Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Timing of Myocardial Trpm7 Deletion During Cardiogenesis Variably Disrupts Adult Ventricular Function, Conduction, and Repolarization
- Twenty-Year Analysis of Trends in the Incidence and In-Hospital Mortality for Lower-Extremity Arterial Thromboembolism
- Intracoronary Delivery of Autologous Cardiac Stem Cells Improves Cardiac Function in a Porcine Model of Chronic Ischemic Cardiomyopathy
- Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension
- Quantification of Incomplete Revascularization and its Association With Five-Year Mortality in the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) Trial Validation of the Residual SYNTAX Score
- An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
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Timing of Myocardial Trpm7 Deletion During Cardiogenesis Variably Disrupts Adult Ventricular Function, Conduction, and Repolarization
Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 have been shown to contribute to cardiac hypertrophy and heart failure in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block and conduction system disease. TRPM7 is unique in that it is an ion channel fused to a kinase domain. It is highly expressed in adult heart and first expressed in embryonic myocardium. Recent work has found TRPM7 to be important for atrial fibroblast differentiation in human atrial fibrillation. Thus, there is an emerging story describing an important connection between TRPM7 and human heart disease, particularly electrophysiological diseases. Our study provides insight into how loss of Trpm7 function may alter adult cardiac electrophysiology and function. We find that genetic deletion of Trpm7 during cardiogenesis modifies the myocardial transcriptional profile and variably disrupts adult ventricular function, inducing heart block, impaired repolarization, and ventricular arrhythmias. We show that this is associated with reduced expression of several repolarizing potassium channel genes (Kcnk3, Kcna1, Kcnd2, Kcnj3, Kcnv2), a hyperpolarization-activated cyclic nucleotide gated channel gene (Hcn4), and a transient receptor potential channel gene (Trpm4). Consistent with these transcriptional changes, transient outward potassium currents were reduced and action potentials prolonged in Trpm7-deleted ventricular myocytes. Similarly, Trpm7-deleted atrioventricular node cells exhibit reduced pacemaker current (If), providing an ionic mechanism for the observed atrioventricular block. We anticipate that these results will encourage further investigations into putative mutations in Trpm7 in patients with unexplained structural or electrophysiological heart disease. See p 101.
Twenty-Year Analysis of Trends in the Incidence and In-Hospital Mortality for Lower-Extremity Arterial Thromboembolism
The goal of this study was to use the National Hospital Discharge Survey administrative database to analyze the incidence, in-hospital mortality, and procedural trends for lower-extremity arterial thromboembolism across the entire United States over a 20-year time period. There is a paucity of epidemiological data on this clinical condition, which comprises a diverse group of both individuals with acute limb ischemia and those with an acute exacerbation of chronic limb ischemia and iatrogenic arterial injury. This large study encompassed a population of 1.76 million hospital admissions and represents the largest retrospective analysis of this high-risk patient population to date. We report a decrease in both age-adjusted incidence and in-hospital mortality of lower-extremity arterial thromboembolism over the specified time period for both male and female patients. An analysis of various procedural trends reveals decreasing use of surgical bypass and amputation and increasing rates of catheter-based thrombolysis to treat lower-extremity arterial thromboembolism. This study also alludes to the limitations in using an administrative database for analyzing the true incidence of acute limb ischemia, given the inability of this data set to distinguish acute limb ischemia from more chronic forms of limb ischemia. See p 115.
Intracoronary Delivery of Autologous Cardiac Stem Cells Improves Cardiac Function in a Porcine Model of Chronic Ischemic Cardiomyopathy
Ischemic cardiomyopathy is a major cause of morbidity and mortality worldwide. Despite numerous advances, current therapies are palliative in the sense that they prolong life and improve symptoms but do not address the underlying problem–the loss of cardiac muscle, hence the enthusiasm surrounding the use of stem cells in ischemic cardiomyopathy. The discovery of self-renewing, clonogenic, and multipotent primitive cells residing within the human heart (cardiac stem cells [CSCs]) provides a new exciting therapeutic option. These resident CSCs have been shown to differentiate into the myocardial lineage and can be harvested from the heart and expanded in culture. Previous studies have shown that administration of CSCs to rats with heart failure results in left ventricular functional improvement. Similar to these results, Stem Cell Infusion in Patients with Ischemic Cardiomyopathy (SCIPIO) (the first clinical trial of CSCs) has demonstrated that infusion of autologous CSCs in patients with ischemic heart failure is feasible, safe, and extremely effective in improving left ventricular function and patient clinical status. Despite these beneficial effects of CSCs in the setting of heart failure, many issues pertaining to the use of CSCs remain unsettled. Thus, we examined the effects of CSCs in a porcine model of chronic ischemic cardiomyopathy. We found that intracoronary infusion of CSCs into a scarred region in a large animal model improves cardiac function and mitigates adverse left ventricular remodeling by promoting cardiac and vascular regeneration. The results support the therapeutic utility of CSCs and provide a model to further study the actions of these promising cells. See p 122.
Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension
Ambulatory blood pressure monitoring (ABPM) is important to identify hypertensive patients at risk. Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. However, less is known about the effect of RDN on 24-hour BP and predictors of response in individuals with true or pseudoresistant hypertension. A total of 346 uncontrolled hypertensive patients (office systolic BP ≥160 mm Hg, ≥150 mm Hg for type 2 diabetes mellitus), separated according to daytime ABPM into 303 with true resistant and 43 with pseudoresistant hypertension, from 10 multinational centers were studied. Office systolic, diastolic and pulse pressure (SBP/DBP/PP) and ABPM (including daytime, nighttime, maximum, minimum BP) were measured at entry, and at 3, 6, and 12 months after RDN. After RDN office SBP, DBP, and PP were significantly reduced in the overall cohort. In patients with true treatment resistance there was a significant reduction after RDN in 24-hour mean SBP, DBP, maximum SBP, and minimum SBP, whereas there was no effect on ABPM in pseudoresistant patients. RDN was equally effective in reducing BP in different subgroups of patients (age, estimated glomerular filtration rate, dipping pattern, diabetic status, etc). Office SBP at baseline was the only independent predictor of BP response. Our data from the largest cohort of patients treated by RDN and followed with ABPM up to 12 months demonstrate that, in patients with true resistant hypertension, the procedure improves relevant aspects of ABPM commonly linked to high cardiovascular risk, whereas it only affected office BP in pseudoresistant hypertension. See p 132.
Quantification of Incomplete Revascularization and its Association With Five-Year Mortality in the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) Trial Validation of the Residual SYNTAX Score
Interpreting the long-term prognostic impact of incomplete revascularization (ICR) in patients with complex coronary artery disease has historically remained difficult. The lack of standardized definitions of ICR, lack of randomized data, unavoidable selection bias inherent to all registry studies, and quality of monitoring and adjudication of outcomes, have led to conflicting results in the literature. The residual Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) Score is based on the principle of being a measure of the myocardial ischemia burden, dependent on the location of the coronary disease, its importance in supplying blood to the myocardium, and the anatomic complexity associated with the obstructive disease. Importantly, the residual SYNTAX Score allowed for the determination of an objective level of reasonable ICR, whereby a threshold value of ICR could be determined (≤8) that would not have a negative impact on long-term mortality and other clinical outcomes. The residual SYNTAX Score was validated in a randomized, all-comers population, consisting of subjects with complex coronary artery disease (unprotected left main coronary artery or de novo 3-vessel-disease) who had undergone 5-year follow-up. Notably, progressively higher residual SYNTAX Scores were shown to be a surrogate marker of sicker patients, with greater baseline clinical comorbidity and anatomic complexity, with consequent adverse long-term clinical outcomes, including all-cause mortality. Results that were equally applicable in subjects with unprotected left main coronary artery disease and medically-treated diabetes mellitus. Such findings are of value in guiding the clinician to reduce the level of reversible myocardial ischemia by treating obstructive lesions to stay within the threshold of reasonable ICR. See p 141.
An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
Doxorubicin (DOXO) is an anthracycline chemotherapeutic that is effective against particular subsets of various cancers; for example, ErbB2-overexpressing breast cancer. However, the use of DOXO is limited by a dose-related cumulative cardiotoxicity that can lead to congestive heart failure. The relationship between DOXO dose and cardiotoxicity is sufficiently well-defined such that oncologists now limit cumulative dosage, and thus DOXO-induced cardiomyopathy is rarely seen clinically. Yet this dose limitation of DOXO is deleterious for those patients for whom it is the best available therapy for their cancer. Therefore, we used protein engineering to exploit the cardioprotective effects of the ErbB receptor ligand neureuglin-1β (the epidermal growth factor-like domain of neureuglin-1β), which is a known cardioprotective protein that also has proneoplastic characteristics. We hypothesized that by taking advantage of known differences in ErbB receptor biology in cancer cells and cardiomyocytes, we could develop a protein that had the cardioprotective qualities of the epidermal growth factor-like domain of neureuglin-1β without the proneoplastic effects. The present study demonstrates that an engineered bivalent neuregulin-1β induces cytostatic and antineoplastic responses in cancer cells that are stimulated toward malignant phenotypes by the epidermal growth factor-like domain of neureuglin-1β while retaining efficacy as a cardioprotective agent in a chronic-administration mouse model of DOXO-induced cardiotoxicity. Based on these results, we believe that an engineered bivalent neuregulin-1β has translational potential as a novel cardioprotective therapeutic for patients with cancer who may need to receive DOXO beyond the current cumulative dose threshold. See p 152.
- © 2013 American Heart Association, Inc.
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