did not eliminate the proliferation of fibrous and smooth-muscle tissue within and around the wire mesh of the stent.
       
    Cognizant of the inhibitory effects of radiation on cellular proliferation, investigators have approached the problem of restenosis by using radiation within the restenosed arterial segment (brachytherapy), generally after repeated balloon angioplasty, atherectomy, or stenting. In 2000, on the basis of data from randomized clinical trials, the FDA approved two brachytherapy devices for the treatment of restenosis within stents implanted during a prior percutaneous coronary intervention. One device has a beta-particle-emitting source, and the other a gamma-ray-emitting source.
      
    Waksman and coworkers report on the use of the latter device to address a particularly difficult problem for interventionists: the treatment of in-stent restenosis within saphenous-vein grafts in patients who have previously undergone coronary-artery bypasss surgery.
      
    At 12 months, significantly fewer radiation-treated patients required rehospitalization for angina, and the need for repeated treatment of restenosis in this group was reduced by 70 percent – important findings from a clinical perspective.
       
    Sousa and coworkers implanted stents coated with sirolimus (previously called rapamycin) in diseased coronary arteries in 45 patients in Brazil and the Netherlands. None of the patients had restenosis, as assessed by coronary angiography and intravascular ultrasonography, one year after treatment.
       

  • Christine M. Albert, Hannia Campos, et al
    Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death
    New Eng J Med. Vol.346, April 11, 2002, pg.1113-8
      
    Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown.
      
    The authors conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians’ Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status.
       
    The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.
       

  • Irwin H. Rosenberg
    Fish – Food to Calm the Heart
    New Eng J Med. Vol.346, April 11, 2002, pg.1102-03
        
    By 1930, it was clear that some fatty acids not only were sources of energy (as a result of oxidation), but also were essential in the diet – thus, the term “essential fatty acids.”
      
    The author’s focus is on long-chain n-3 fatty acids, which are characterized by the presence of a double bond three carbons from the n end of the molecule. Two such acids – docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – derived largely from marine species, especially fatty fish (salmon, bluefish, mackerel, arctic char, and sword- fish), are mainly responsible for the protective effects of this group of substances, although they can be made from shorter-chain a-linolenic acid, which is present in some vegetable oils, nuts, and seeds.
       
    The result of the protective action of n-3 fatty acids in blood (these substances are really markers of dietary patterns, as the authors point out), but rather the effect of diet on the fatty-acid content of phospholipids in heart-cell membranes in the functionally critical SN2 position.
      
    In the event of severe physiological stress, such as that caused by the loss of blood supply to a portion of the heart early in an ischemic attack, the DHA or EPA occupying the SN2 position in phospholipids is released and protects the heart cell locally participating in the genesis and propagation of ventricular tachycardia, which can result in cardiac arrest and sudden death.
      
    This protective effect, which is absent if other fatty acids derived from the diet occupy the SN2 position, depends on the unique ability of these n-3 fatty acids to stabilize all contractile heart cells electrically and thus protect against sudden death from arrhythmias.
      
    The mechanism underlying the prevention of sudden death from cardiac causes differs from that of prevention of atherosclerotic heart disease, and n-3 fatty acids play a critical part. It is both safe and prudent to eat, as recommended by the American Heart Association, at least two servings of fish per week, especially fatty fish. There are also likely to be other beneficial effects of the intake of n-3 fatty acids including those on blood triglyceride levels, the immune system, the developing central nervous system (by the transmission of fatty acids through breast milk).
        

  • N T Mulvihill, and J B Foley
    Review: Inflammation in Acute Coronary Syndromes
    Heart Vol.87(3), March 2002, pg.201-204
      
    There is substantial evidence implicating an inflammatory process in the pathogenesis of acute coronary syndromes. Local inflammatory cells can generate and release cytokines that have the potential to activate the endothelium, transforming its natural antiadhesive and anticoagulant properties.
      
    Furthermore, inflammatory cytokines may reduce matrix synthesis and increase its degradation, favouring plaque rupture. Finally, cytokines may enhance synthesis of endothelin in endothelial cells and macrophages, resulting in increased smooth muscle cell reactivity to local vasoconstrictors. The evidence supporting this hypothesis that inflammation is critical in the pathogenesis of acute coronary syndromes comes from a variety of sources.
      
    Histological analysis of atherosclerotic coronary arteries taken from patients who died of acute coronary syndromes has shown that unstable or ruptured atherosclerotic plaques are characterised by the presence of foam cells, macrophages, lymphocytes, and mast cells. Macrophages and to a lesser extent T lymphocytes were the dominant cell type at the site of plaque rupture or erosion. These inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption.
      
    Activated mast cells are abundant in the adventitial layer of infarct related coronary vessels and, interestingly, mast cell densities were twofold higher in normal segments of the infarct related artery, suggesting that the entire adventitial layer of the vessel is involved in an inflammatory process. When activated, the mast cells can release histamine as well as other endogenous vasoconstrictors and the resultant coronary spasm can contribute to the clinical syndrome.
      
    It may be concluded that, there is extensive evidence to support a pathogenic role for both local and systemic inflammation in acute coronary syndromes. There is also evidence that increased concentrations of inflammatory markers at presentation can identify patients at high risk of future ischaemic events, suggesting that the intensity of the inflammatory response influences clinical outcome in acute coronary syndromes.
      
    It remains to be elucidated whether the inflammatory process observed is a precursor or a consequence of coronary plaque rupture; the emerging data suggest that the inflammatory process is indeed a precursor of the clinical event.
       

  • Y Fukuda, H Teragawa, et al
    Tetrahydrobiopterin Restores Endothelial Function of Coronary Arteries in Patients with Hypercholesterolaemia
    Heart Vol.87(3), March 2002, pg.264-269
      
    The objective of this study was to examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients.
      
    Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine (ACh).
      
    ACh was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 before and after infusion of L-NG-monomethyl-L-arginine (L-NMMA).
      
    The conclusion of the study was that intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients.
      

  • M Komajda
    Editorial: Are Angiotensin II Receptor Blockers Indicated in Chronic Heart failure?
    Heart Vol.87(1), January 2002, pg.1-2
      
    Chronic heart failure is one of the most serious cardiac problems encountered in clinical practice. Modulation of the renin angiotensin system is a key element in the treatment of this syndrome. There is overwhelming evidence in favour of the benefit of angiotensin converting enzyme (ACE) inhibitors on morbidity and mortality in mild to severe heart failure and in heart failure or left ventricular dysfunction following acute myocardial infarction.
      
    It is not known, however, whether the benefit of ACE inhibition is solely attributable to blockade of angiotensin II production or also related to bradykinin accumulation. Morevover, bradykinin accumulation has been implicated in the adverse effects observed with ACE inhibitors such as cough and might result in prejunctional noradrenaline (norepinephrine) release.
      
    The development of orally active, non-peptide angiotensin II type I receptor blockers (ARBs) has raised hopes for a new generation of modulators of the renin angiotensin system better tolerated and potentially more powerful. Since ARBs block directly the binding of angiotensin II to the receptor which mediates harmful biological actions such as vasoconstriction, aldosterone synthesis, and trophic effects, one potential advantage is to avoid the ACE independent pathway generation to angiotensin II.
      
    ARBs might be a useful alternative agent to block the renin angiotensin system in patients who do not tolerate ACE inhibitors.
      
    The results of Val-HeFT trial demonstrate a modest benefit for ARBs over ACE inhibitors in morbidity and mortality.
      
    The dual combination ACE inhibitor-b blocker is so powerful in reducing morbidity and mortality that the addition of a third neuromodulator, valsartan, does not result in any benefit because of a “plateau” effect.
       

  • Eugene Crystal, Stuart J Connolly
    Evolution of the Implantable Cardioverter Defibrillator
    Lancet Vol. 359, April 20, 2002, Pg. 1362-63
      
    Ventricular fibrillation is a leading cause of preventable death in patients with heart disease, and use of the implantable cardioverter defibrillator (ICD) is key in reducing mortality from this cause. Either spontaneous or inducible sustained ventricular fibrillation or tachycardia is a leading indication for an ICD.
      
    The ICD is evolving from an instrument for stopping ventricular fibrillation to one for the management of heart failure. The convergence of technology for defibrillation and for biventricular pacing is another step on this path. More and more, myocardial dysfunction, with or without overt arrhythmia, will become the prime indication for ICD.
       

  • Arthur J. Moss, Wojciech Zareba, et al for the Multicenter Automatic Defibrillator Implantation Trial II Investigators
    Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction
    N Engl J Med Vol. 346, March 21, 2002, Pg. 877-83
      
    In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy.
       

  • Paul Dorian, Dan Cass, et al
    Amiodarone As Compared With Lidocaine for Shock-Resistant Ventricular Fibrillation
    N Engl J Med Vol. 346, March 21, 2002, Pg. 884-90
      
    As compared with lidocaine, amiodarone leads to substantially higher rates of survival to hospital admission in patients with shock-resistant out-of-hospital ventricular fibrillation.
        

 

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