Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Intracardiac Electrogram T-Wave Alternans/Variability Increases Before Spontaneous Ventricular Tachyarrhythmias in Implantable Cardioverter-Defibrillator Patients: A Prospective, Multi-Center Study
- Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)
- Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice
- Immunotherapy With Tolerogenic Apolipoprotein B-100–Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice
- Prevalence of C-Reactive Protein Elevation and Time Course of Normalization in Acute Pericarditis: Implications for the Diagnosis, Therapy, and Prognosis of Pericarditis
- Cardiovascular and Renal Outcomes With Telmisartan, Ramipril, or Both in People at High Renal Risk: Results From the ONTARGET and TRANSCEND Studies
- Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications
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Intracardiac Electrogram T-Wave Alternans/Variability Increases Before Spontaneous Ventricular Tachyarrhythmias in Implantable Cardioverter-Defibrillator Patients: A Prospective, Multi-Center Study
Clinically, T-wave alternans (TWA), the surface ECG manifestation of action-potential repolarization alternans, is measured to estimate long-term risk of VT/VF. TWA and nonalternans variability (TWA/V) also increases immediately before ventricular tachycardia (VT) or fibrillation (VF) under some conditions. This suggests that TWA/V may warn of VT/VF in implantable cardioverter-defibrillator patients. Recently, we described a method for measuring TWA/V from intracardiac electrograms stored in implantable cardioverter-defibrillators (ICDs) before VT/VF. In the present prospective, multicenter study, we found that electrogram TWA/V was greater (by a factor of 2 to 4) before VT/VF than during 4 independent types of control recordings. However, improved specificity is required before electrogram TWA/V can be applied as a clinical tool in ICDs. Software that measures electrogram TWA/V on a continuous, real-time basis in ICDs is necessary to optimize specificity of electrogram TWA/V. If VT/VF can be predicted with sufficient accuracy, even with a warning as short as ≈15 seconds, adaptive pacing algorithms could be initiated to prevent VT/VF. Warning times of several minutes would permit patients to cease activities such as driving and to avoid fall-related injuries or other accidents. Longer warnings might permit titration of antiarrhythmic drugs during periods of greater vulnerability to VT/VF. See p 1052.
Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)
There is an increasing interest and need to identify heart failure patients who benefit from cardiac resynchronization therapy (CRT), as well as those who do not. In patients with a wide QRS complex who qualify for CRT, QRS morphology indicates different conduction delays, represented on the ECG as left bundle-branch block (LBBB), right bundle-brunch block (RBBB), or nonspecific intraventricular conduction disturbances. The Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) demonstrated that in patients with mild to moderate heart failure, CRT with defibrillator implantation (CRT-D) significantly reduced the risk of heart failure events or death compared with treatment with only an implantable cardioverter-defibrillator. This analysis of the MADIT-CRT trial data demonstrated that compared with non-LBBB patients (those with RBBB or nonspecific intraventricular conduction disturbances), patients with LBBB QRS morphology showed significant clinical benefit from CRT-D therapy, as measured by reduced risk of heart failure event or death and risk of ventricular tachycardia/fibrillation or death. Non-LBBB patients did not benefit clinically despite a significant reduction in left ventricular volumes. These findings formed the basis for recent Food and Drug Administration approval of new broadened indications for CRT in mild or asymptomatic heart failure patients with LBBB. There is still a question as to whether CRT therapy should be used in non-LBBB patients even when advanced heart failure is present and which non-LBBB patients might still benefit clinically from CRT. Further research investigating the rationale, mechanisms, and clinical benefit is needed to determine whether CRT therapy should be pursued in non-LBBB patients. See p 1061.
Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice
Mammalian target of rapamycin (mTOR) is an evolutionary conserved kinase that regulates cell growth. Rapamycin is clinically used as an immunosuppressant and as potent antiproliferative agents; several rapalogs are in trials for cancer therapy. Rapamycin inhibits, at least in part, the activities of mTOR in mTOR complex (mTORC) 1, 1 of the 2 distinct multiprotein complexes in which mTOR is found. The recently developed active-site mTOR inhibitors inhibit mTORC1 and mTORC2. In the present study, we established that mTORC1 is essential for normal cardiac function and that its activity becomes even more important with increased cardiac work. Thus, deletion of raptor, an essential component of mTORC1, from cardiomyocytes in adult mice caused dilated cardiomyopathy within 6 weeks. Moreover, increased load by dynamic exercise or aortic constriction accelerated progression into heart failure without a prior phase of adaptive hypertrophy. This strengthens the perception that appropriate growth responses with intact signaling via the insulin/insulin-like growth factor/Akt/mTOR pathway are important when the heart has to generate more work, which applies to various clinical conditions such as hypertension, postinfarct remodeling, and valve disease. Notably, this signaling pathway is affected during anticancer therapy and therefore may be involved in the development of cardiomyopathy in these patients. Besides slowing of protein synthesis, we show that cardiac mTORC1 inactivation affects mitochondria, substrate oxidation, autophagy, and apoptosis. These mechanistic insights may lead to the development of novel approaches to prevent cardiac dysfunction. Our study also underlines that monitoring of cardiac performance in clinical trials with active-site mTOR inhibitors is important. See p 1073.
Immunotherapy With Tolerogenic Apolipoprotein B-100–Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice
In recent years, the perception of atherosclerotic cardiovascular disease has changed from that of a vascular lipid disorder to a chronic inflammatory condition elicited by lipoprotein retention in the vessel wall. Components of the accumulating low-density lipoprotein particles are immunogenic and can activate T cells and macrophages that promote inflammation, lesion growth, and plaque vulnerability. We devised a cell-therapy strategy to dampen inflammation and reduce atherosclerosis by injecting tolerogenic dendritic cells into hypercholesterolemic mice. Before transfer, dendritic cells were loaded with apolipoprotein B100, the protein part of low-density lipoprotein, and subsequently exposed to the antiinflammatory cytokine interleukin-10. Such dendritic cells suppressed the activity of apolipoprotein B100–reactive T cells. A single injection of tolerogenic dendritic cells loaded with apolipoprotein B100 significantly reduced atherosclerosis and increased plaque-stabilizing collagen in hypercholesterolemic mice. Because similar immune responses occur in human atherosclerosis, tolerogenic dendritic cell therapy may represent a new strategy for reduction and stabilization of atherosclerotic lesions in humans. See p 1083.
Prevalence of C-Reactive Protein Elevation and Time Course of Normalization in Acute Pericarditis: Implications for the Diagnosis, Therapy, and Prognosis of Pericarditis
Pericarditis is an inflammatory disease, and evidence of elevated markers of inflammation could support the diagnosis. Unfortunately, the appropriate length of therapy is unknown, and drugs are administered empirically. Nevertheless, markers of inflammation (ie, C-reactive protein [CRP]) may be a useful guide for treatment because it can be assumed that anti-inflammatory therapy should be continued until the inflammation is extinguished. On this basis, persistent elevation of inflammatory markers, as evidence of disease activity, could be associated with a worse prognosis. No prospective study has evaluated the prevalence and clinical meaning of CRP for diagnosis, therapy, and prognosis in acute pericarditis. The main conclusions of the study are as follows: (1) high-sensitivity CRP (hs-CRP) is elevated at the initial presentation in ≈3 of 4 cases of acute pericarditis, and thus a normal value of hs-CRP at presentation does not exclude the diagnosis but may confirm the clinical suspicion; (2) persistently elevated hs-CRP may identify patients at higher risk of recurrence; (3) for patients with elevated hs-CRP, the attack dose of anti-inflammatory therapy should be continued until hs-CRP normalization instead of an empirical therapy length, as is commonly done in clinical practice; and (4) in some patients, hs-CRP is normal at presentation but may increase within the first week, and thus appropriate serial testing for hs-CRP should be planned for patients with an initial negative result. Hs-CRP is elevated at the initial presentation in ≈3 of 4 cases of acute pericarditis, identifies patients at higher risk of recurrence, and could be used to monitor disease activity and select appropriate therapy length. See p 1092.
Cardiovascular and Renal Outcomes With Telmisartan, Ramipril, or Both in People at High Renal Risk: Results From the ONTARGET and TRANSCEND Studies
Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with cardiovascular and renal risk has resulted in patient benefits with either therapy. There has been increasing interest in whether additional blockade of the renin-angiotensin-aldosterone system by combining an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker as dual therapy, particularly in patients with renal risk, can further reduce cardiovascular and renal events. This post hoc analysis is of 2 large trials: Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND). It compares dual therapy with monotherapy to identify whether the treatment effects observed in the overall population are consistent in subpopulations defined by normal and low glomerular filtration rate and normoalbuminuria, microalbuminuria, and macroalbuminuria at baseline. The treatment effects in the subpopulations are similar to those in the overall population, and no benefit of dual therapy over monotherapy is seen, even in the group at highest renal risk, namely, those with low glomerular filtration rate and macroalbuminuria. Dual therapy was associated, however, with a higher rate of hyperkalemia and acute dialysis. The conclusion in the population tested is that there is no evidence of a cardiovascular or renal benefit of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker dual therapy over monotherapy. See p 1098.
Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications
Clinical trials have shown that low-dose acetylsalicylic acid (ASA) and clopidogrel are associated with an increased risk of upper gastrointestinal bleeding (UGIB). Other medications that are commonly coadministered with low-dose ASA and clopidogrel can also increase the risk of UGIB. However, few studies have quantified the risk of UGIB associated with specific combinations of these therapies in the general population. We used The Health Improvement Network (a UK primary care database) to identify 2049 patients with a UGIB diagnosis in 2000 to 2007 and 20 000 controls with no UGIB diagnosis. We evaluated drug use in these patients and estimated the relative risk (RR) of UGIB associated with various medications. We found that the RR of UGIB was 1.80 (95% confidence interval [CI], 1.59 to 2.03) in users of low-dose ASA and 1.67 (95% CI, 1.24 to 2.24) in users of clopidogrel. Compared with low-dose ASA monotherapy, the risk of UGIB was significantly increased when low-dose ASA was coadministered with clopidogrel (RR, 2.08; 95% CI, 1.34 to 3.21), oral anticoagulants (RR, 2.00; 95% CI, 1.15 to 3.45), low-/medium-dose nonsteroidal antiinflammatory drugs (RR, 2.63; 95% CI, 1.93 to 3.60), high-dose nonsteroidal antiinflammatory drugs (RR, 2.66; 95% CI, 1.88 to 3.76), or high-dose oral corticosteroids (RR, 4.43; 95% CI, 2.10 to 9.34). Our findings confirm that low-dose ASA and clopidogrel are associated with an increased risk of UGIB in the general population and show that the risk of UGIB is increased further in patients using combination therapies. These factors should be taken into account when assessing the risk-to-benefit ratio of low-dose ASA. See p 1108.
- © 2011 American Heart Association, Inc.
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