Clinical Summaries

Clinical Summaries

https://doi.org/10.1161/CIRCULATIONAHA.109.192176
Circulation. 2009;119:1177-1179
Originally published March 9, 2009

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Predictors of Initial Nontherapeutic Anticoagulation With Unfractionated Heparin in ST-Segment Elevation Myocardial Infarction

Although weight-based nomograms have improved the efficacy and safety of dosing unfractionated heparin in ST-segment elevation myocardial infarction, achieving therapeutic anticoagulation in practice remains challenging. The Enoxaparin and Thrombolysis in Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction (E-TRACT-TIMI) 25 study provided the opportunity to investigate the contemporary efficacy and safety of unfractionated heparin, dosed according to the American College of Cardiology/American Heart Association weight-based nomogram. Despite close adherence to recommended dosing, only 33.8% of initial activated partial thromboplastin times (at 4 to 8 hours after the start of unfractionated heparin) were therapeutic (1.50 to 2.00 times control); 13.2% were markedly low (<1.25 times control); and 16.3% were markedly high (≥2.75 times control). Markedly high activated partial thromboplastin times were more likely in patients who were older (14% increased risk per decade), were female (46% increased risk), were of lower weight (19% increased risk per 10-kg decrease), or had renal dysfunction (8% increased risk per 0.2-mg/dL increase in creatinine). Markedly high activated partial thromboplastin times also were associated with a 2-fold increased risk of TIMI major or minor bleeding by 48 hours; conversely, markedly low activated partial thromboplastin times were associated with a 2-fold increased risk of fatal or nonfatal reinfarction by 48 hours. Thus, despite the use of a standard weight-based unfractionated heparin nomogram in ST-segment elevation myocardial infarction, nontherapeutic anticoagulation is frequent and more likely among certain vulnerable patient groups, with excess anticoagulation associated with increased bleeding and inadequate anticoagulation associated with reinfarction. These findings should be considered when dosing unfractionated heparin in support of fibrinolytic therapy. See p 1195.

Long-Term Trends in Myocardial Infarction Incidence and Case Fatality in the National Heart, Lung, and Blood Institute’s Framingham Heart Study

Whereas the prevalence of coronary heart disease risk factors has declined over past decades in the United States, acute myocardial infarction (AMI) rates have been steady. Because the diagnosis of AMI is evolving, it is a challenge to characterize the “true” epidemiology of AMI accurately. Among Framingham Heart Study participants, we found that over the past 40 years, rates of AMI diagnosed by ECG have declined by 50%, whereas rates of AMI diagnosed by biomarkers have doubled. The advent of increasingly sensitive biomarkers for AMI diagnosis has substantially influenced AMI detection rates in the United States over the past several decades. Our findings offer an explanation for the apparently steady national AMI rates in the face of improvements in primary prevention. See p 1203.

Thirty-Year Trends (1975 to 2005) in the Magnitude of, Management of, and Hospital Death Rates Associated With Cardiogenic Shock in Patients With Acute Myocardial Infarction: A Population-Based Perspective

The results of this population-based epidemiological study demonstrate that cardiogenic shock remains a relatively frequent complication of acute myocardial infarction, affecting ≈1 in every 15 patients hospitalized with acute myocardial infarction. Although the incidence rates of cardiogenic shock have remained relatively stable over the past 30 years (1975 to 2005) in our investigation of residents of a large New England metropolitan area hospitalized with acute myocardial infarction at all area medical centers, encouraging improvements in the hospital survival of these high-risk patients have occurred coincidentally with the increasingly aggressive management of patients who developed cardiogenic shock. Our findings also provide insights into the characteristics of patients who died after an episode of cardiogenic shock to whom targeted surveillance and therapeutic efforts might be directed. See p 1211.

Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy

Cardiac resynchronization therapy (CRT) with biventricular pacing improves symptoms, cardiac function, and exercise capacity, and when combined with defibrillator therapy, it reduces mortality in patients with heart failure who have dyssynchronous contraction (DHF). CRT reduces stress-strain disparities and thus improves the efficiency of contraction of the ventricle. However, the role of CRT in preventing arrhythmias or reversing adverse electrical remodeling remains controversial. The present study provides novel information on the altered regional expression and function of ionic currents and calcium (Ca2+) transients in DHF and partial restoration by CRT in a canine pacing-induced DHF model. CRT partially restores the DHF-induced reduction of selected K+ currents and significantly improves Ca2+ homeostasis, especially in the lateral wall of the left ventricle. The overall effect of CRT is abbreviation of the DHF-induced prolongation of action potential duration in cells isolated from the lateral left ventricle, thus reducing the regional action potential duration gradient and the frequency of potentially arrhythmogenic early afterdepolarizations compared with DHF. Thus, CRT partially reverses both the cellular triggers and substrate for arrhythmias in DHF. See p 1220.

Mechanisms of Enhanced β-Adrenergic Reserve From Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure and dyssynchrony caused by conduction delay and is to date the only therapy that can both in the short-term and long-term improve chamber systolic function and yet reduce long-term mortality. The chamber mechanical impact of CRT is well documented and occurs rapidly. However, more long-term influences on both myocyte function and adrenergic modulation that may underlie sustained benefits are largely unknown. To address this, we developed an experimental canine model of dyssynchronous heart failure (tachypacing with a left bundle-branch block) with or without subsequent resynchronization (biventricular tachypacing, CRT). Both models display global heart failure, although CRT did improve systolic function as observed in humans. Here, we show marked global reductions in both resting and β-adrenergic–stimulated myocyte function and whole-cell calcium handling in dyssynchronous heart failure and demonstrate that both were markedly improved (β-adrenergic reserve to nearly normal levels) by CRT. Changes involved calcium homeostasis, increased adrenergic receptor (β1) density and adenylate cyclase activity, and novel suppression of inhibitory G-protein signaling. Accompanying this adrenergic upregulation was a decline in myocardial catecholamines from the higher levels observed in dyssynchronous heart failure hearts. Thus, CRT effectively restored a more normal balance of greater cellular adrenergic responsiveness with reduced chronic sympathetic stimulation. This may play an important role in the long-term efficacy of CRT on clinical symptoms and survival and its interaction with concurrent pharmacological neuroblockade treatment. See p 1231.

Long-Term Cardiac-Targeted RNA Interference for the Treatment of Heart Failure Restores Cardiac Function and Reduces Pathological Hypertrophy

RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. Whereas gene therapy (already used for cardiac disorders) rests on recombinant protein expression as its basic principle, RNAi therapy instead uses regulatory RNAs to achieve its effect. Fundamental limitations of the use of chemically synthesized small interfering RNAs to mediate RNAi are their rapid degradation in plasma and target cells and the unsolved problem of adequate targeting in vivo. The present study shows for the first time the high efficacy of an RNAi therapeutic strategy in a cardiac disease in vivo. It demonstrates successful treatment of heart failure in a rat model by cardiac-targeted RNAi ablating phospholamban, a key regulator of cardiac Ca2+ homeostasis. A novel vector was developed based on a cardiotropic adeno-associated virus (rAAV9) that carries RNAi activity to the heart after intravenous injection. Over a period of 3 months, this therapy restored cardiac function, reversed cardiac dilation and hypertrophy, and reduced cardiac fibrosis. In recent years, adeno-associated virus–based vectors have overcome key challenges to gene therapy, such as stability, safety, and host immune response. The present study shows that under the precondition of careful adeno-associated virus vector adaptation to the specific requirements of RNAi, if regulatory RNA sequences with high intrinsic activity and target specificity are selected, they may also serve as valuable tools for cardiac RNAi therapy and offer clinical potential. Specifically, for targets such as phospholamban, for which pharmacological approaches have failed so far, the RNAi approach may enhance the therapeutic repertoire. See p 1241.

Cardiac Myosin Binding Protein-C Phosphorylation in a β-Myosin Heavy Chain Background

Discovering the function of cardiac myosin binding protein-C (cMyBP-C) is important clinically because mutations in the protein can cause familial hypertrophic cardiomyopathy. cMyBP-C modulates myosin assembly and helps to control cardiac contractility. Decreased cMyBP-C phosphorylation is associated with the development of heart failure or pathological hypertrophy in mice and humans. One of the major questions with respect to the many mouse models used to understand human disease is their relevance. This is of particular concern when dealing with the contractile apparatus of the heart because the major motor protein in the mouse heart, α-myosin heavy chain (MyHC), differs from the human heart, which contains the slower β-MyHC. In this study, we defined the impact(s) of cMyBP-C phosphorylation in a β-MyHC background to understand whether cMyBP-C–mediated cardioprotection in the face of ischemic injury could work in a myosin background that is more like the human’s. Our data confirm that cMyBP-C phosphorylation is essential in a β-MyHC background, and, in contrast to the α-MyHC background, a phosphomimetic cMyBP-C improves the rates of contraction and relaxation while also remaining cardioprotective. These results suggest that cMyBP-C phosphorylation can have direct effects on the contractile properties and sarcomere organization of the human heart and that it can also protect the heart from ischemic injury. Selective cMyBP-C phosphorylation may provide a novel therapeutic strategy to improve muscle function in patients in the early or even late stages of heart failure. See p 1253.

Reciprocal Regulation of Myocardial microRNAs and Messenger RNA in Human Cardiomyopathy and Reversal of the microRNA Signature by Biomechanical Support

Prognosis in heart failure is notoriously difficult to assess. Interindividual variability in disease susceptibility, course, and response to therapy is a major problem for physicians, their patients, and the healthcare system in general. Improved metrics for categorizing patients on the basis of relative risk and benefit for particular treatment strategies could greatly facilitate clinical decision making. Toward this end, transcriptional profiling of myocardial messenger RNA (mRNA) has been used in attempts to identify unique genomic “signatures” for heart failure of different causes and, more importantly, different prognoses. However, these efforts have met with limited success, in part because the mRNA signature for end-stage heart failure does not adequately discriminate between ischemic and nonischemic cardiomyopathy or between hearts with poor function versus those with better function. The latter functional analyses are based on mRNA profiling of hearts with and without mechanical unloading from left ventricular assist devices, which markedly improve ventricular ejection performance and, in rare instances, facilitate long-term myocardial recovery after device removal. We identified a likely molecular signature for this myocardial “recovery” phenotype using microarray technology to comprehensively assay both microRNA and mRNA levels from 38 normal, failing, or left ventricular assist device–treated hearts. Although neither mRNA profile nor microRNA profile alone provided acceptable specificity and sensitivity to differentiate the 3 categories of hearts, combining the 2 molecular signatures correctly classified 22 of 23 samples. These studies reveal a promising approach for individual genomic profiling of failing myocardium to improve clinical prognostication. See p 1263.

Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart

Obesity and diabetes mellitus may increase the risk of heart failure. The mechanisms are multifactorial, but recent studies have implicated a potential role for mitochondrial dysfunction. Studies in animal models of obesity and type 2 diabetes mellitus have suggested that insulin resistance develops in the myocardium. However, the consequences of insulin resistance in the heart are incompletely understood. The present study sought to determine whether impaired myocardial insulin signaling could impair mitochondrial function in the heart. Using genetically engineered mice with deletion of insulin receptors in cardiomyocytes, we show that impaired myocardial insulin signaling leads to multiple mitochondrial defects that include reduced oxygen consumption and ATP synthesis, reduced levels of mitochondrial enzymes that regulate pyruvate and fatty acid metabolism, and decreased content of citric acid cycle (tricarboxylic acid) proteins. Insulin signaling also regulates the expression of genes such as peroxisome proliferator-activated receptor-α in the heart, which controls the capacity of mitochondria to oxidize fatty acids. In addition, mitochondria from hearts with defective insulin signaling demonstrate evidence of oxidative stress. This study identifies novel roles for insulin signal transduction in the regulation of cardiac mitochondrial function and identifies mechanisms that could potentially contribute to myocardial dysfunction when the heart becomes insulin resistant. See p 1272.

Nuclear Factor-κB Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans

Middle-aged and older overweight and obese adults are at elevated risk of cardiovascular disease. This is attributable in part to vascular endothelial dysfunction, as indicated by impaired endothelium-dependent dilation; however, the cellular and molecular mechanisms involved are incompletely understood. The present study provides direct in vivo evidence that supports a key role for the proinflammatory, redox-sensitive transcription factor nuclear factor κB (NF-κB) in mediating vascular endothelial dysfunction in overweight/obese middle-aged and older adults. In 14 nondiabetic (body mass index ≥25 kg/m2) men and women 52 to 68 years of age (randomized, double-blind, placebo-controlled crossover study), 4 days of treatment with oral salsalate (nonacetylated salicylate, 4500 mg/d), an NF-κB inhibitor, reduced total and nuclear NF-κB in vascular endothelial cells and improved brachial artery flow-mediated dilation by 74%. Improvements in brachial artery flow-mediated dilation with salsalate were inversely related to baseline flow-mediated dilation (r=−0.77). Infusion of the antioxidant vitamin C improved brachial artery flow-mediated dilation during placebo but not after salsalate. Salsalate reduced nitrotyrosine, a marker of oxidative stress, and expression of the oxidant enzyme NADPH oxidase p47phox in vascular endothelial cells. Salsalate also reduced systolic blood pressure and improved plasma lipids and glucose. The present findings suggest that NF-κB, in part via stimulation of oxidative stress, plays an important role in mediating endothelial dysfunction in peripheral conduit arteries in humans. Our results provide support for the concept that inhibition of NF-κB may be an effective therapeutic strategy in the prevention and treatment of age- and obesity-related vascular endothelial dysfunction. See p 1284.

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  • Clinical Summaries
    Circulation. 2009;119:1177-1179, originally published March 9, 2009
    https://doi.org/10.1161/CIRCULATIONAHA.109.192176
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