bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations.
Authors: Fananapazir L , Epstein N D 
Published: June 2012

BACKGROUND
We have previously described two distinct mutations in the beta-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Leu-->Val mutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg-->Gln mutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606Val-->Met, has been reported to be associated with "near normal survival" and offered as evidence for the benign nature of neutral charge substitutions.

METHODS AND RESULTS
We report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly-->Glu mutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val-->Met mutation with four sudden cardiac deaths in eight affected individuals, and (3) a Korean kindred with the 403Arg-->Gln mutation. Although the disease occurred early and was associated with a high prevalence of myocardial ischemia in both of our kindreds with the 403Arg-->Gln mutation, no sudden cardiac death or syncope has occurred in the Korean kindred. Furthermore, in the Caucasian kindred, all patients had nonobstructive hypertrophic cardiomyopathy, but most of the patients in the Korean kindred had left ventricular outflow obstruction.

CONCLUSIONS
The conclusions are as follows: (1) Although several sudden cardiac deaths are sufficient to establish that a mutation is malignant, study of a large kindred is necessary to be certain that a mutation is benign. To date, only the 908Leu-->Val and the 256Gly-->Glu mutations satisfy this requirement. (2) The 256Gly-->Glu mutation demonstrates that not all mutations that result in a charge change are malignant. (3) Conversely, the 606Val-->Met mutation is malignant in some kindreds; hence, despite the absence of a charge change, minor substitutions in critical regions of beta-myosin heavy chain protein may also have serious consequences. (4) The diverse ethnic origins of the two 403Arg-->Gln kindreds provide evidence suggesting that the identical mutation occurred independently and was associated with different genetic backgrounds. Their distinct phenotypes underline the importance of modifying genes and nongenetic factors.
A comparison of low- with high-osmolality contrast agents in cardiac angiography. Identification of criteria for selective use.
Authors: Matthai W H , Kussmaul W G , Krol J , Goin J E , Schwartz J S , Hirshfeld J W 
Published: June 2012

BACKGROUND
Controversy exists as to whether low-osmolality radiographic contrast agents, which have less detrimental pharmacological effects but are considerably more expensive than high-osmolality agents, should be used universally or only for selected high-risk patients.

METHODS AND RESULTS
A randomized, double-blind study was used to compare the frequency and severity of adverse events in 2245 consecutive patients undergoing diagnostic cardiac angiography. Two thousand one hundred sixty-six patients were successfully randomized to either iohexol, a low-osmolality contrast agent, or diatrizoate (as Hypaque 76), a high-osmolality agent. The end point event included clinically important adverse events (which jeopardized the patient or required aggressive treatment), contrast agent-related procedure abbreviations, and conversion to open-label contrast agent. Clinically important end point events were associated with increased age, New York Heart Association functional class, left ventricular end-diastolic pressure, arteriovenous oxygen difference, severity of coronary artery disease, and history of a previous reaction to contrast agent. End point events were less frequent in patients receiving iohexol (2.6% versus 4.6%; adjusted odds ratio, 1.59; 95% confidence interval, 0.97-2.60; P = .07). The difference in event frequency between iohexol and diatrizoate was confined to the highest-risk quartile of the patient population. An algorithm was developed to classify patients as being at high or low risk for an event based on patient age, New York Heart Association class, history of a prior contrast reaction, and left ventricular end-diastolic pressure. Application of this algorithm for selective use of low-osmolality agents only for high-risk patients to a theoretical population of 1000 patients reduced contrast agent costs 66% without increasing the frequency of contrast agent-related adverse events.

CONCLUSIONS
The advantages of low-osmolality contrast agents are clinically important in patients with severe heart disease but are not in less ill patients. Universal use of low-osmolality agents for cardiac angiography in an unselected population is not necessary. Appropriately guided selective use of low-osmolality contrast agents is feasible and has the potential to reduce cost substantially without compromising safety or effectiveness.
Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine.
Authors: Kim C H , Fan T H , Kelly P F , Himura Y , Delehanty J M , Hang C L , Liang C S 
Published: June 2012

BACKGROUND
Myocardial ouabain-binding sites and Na,K-ATPase activity are reduced in congestive heart failure (CHF), but the mechanisms by which CHF reduces the Na,K-ATPase remain unknown. We proposed to investigate whether the changes are accompanied by isoform-specific reductions of the Na,K-ATPase alpha-subunit proteins in CHF and whether similar changes could be produced by exogenous norepinephrine administration.

METHODS AND RESULTS
CHF was induced in dogs by rapid ventricular pacing at a rate of 225 beats per minute for 8 weeks (protocol 1). A second group of dogs were paced at 100 beats per minute and served as controls. In protocol 2, norepinephrine was infused in normal dogs using a subcutaneous osmotic minipump for 8 weeks. The control dogs received normal saline through the pump. Animals were studied after 8 weeks of pacing or norepinephrine infusion. After the baseline hemodynamics and interstitial norepinephrine concentration had been obtained, the hearts were removed for measuring [3H]ouabain-binding sites and Na,K-ATPase alpha-subunit proteins using isoform-specific monoclonal antibodies.

RESULTS
Myocardial [3H]ouabain-binding sites were reduced in dogs with CHF and chronic norepinephrine infusion. The Western blot analysis showed that adult canine hearts possess both alpha 1 and alpha 3 isoforms of the Na,K-ATPase alpha-subunit but not the alpha 2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase alpha 1-subunit protein but did reduce the alpha 3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial alpha 3 isoform protein and interstitial norepinephrine content in the dogs. In contrast, the specific activity of the sarcolemmal marker 5'-nucleotidase did not differ among the groups of animals.

CONCLUSIONS
The reduction of myocardial Na,K-ATPase in CHF is limited to the alpha 3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase alpha 3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.
Nitric oxide mediates flow-dependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs.
Authors: Canty J M , Schwartz J S 
Published: June 2012

BACKGROUND
Although epicardial coronary arteries dilate in response to changes in flow, the mechanisms responsible for this and the mechanical stimuli that are sensed by the endothelium are not completely defined. We performed the present study to determine the importance of nitric oxide in eliciting epicardial dilation to sustained changes in mean flow and pulse frequency in the coronary circulation of conscious dogs.

METHODS AND RESULTS
Dogs were chronically instrumented with a circumflex coronary occluder, piezoelectric crystals to measure epicardial diameter, and a coronary artery catheter placed distal to the crystals for intracoronary drug infusion. Studies were conducted in dogs in the conscious state. We inhibited nitric oxide production by administering the arginine analog N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg IV), which attenuated the epicardial artery diameter changes to left atrial infusions of acetylcholine (10 micrograms/min) from 140 +/- 23 (+/- SEM) to 46 +/- 20 microns (P < .05). Epicardial dilation to sustained increases in mean coronary artery at a constant heart rate. Intracoronary adenosine increased mean flow to the same extent (180 +/- 21 versus 177 +/- 24 mL/min after L-NAME, P = NS), but inhibiting nitric oxide production had no effect on flow-mediated epicardial dilation, with coronary diameter increasing by 264 +/- 36 microns under control conditions and 294 +/- 67 microns after L-NAME (P = NS). In contrast, when pulse frequency was increased by pacing to a rate of 200 beats per minute, mean coronary flow increased to a similar level (78 +/- 9 versus 75 +/- 9 mL/min after L-NAME), but the epicardial diameter change to pacing was attenuated from 170 +/- 29 microns under control conditions to 54 +/- 23 microns after L-NAME (P < .01).

CONCLUSIONS
These results demonstrate that in vivo, nitric oxide production is primarily responsible for eliciting epicardial coronary vasodilation to endothelium-dependent agonists and changes in coronary flow pulse frequency. The failure of L-NAME to affect epicardial vasodilation during sustained increases in mean flow when pulse frequency is held constant suggests that additional mechanisms are involved in flow-mediated vasodilation of epicardial coronary arteries.
Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes.
Authors: Sun D , Nguyen N , DeGrado T R , Schwaiger M , Brosius F C 
Published: June 2012

BACKGROUND
Acute myocardial ischemia is accompanied by an increase in glucose uptake and metabolism, which appears to be important in protecting myocardial cells from irreversible ischemic injury. Because insulin augments myocardial glucose uptake by inducing the translocation of glucose transporters from an intracellular compartment to the plasma membrane, we hypothesized that acute ischemia would trigger a similar translocation.

METHODS AND RESULTS
We used a subcellular fractionation method to separate intracellular membrane and plasma membranes from control, ischemic, and hypoxic Langendorff-isolated perfused rat hearts and determined the expression of the major myocardial glucose transporter, GLUT4, in these separated membrane fractions. We found that translocation of GLUT4 molecules occurred in ischemic, hypoxic, and insulin-treated hearts and in hearts that underwent ischemia plus insulin treatment. The percentages of GLUT4 molecules present on the plasma membrane in the different conditions were as follows: control, 18.0 +/- 2.8%; ischemia, 41.3 +/- 9.4%; hypoxia, 31.1 +/- 2.9%; insulin, 61.1 +/- 2.6%; and ischemia plus insulin, 66.8 +/- 5.7%. Among the statistically significant differences in these values were the difference between control and ischemia and the difference between ischemia alone and insulin plus ischemia.

CONCLUSIONS
Ischemia causes substantial translocation of GLUT4 molecules to the plasma membrane of cardiac myocytes. A combination of insulin plus ischemia stimulates an even greater degree of GLUT4 translocation. GLUT4 translocation is likely to mediate at least part of the increased glucose uptake of ischemic myocardium and may be a mechanism for the cardioprotective effect of insulin during acute myocardial ischemia.
Native beta-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function.
Authors: Nagatsu M , Zile M R , Tsutsui H , Schmid P G , DeFreyte G , Cooper G , Carabello B A 
Published: June 2012

BACKGROUND
It is generally accepted that the adrenergic nervous system provides inotropic support for the failing heart. However, the magnitude of this support has never been studied extensively. The present study was performed to test the hypothesis that the adrenergic nervous system is capable of maintaining indexes of pump and contractile function in the normal range despite significant innate myocardial depression.

METHODS AND RESULTS
We used our model of experimental canine mitral regurgitation, which produces left ventricular dysfunction after 3 months of volume overload. We studied indexes of contractile function on and off beta-blockade at baseline and again on and off beta-blockade 3 months after chronic mitral regurgitation had induced significant contractile dysfunction. At baseline, acute beta-blockade caused insignificant reductions in the mass-corrected slope of the end-ejection stress-volume relation (EESVR), the end-systolic stiffness constant, and the ejection fraction-end-systolic stress and the mean velocity of circumferential fiber shortening (VCF)-end-systolic stress relations. After 3 months of chronic mitral regurgitation, all indexes of contractile function were normal in the unblocked state except for the VCF-stress relation, which was mildly reduced. However, after acute beta-blockade after 3 months of chronic mitral regurgitation, the EESVR fell to 303 +/- 27 versus 443 +/- 24 during acute beta-blockade before mitral regurgitation was created (P < .05), and the end-systolic stiffness constant was reduced to 2.54 +/- 0.15 versus 3.27 +/- 0.11 (P < .05). Only after beta-blockade was the ejection fraction-stress relation significantly reduced for dogs with chronic mitral regurgitation. The VCF-stress relation became markedly more abnormal. The viscosity-velocity relation of myocytes isolated from the ventricles of the dogs with mitral regurgitation confirmed that substantial innate contractile depression was present.

CONCLUSIONS
After 3 months of chronic mitral regurgitation, the adrenergic nervous system was able to maintain most indexes of contractile function in the normal range despite significant depression in innate contractile function. Thus, in the absence of beta-blockade, significant innate contractile depression may be obscured by adrenergic support.
Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis.
Authors: Burwash I G , Thomas D D , Sadahiro M , Pearlman A S , Verrier E D , Thomas R , Kraft C D , Otto C M 
Published: June 2012

BACKGROUND
Valve areas derived by the Gorlin formula have been observed to vary with transvalvular volume flow rate. Continuity equation valve areas calculated from Doppler-echo data have become a widely used alternate index of stenosis severity, but it is unclear whether continuity equation valve areas also vary with volume flow rate. This study was designed to investigate the effects of changing transvalvular volume flow rate on aortic valve areas calculated using both the Gorlin formula and the continuity equation in a model of chronic valvular aortic stenosis.

METHODS AND RESULTS
Using a canine model of chronic valvular aortic stenosis in which anatomy and hemodynamics are similar to those of degenerative aortic stenosis, each subject (n = 8) underwent three studies at 2-week intervals. In each study, transvalvular volume flow rates were altered with saline or dobutamine infusion (mean, 10.3 +/- 5.1 flow rates per study). Simultaneous measurements were made of hemodynamics using micromanometer-tipped catheters, of ascending aortic instantaneous volume flow rate using a transit-time flowmeter, and of left ventricular outflow and aortic jet velocity curves using Doppler echocardiography. Valve areas were calculated from the invasive data by the Gorlin equation and from the Doppler-echo data by the continuity equation. In the 24 studies, mean transit-time transvalvular volume flow rate ranged from 80 +/- 33 to 153 +/- 49 mL/min (P < .0001). Comparing minimum to maximum mean volume flow rates, the Gorlin valve area changed from 0.54 +/- 0.22 cm2 to 0.68 +/- 0.21 cm2 (P < .0001), and the continuity equation valve area changed from 0.57 +/- 0.18 cm2 to 0.70 +/- 0.20 cm2 (P < .0001). A strong linear relation was observed between Gorlin valve area and mean transit-time volume flow rate for each study (median, r = .88), but the slope of this relation varied between studies. The Doppler-echo continuity equation valve area had a weaker linear relation with transit-time volume flow rate for each study (median, r = .51).

CONCLUSIONS
In this model of chronic valvular aortic stenosis, both Gorlin and continuity equation valve areas were flow-dependent indices of stenosis severity and demonstrated linear relations with transvalvular volume flow rate. The changes in calculated valve area that occur with changes in transvalvular volume flow should be considered when measures of valve area are used to assess the hemodynamic severity of valvular aortic stenosis.
Identification of concealed posteroseptal Kent pathways by comparison of ventriculoatrial intervals from apical and posterobasal right ventricular sites.
Authors: Martínez-Alday J D , Almendral J , Arenal A , Ormaetxe J M , Pastor A , Villacastín J P , Medina O , Peinado R , Delcán J L 
Published: June 2012

BACKGROUND
The differential diagnosis of supraventricular tachycardia with concentric atrial activation usually requires the inducibility of sustained tachycardia and needs a complex and time-consuming electrophysiological evaluation. To develop a simple test to establish if ventriculoatrial conduction uses a posteroseptal accessory pathway or the normal conduction system, we compared the ventriculoatrial intervals during right ventricular pacing from apical and posterobasal sites.

METHODS AND RESULTS
Continuous pacing was performed from an apical and a posterobasal right ventricular site in 34 patients with retrograde conduction over the normal conduction system (group A) and in 22 patients with conduction over a posteroseptal accessory pathway (group B). During apical pacing, ventriculoatrial intervals in group A (176 +/- 40 milliseconds) were not significantly different than those in group B (197 +/- 47 milliseconds, P = NS). During posterobasal pacing, group B patients had significantly shorter ventriculoatrial intervals than group A patients (158 +/- 46 versus 197 +/- 39 milliseconds, P < .01). The difference between the ventriculoatrial interval obtained during apical pacing and that obtained during posterobasal pacing (ventriculoatrial index) discriminated between the two groups without overlapping: It was positive in all group B patients (39 +/- 19; range, +10 to +70 milliseconds) and negative in all except two group A patients (-21 +/- 13; range, -50 to +5 milliseconds; P < .001).

CONCLUSIONS
This ventriculoatrial index can identify accurately and in the absence of tachycardia whether concentric retrograde conduction is proceeding over a posteroseptal accessory pathway or over the normal conduction system.
Prospective, randomized comparison in humans of a unipolar defibrillation system with that using an additional superior vena cava electrode.
Authors: Bardy G H , Dolack G L , Kudenchuk P J , Poole J E , Mehra R , Johnson G 
Published: June 2012

BACKGROUND
A unipolar defibrillation system using a single right ventricular (RV) electrode and the active shell or "CAN" of the implantable cardioverter-defibrillator itself situated in a left infraclavicular pocket has been shown to be as efficient in defibrillation as an epicardial lead system. The purpose of this study was to determine whether defibrillation efficacy can be improved further by adding a superior vena cava (SVC) electrode to this already efficient defibrillation system.

METHODS AND RESULTS
We prospectively and randomly compared the defibrillation efficacy of a simplified unipolar defibrillation system, RV-->CAN, with that of one incorporating a high SVC electrode, RV-->SVC + CAN, in 15 consecutive cardiac arrest survivors undergoing implantation of a presently available transvenous defibrillation system. The RV defibrillation electrode was a 5-cm coil located on a 10.5F lead used as the anode in both lead configurations examined. The active CAN was a 108-cm2 surface area shell of a titanium alloy pulse generator used as the cathode in both configurations and placed in a left infraclavicular pocket. The SVC electrode was a 6F 5-cm-long coil and was used as an additional cathode positioned at the junction of the SVC and the left innominate vein. The defibrillation pulse used was a 65% tilt, asymmetric biphasic waveform delivered from a 120-microF capacitor. The defibrillation threshold (DFT) stored energy, leading edge voltage, current, and pulsing resistance were measured for both lead systems. The single-lead unipolar system, RV-->CAN, resulted in a stored energy DFT of 7.4 +/- 5.2 J, and the three-electrode dual pathway system, RV-->SVC + CAN, resulted in a DFT of 6.0 +/- 3.4 J (P = .20). There was no difference in defibrillation efficacy with the more complicated three-electrode system over the unipolar system despite a decrease in pulsing resistance to 48.6 +/- 3.5 omega compared with 61.2 +/- 5.9 omega for the unipolar system (P < .0001) and a slight rise in delivered current to 6.3 +/- 1.8 A compared with 5.5 +/- 2.0 A for the unipolar system (P = .062).

CONCLUSIONS
The unipolar single-lead transvenous defibrillation system provides defibrillation at energy levels comparable to that reported with present epicardial lead systems. Coupling of this lead system to a third SVC electrode increases system complexity but offers little defibrillation advantage despite a large decrease in pulsing resistance and a modest increase in delivered current.