Apr 17, 2018
Dr. PaulWang:Welcome to the monthly podcast On the Beat for CirculationArrhythmia and Electrophysiology. I'm Dr Paul Wang,editor-in-chief, with some of the key highlights for this month'sissue. We'll also hear from Dr. Suraj Kapa reporting on newresearch from the latest journal articles in the field.
In our first article, Barry Maron associates report on the longterm clinical course of hypertrophic cardiomyopathy patientsfollowing ICD therapy for ventricular arrhythmias. They studied acohort of 486 high-risk hypertrophic cardiomyopathy patients withICDs from eight international centers. Of these 486 patients over6.4 years, 94 patients or 19% experienced appropriate ICDinterventions, terminating VT or VF. Of the 94 patients receivingappropriate ICD therapy, 87 were asymptomatic or only mildlysymptomatic at the time of appropriate ICD interventions. Of these87 patients, 74 or 85% remained in classes one or two withoutsignificant change in clinical status of the subsequent 5.9 yearsup to 22 years. Among the 94 patients, there was one sudden deathin three patients who died from non arrhythmic hypertrophiccardiomyopathy related processes. Post ICD intervention, freedomfrom hypertrophic cardiomyopathy, mortality was 100% at one year,97% at five years, and 92% at 10 years, distinctly lower than therisk of ischemic or non ischemic cardiomyopathy in ICD trials.
Hypertrophic cardiomyopathy patients with ICDs interventionsreported the heightened anxiety and expectation of future shocks.However, they did not affect general psychological well-being orquality of life. The authors concluded that in hypertrophiccardiomyopathy, unlike ischemic heart disease, prevention of suddendeath with ICD therapies unassociated with a significant increasein cardiovascular morbidity and mortality, nor transformation intoheart failure deterioration, ICD therapy does not substantiallyimpair overall psychological and physical well-being. In our nextarticle, Abdulla Damluji and associates examined the cost ofhospitalizations for cardiac arrest using the US nationwideinpatient sample from 2003 to 2012. Using the log transformation ofinflation adjusted costs the authors examined 1,387,396 patientswho were hospitalized after cardiac arrest. They had a mean age of66 years. Inpatient procedures included coronary angiography in15%, PCI in 7%, intra-aortic balloon pump in 4.4%, therapeutichypothermia in 1.1%, and mechanical circulatory support in 0.1% ofpatients.
Notably the rates of therapeutic hypothermia increased from 0 in2003 to 2.7 in 2012, p less than 0.001. Both hospital chargesinflation adjusted costs linear increased over time. In amulti-variant analysis predictors of inflation adjusted costsincluded large hospitals size, urban teaching hospital, and lengthof stay. Among co-morbidities, atrial fibrillation or fluid andelectrolytes imbalance were the most common associated with cost.The authors found that during the period between 2003 and 2012 postcardiac arrest, hospitalizations had a steady rise and associatedhealthcare costs likely related to increase length of stay, medicalprocedures and systems of care.
In our next paper, Peter Huntjens and associates examined intrinsicinterventricular dyssynchrony as a predictor of human dynamicresponse to cardiac resynchronization. The authors use acardiovascular computational model CircAdapt to characterize theisolated effect of intrinsic interventricular or intraventricularactivation on resynchronization therapy response that is the changein LV dP/dt max. The simulated change in LV dP to dt max had arange of 1.3 to 26.5% increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony was limited with the change in the LVdP/dt max range and the left ventricle from 12.3 to 18.3% in theright ventricle from 14 to 15.7%.
Secondly, electrocardiographic imaging derived activationcharacteristics of 51 CRT candidates were used to create individualmodels of ventricular activation in CircAdapt. The model predictedchange in LV dP/dt max was close to the actual value in left bundlebranch block patients with 2.7% difference between measured andsimulated when only intrinsic interventricular dyssynchrony waspersonalized. Among non left bundle branch block patients a changein LV dP/dt max was systematically over predicted by CircAdapt witha 9.2% difference between measured and simulated. Adding intraventricular activation to the model did not improve the accuracy ofresponse prediction. The authors found that computer revealedintrinsic interventricular dyssynchrony is the dominant componentof the electrical substrate driving the response to CRT.
In the next paper Kenji Kuroki and associates examined the use ofvoltage limit adjustment of substrate mapping and fast Fouriertransform analysis of local ventricular bipolar electrograms duringsinus rhythm to predict VT isthmuses. They performed these studiesand nine post infarction patients who underwent catheter ablationfor total of 13 monomorphic ventricular tachycardias. Relativelyhigher voltage areas on electroanatomical map or defined as highvoltage channels, which were further classified as full or partialif the entire or more than 30% of the high voltage channel wasdetectable. 12 full high voltage channels were identified in sevenof nine patients. Relatively higher fast Fourier transform areaswere defined as high frequency channels, which were located onseven of 12 full high voltage channels. Five VT isthmuses or 71%were included in the seven full high voltage channels positive inhigh frequency channel positive sites.
While no VT isthmuses were found in five full high voltage channelpositive but high frequency channel negative sites, high frequencychannels were identical to 9 out of 16 partial high voltagechannels. Eight VT isthmuses or 89% were included in nine partialhigh voltage channel positive in high frequency channel positivesites, whereas no VTs isthmuses were found in the seven partialhigh voltage channel positive and high frequency channel negativesites.
All high voltage channel positive in high-frequency channelpositive sites predicted VT isthmus with a sensitivity of 100% andspecificity of 80%. The authors concluded that based on this smallseries that combined use of voltage, limited adjustment and fastFourier transform analysis may be useful method to detect VTisthmuses.
In the next study, John Whitaker and associates examined the use oflesion index, LSI index, a proprietary algorithm combining contactforce, radio-frequency application duration, and RF current.Cardiac CT was used to assess atrial tissue thickness. Ablationlines two to three per animal were created in the right atrium inseven mini pigs with point lesions using 25 watts of energy. Twoweeks after the ablation, serial sections of targeted atrial tissueor examine histologically to identify gaps and transmural ablation.LSI guidelines had a lower incidence of histological gaps. Fourgaps in the 69 catheter moved or 5.8% compared to ablation usingLSI plus two millimeter lines in which there is seven gaps in 33catheter moves or 21.2% and using LSI plus four millimeter lines inwhich there are 15 gaps in 23 moves or 65.2% p less than 0.0. Thechange in LSI was calculated retrospectively is a distance betweentwo adjacent lesions above the mean LSI of the two lesions.Changing LSI values of 1.5 or less were associated with no gaps intransmural ablation.
The authors concluded that in this mod of chronic atrial ablationdelivery of uninterrupted transmural linear lesions may befacilitated using LSI to guide catheter movement. When change inLSI between adjacent legions is 1.5 millimeters or lower, no gapsin atrial linear lesions should be expected.
In our next paper, Matthew Bennett and associate examined whethertheir response to antitachycardia pacing in patients with ICD couldfurther discriminate ventricular from super ventricular arrhythmiasin patients receiving ATP in the RAFT trial. The RAFT trialrandomized 1,798 patients with New York Heart Association class twoor three heart failure, left ventricular ejection fraction lessthan or equal to 30%, in QRS duration 120 millisecond or greater,to an ICD plus or a minus cardiac resynchronization. Beginning with10,916 ATP attempts for 8,150 tachycardia episodes in 924 patients,the author's excluded tachycardias where ATP terminated the episodeor were the specific etiology tachycardia was uncertain. In thisstudy, they analyzed 3,676 ATP attempts delivered to 2,046tachycardia episodes in 541 patients. The authors found that ashorter difference between the post pacing interval is PPI minusTCL, was more likely to be associated with VT than SVT, mean of138.1 milliseconds for VT and 277.4 milliseconds for SVT p, lessthan 0.001. A PPI minus TCL value of less than or equal to 300milliseconds had a sensitivity in 97.4% and a specificity of 28.3%for VT.
The authors concluded that specifically the PPI minus TCL followingantitachycardia pacing may help distinguish ventricular fromsupraventricular arrhythmias.
In the next study, Shailee Shah and Amr Barakat and associatesexamined the outcomes after repeat AF ablation. The authorsexamined 137 patients out of a total of 10,378 patients undergoingAfib ablation who had had initial long-term success defined fromrecurrent arrhythmias for greater than 36 months offanti-arrhythmic drugs in subsequent underwent repeat ablation forrecurrent atrial fibrillation. The median arrhythmia free periodthat define long-term success was 52 months. In redo-ablationsreconnection of at least one of the pulmonary veins was found in111 or 81% of patients. Additional non PV ablations were performedin 127 or 92.7% of patients. After a mean follow-up of 17 months,103 patients or 75% were arrhythmia-free, 79 off anti-arrhythmics,and 24 on arrhythmics. The authors found that repeat ablations withre-isolation to the point of veins and modifying the atrialsubstrate had a good success rate.
In the next article Qiongling Wang and associates hypothesized thatgenetic inhibition of CaMKII oxidation in a mouse model of Duchennemuscular dystrophy can alleviate abnormal calcium homeostasis thuspreventing ventricular arrhythmias. The authors tested whether theselective loss of oxidation of the CaMKII effects ventriculararrhythmias in the mouse model of Duchenne muscular dystrophy.Genetic inhibition of ox-CaM kinase II by knocking replacement ofthe regulatory domain methionines with valines, which we'll callMMVV, prevented ventricular tachycardia in the mdx mice. Confocalcalcium imaging of ventricular myocytes, isolated from the mdx MMVVmice revealed normalization of intra-calcium release eventscompared to myocytes from the mdx mice. Abnormal action potentialsas assessed by optical mapping mdx were also alleviated by geneticinhibition of ox-CaMK II. Knockout of the NADPH oxidase regulatorysub-unit P 47 Fox normalized elevated ox-CaMK II, repairedintracellular calcium hemostasis and rescued inducible ventriculararrhythmias in the mdx mice. The authors concluded that inhibitionof ROS or ox-CaMK II protects against pro-arrhythmic intracellularcalcium handling, preventing ventricular arrhythmias in a mousemodel of Duchenne muscular dystrophy.
In the next article, Kyohei Marume and Teruo Noguchi and associatesexamined whether the combination of QRS duration of 120milliseconds or greater in late gadolinium enhancement is a preciseprognostic indicator for the primary endpoint of all cause deathand a composite of sudden cardiac death or aborted sudden cardiacdeath in 531 patients with dilated cardiomyopathy. They alsoanalyzed the association between the combination of late gadoliniumenhancement and increased QRS duration in these end points amongpatients with a class one indication for implantable defibrillator.The author's divided study patients in three groups according tolate gadolinium enhancement in QRS duration. Two negative indicesthat is late gadolinium enhancement negative and narrow QRS, onepositive index with either late gadolinium enhancement positive orwide QRS or two positive indices late gadolinium positive and wideQRS and followed them for 3.8 years. Multiple variable Coxregression analysis identified to positive indices as significantpredictors of all cause death. A hazard ratio of 4.29 p equals0.026. Among the 317 patients with a class one indication for ICD,the five year event rate of sudden cardiac death or aborted suddencardiac death was lowest in the two negative indices groups, 1.4%.With propensity score matching cohorts the two negative indicesgroup had a significant lower event rate of sudden cardiac death oraborted sudden cardiac death than to two other groups hazard ratio0.2, p equals 0.046.
The authors concluded that the combination of late gadoliniumenhancement in wide QRS provides additional prognosticstratification compared to late gadolinium enhancement statusalone.
In the next study, Matthew Sulkin and associates examined whether anovel local impedance measurement on an ablation catheteridentifies catheter tissue coupling and is predictive of lesionformation. The author's first studied explanted hearts, 10 swine,and then in vivo 10 swine, using an investigational electroanatomical mapping system that measures impedance from an ablationcatheter with mini electrodes incorporated into the distalelectrode. Rhythmia and Intellanav, Boston Scientific.
Explanted tissue was placed in a warmed 37 degree celsius salinebath mounted on a scale, and the local impedance was measured 15millimeters away from the tissue to five millimeters of cathetertissue compression at multiple catheter angles. Lesions werecreated for 31 and 50 watts from 5 to 45 seconds for an N of 70.During in vivo valuation of the local impedance measurements of themyocardium 90 and blood pool 30 were guided by intracardiacultrasound while operators were blinded to the local impedancedata. Lesions were created with 31 and 50 watts for 45 seconds inthe ventricle with an n of 72. The local impedance of myocardium,which was 119.7 ohms, was significantly greater than in blood pool67.6 ohms the p of less than 0.01. Models that incorporate localimpedance drop to predict lesion size had better performance thatmodels incorporate force time integral r squared of 0.75 versus rsquared of 0.54 and generator impedance drop r squared of 0.2versus r squared of 0.58. Steam pops displayed a significantlyhigher starting local impedance and a larger change in localimpedance compared to successful RF applications, p less than0.01.
The authors concluded that local impedance recorded for miniatureelectrodes provides a valuable measure of catheter tissue couplingand the change in local impedance is predictive of lesion formationduring RF ablation.
In the next paper, Boaz Avitall and associates found that therising impedance recorded from a ring electrode placed twomillimeters from the cryoballoon signifies ice formation coveringthe balloon surface and indicates ice expansion. The authorsstudied 12 canines in a total of 57 pulmonary veins, which weretargeted for isolation. Two cryoapplications were delivered pervein with a minimum of 90 and a maximum 180 second duration.Cryoapplications was terminated upon reaching a 500 ohm change frombaseline. Animals recovered 38 plus or minus six days postprocedure, and the veins were assessed electrically for isolation.Heart tissue was histological examined. Extra cardiac structureswere examined for damage. Pulmonary vein isolation was achieved in100% of veins if the impedance reached 500 ohms in 90 to 180seconds. When the final impedance was between 200 and 500 ohmswithin 180 seconds of freeze time, pulmonary vein isolation wasachieved in 86.8%. For impedance of less than 200 ohms pulmonaryvein isolation was achieved in 14%. No extra cardiac damage wasrecorded. The authors found that impedance rise of 500 ohms at lessthan 90 seconds with a freeze time of 90 seconds resulted in 100%pulmonary vein isolation.
In our final papers Sally-Ann Clur and associates examined leftventricular isovolumetric relaxation time as the potentialdiagnostic marker for fetal Long QT Syndrome. Left ventricularisovolumetric contraction time, ejection time, left ventricularisovolumetric relaxation time, cycle length, and fetal heart ratewere measured using pulse doppler wave forms in fetuses. Timeintervals were expressed as percentage of cycle length, and theleft ventricular myocardium performance index was calculated.Single measurements were stratified and compared between Long QTSyndrome fetuses and controls. Receiver operator curves werereformed for fetal heart rate in normalized left ventricularisovolumetric relaxation time. A linear mixed effect modelincluding multiple measurements was used to analyze fetal heartrate, the left ventricular iso volume metric relaxation time, andthe left ventricular myocardial performance index. There were 33Long QT fetuses in 469 controls. In Long QT fetuses the leftventricular isovolumetric relaxation time was prolonged in allgroups, p less than 0.001, as was the left ventricularisovolumetric relaxation time.
The best cutoff to diagnose Long QT syndrome was the normalizedleft ventricular isovolumetric relaxation time greater than equalto 11.3 at less than or equal to 20 weeks, giving a sensitivity in92% and a specificity of 70%. Simultaneous analysis of thenormalized left ventricular isovolumetric relaxation time and fetalheart rate improved the sensitivity and specificity of Long QTSyndrome, AUC of 0.96. The normalized left ventricularisovolumetric relaxation time, the left ventricular myocardialperformance index, and fetal heart rate trends differedsignificantly between Long QT Syndrome fetuses and controlsthroughout gestation.
The authors concluded that left ventricular volumetric relaxationtime is Prolonged QT fetuses. Findings of a prolonged normalizeleft ventricular isovolumetric relaxation time, and sinusbradycardia can improve the prenatal detection of fetal Long QTSyndrome.
That's it for this month, but keep listening. Suraj Kapa will besurveying all journals for the latest topics of interest in ourfield. Remember to download the podcasts On the Beat. Take it awaySuraj.
SurajKapa:Thank you, Paul and welcome back to On the Beat were we will besummarizing hard-hitting articles across the entireelectrophysiologic literature. Today we'll be starting within therealm of atrial fibrillation where we're review an article withinthe realm of anticoagulation and stroke prevention. Quon et al.published in last month's issue of JACC cardiac electrophysiologyon anticoagulant use and risk of ischemic stroke and bleeding inpatients with secondary atrial fibrillation. It is well known thatuse of anticoagulation in atrial fibrillation can reduce overallthromboembolic outcomes. However, its role in secondary atrialfibrillation is unclear. Thus, the authors sought to evaluate theeffects anticoagulant use on stroke and bleeding risk. Amongstthose where atrial fibrillation occurred in the setting of acutecoronary syndrome, pulmonary disease, or sepsis. Amongst around2300 patients evaluated retrospectively there was no evidence of alower incidence of ischemic stroke among those treated withanticoagulants compared to those who are not.
However, anticoagulation was associated with a higher risk ofbleeding in those with new onset AF associated with acute pulmonarydisease. The authors suggest as a result that there is unclearoverall benefit for long-term anticoagulation in patients withpresumed secondary atrial fibrillation. The difficulty in assessingthis is how to define secondary atrial fibrillation. However, inmany studies patients who developed in the setting of acute illnessstill had a high risk of developing quote unquote clinicallysignificant AF in long-term follow-up. However, this was notnecessarily absolute as many patients not necessarily develop AFthat could be considered clinically significant. Thus, the clinicalquestion that arises is: how long should we treat a patient withanticoagulation when they have presumed secondary atrialfibrillation. These data seem to suggest that there may be no netoverall benefits. In other words, all-comers with secondary atrialfibrillation should not necessarily be forever treated withanti-coagulation. However, this slightly requires clinical trialsto evaluate further.
Next we delve into the realm of cardiac mapping and ablation wherewe view an article by Gaita et al. entitled 'Very long-term outcomefollowing transcatheter ablation of atrial fibrillation. Areresults maintained after 10 years of follow-up?', published inEuropace last month. While pulmonary vein isolation is a widelyaccepted approach for treatment of atrial fibrillation, mostreported studies review outcomes in terms of freedom of AF over arelatively short time period, generally two to five years. Howeverlonger term follow up is inconsistently reported. Gaita et al.sought to review 10 year outcomes amongst 255 patients undergoingablation in a single center. They noted 52% remainderarrhythmia-free amongst a mixed cohort of both paroxysmal andpersistent patients while 10% progressed to permanent atrialfiBrillation. They found that absence of increases in bloodpressure, BMI, and fasting glucose was protective against anarrhythmia recurrence.
These findings suggest that in a relatively small cohort ofpatients limited to a single center that even long-term outcomesafter pulmonary vein isolation are generally quite good, exceeding50%. However, future freedom from atrial fibrillation is heavilytied to control of other risk factors. In other words, if a patientis going to have poor control of diabetes, blood pressure, or gainweight, the benefit of their pulmonary vein isolation overlong-term follow-up is likely less. These data thus highlight boththe potential long-term benefit of PVI, but also the importance ofcounseling patients regarding the need for continued management andcontrol of future and existing risk factors.
Staying within the realm of atrial fibrillation we next review anarticle by Weng et al. entitled 'Genetic Predisposition, ClinicalRisk Factor Burden, and Lifetime Risk of Atrial Fibrillation'published in last month's issue of circulation. The probability ofdetecting atrial fibrillation in patients based on clinical factorsand genetic risk is unknown. Weng et al. sought to clarify whethera combination of clinical and polygenic risk scores could be usedto predict risk of developing atrial fibrillation over long-termfollowup in the Framingham Heart Study. Amongst 4,600 individuals,580 developed incident atrial fibrillation and had an overalllifetime risk of developing atrial fibrillation of 37%. Those arethe lowest risk tertile based on clinical risk factor burden andgenetic predisposition had a lifetime risk of 22% versus 48% in thehighest. Furthermore, a lower clinical risk factor burden wasassociated with delayed atrial fibrillation onset. In order toidentify patients with atrial fibrillation, before negativesequelae such as stroke occur, patient and physician understandingof risk and monitoring needs is necessary. The fact is that it willbe great to identify every single patient who has atrialfibrillation before they have a negative sequela of that atrialfibrillation such as ischemic stroke.
However, performing continuous monitoring of all patients withpotential negative sequelae of atrial fibrillation isextraordinarily difficult. The reason is it's excessively costly.We cannot monitor the entire population irrespective of whateverthe risk factors are. However, if we're able to identify thehighest risk cohorts early on before the atrial fibrillationonsets, this may offer opportunities for use of newer cheapermonitors. The work by Weng et al. suggests one such possibleapproach combines clinical and polygenic risk scores. Actionabilityof these data, however, remains to be seen and further validationother cohorts is necessary to clarify generalized ability.
The next article we review is published in last month's issue ofthe Journal of American College of Cardiology by Lopes at al.entitled 'Digoxin and Mortality in Patients With AtrialFibrillation. Lopes et al. sought to evaluate the impact of theDigoxin on mortality in patients with atrial fibrillation and theassociation with the Digoxin serum concentration and heart failurestatus. They value this association in over 17,000 patients. Atbaseline 32% were receiving Digoxin. Baseline Digoxin use did notassociate with risk of death, but even in these patients a serumconcentration of greater than 1.2 nanograms per milliliter wasassociated with a 56% increase in mortality risk. For each .5nanogram per milliliter increase in oxygen concentration the hazardratio increased by 19% for overall mortality. This was irrespectiveof heart failure status. Furthermore, in patients who are newlystarted in Digoxin over the follow-up period, the risk and deathand sudden death was higher. These data suggests a significant riskassociated with Digoxin use for management of atrial fibrillationirrespective of heart failure status. Furthermore, serum valleysabove 1.2 require close consideration of dose de-escalation.Whether there is any optimal dose, however, from the study isunclear. These data amongst a host of prior data strongly suggestagain strategic use of Digoxin principally for the managementof atrial fibrillation.
Moving on within the realm of atrial fibrillation, we review anarticle published in last month's issue of Circulation Research byYan et al. entitled Stress Signaling JNK2 Crosstalk with CaMKIIUnderlies Enhanced Atrial Arrhythmogenesis. In this more acellularbased study the mechanism underlying atrial arrhythmogenesisassociated with aging was evaluated. Yan et al. sought to figureout whether the stress response JNK in calcium mediated arrhythmiasmight contribute to atrial arrhythmogenesis in aged transgenicmouse models. They demonstrated significant increased activity ofJNK2 and aging atria, those furthermore associated with rhythmicremodeling. This association was mediated through CaMKII andryanodine receptor channel function, with activation of the formerleading to increased calcium leak mediated by the ladder. This inturn related to increase atrial fibrillation likelihood.Identifying novel targets for atrial fibrillation therapy iscritical. Given atrial fibrillation is a complex disease processrelated to a multitude of risk factors it can be assumed that thecontribution of any single factor may be mediated through distinctmechanisms.
Aging in particular as well regarded, but considered to benon-modifiable risk factor for atrial fibrillation. Identifyinggenes or pathways, the immediate aging associated fibrillation, maytake the risk of aging as no longer a non-modifiable thing. Thefinding of the significance of JNK2 and associate downstreameffects with AF risks and aging hearts may hold potential inoffering unique therapeutic targets.
Finally, within the realm of atrial fibrillation, we're viewingarticle by Chen et al. in last month's issue of the Journal of theAmerican Heart Association entitled Association of AtrialFibrillation With Cognitive Decline and Dementia Over 20 Years: TheARIC-NCS Study. Multiple studies have suggested a significantassociation between atrial fibrillation risk of dementia. However,these studies have limited time follow-up and were often done andpredominantly white patients. Thus, the authors sought to use thedata from ARIC, the Atherosclerosis Risk in CommunitiesNeurocognitive Study, to assess the risk of cognitive declineassociated with atrial fibrillation. Amongst over 12,000participants, a quarter of whom are black and half of whom arewhite, they noted 2100 patients developed atrial fibrillation and1,150 develop dementia over a 20 year follow up period.
There was a significantly greater risk of cognitive decline amongstthose who developed atrial fibrillation. In turn incident atrialfibrillation for the follow-up period was associated with a higherrisk of dementia even after adjusting for other clinical andcardiovascular risk factors such as incidents that ischemic stroke.These data further strengthened prior evidence of a direct linkbetween atrial fibrillation and risk of cognitive decline anddementia. Understanding this long-term risk raises the need toadditionally identify approaches to prevent this occurrence, whichin turn is dependent on understanding the underlying mechanisms.The finding that the risk of cognitive decline dementiasindependent of ischemic stroke events raises concern that eithersubclinical micro-embolic events or other factors may be playing arole in this risk and in turn raises question as to how best toprevent them. Until better understood, however, the question ofwhether the association is causal remains to be seen.
Changing gears yet again, we now delve into the realm of ICDs,pacemakers and CRT. Published in last month, issue of Heart RhythmTarakji et al. published a paper entitled 'Unrecognized venousinjuries after cardiac implantable electronic device transvenouslead extraction.' Overall risk of transvenous lead extractionincludes that of potentially fatal venous laceration. The authorssought to evaluate the incidence of venous injury that may beunrecognized based on microscopic study of extracted leads. Amongst861 leads obtained from 461 patients they noted 80 leads or almost9%. Amongst 15% of patients showed segments vein on the lead body,most of which were transmural including the tissue layer. However,in terms of clinical significance, only 1% had need for emergentsurgical intervention for clinically significant venous laceration.Risk factors for having the entire vein on the lead included age oflead, ICD leads, and the use of the laser sheath.
These findings suggest that there may be a high incidence ofsubclinical venous injury after lead extraction though rarelyresulting clinically apparent sequelae. As would be expected,venous injury, including transmural removal of portions of the veintraversed by the lead, was more common amongst older leads, whichgenerally more often require laser sheets and ICD leads. Thequestion is however, whether this carries any direct clinicalimplications. One they may be considered is the potential additiverisk of an advancing new lead through the same venous channel,particularly in the setting of potential transmural venous injurythat already exists.
Next in last month's issue of Heart Rhythm we review an article bySharma at al. entitled 'Permanent His-bundle pacing as analternative to biventricular pacing for cardiac resynchronizationtherapy: A multicenter experience.' The use of resynchronizationtherapy for treatment of patients with heart failure and wide QRShas been shown to offer morbidity and mortality benefits. However,many patients maybe non-responders, and recent studies on Hisbundle pacing of suggested potential clinical benefits. His bundlepacing essentially only requires one pacing catheter attachedwithin the region of the His bundle Sharma et al. sought toevaluate the safety and success rates of His bundle pacing forpatients who have either failed standard resynchronization therapyor in whom most tried as a primary intervention. They noted Hisbundle pacing was successful in 90% of patients with reasonablemyocardial and His bundle capture thresholds. Patients in bothgroups exhibits significant narrowing of QRS morphology andimprovement in left ventricular ejection fraction from a mean of 30to 43%. However, a total of seven patients had lead relatedcomplications.
These database on a retrospective analysis of two types ofpatients, those failing standard biventricular therapy, and thoseon whom his bundle pacing was attempted as a primary modalitysuggest overall safety and efficacy in a handful of experiencedcenters. The promise of His bundle pacing is that a may allow formore effective resynchronization than standard approaches. The highrate of success suggests that His bundle pacing maybe both safe andreasonable to pursue. However randomized trials across more centersare needed to fully prove its benefit, particularly as a primarymodality of treatments.
Next we review ICDs and chronic kidney disease. In last month'sissue of JAMA cardiology by Bansal at al. entitled 'Long-termOutcomes Associated With Implantable Cardioverter Defibrillator inAdults With Chronic Kidney Disease.' While the benefit of ICDs inpatients with low EF is widely recognized, modifying factors thatmay increase risk of death are not as well defined. These includethings like advanced age and chronic kidney disease. Bansal et al.sought to evaluate long-term outcomes and ICD therapy in patientswith chronic kidney disease. In retrospective study of almost 5,900ambulatory patients amongst whom 1550 had an ICD, they found nodifference in all cause mortality. However, ICD placement wasassociated with an increased risk of subsequent hospitalization dueto heart failure or any cause hospitalization.
In light of recent studies such as DANISH the robust sense of ICDbenefit is being questioned. One of the thoughts for the absence ofsimilar benefit to prior studies lies in the improving care ofambulatory heart failure patients. In patients with chronic kidneydisease several questions rises to the risk with ICD, includinginfectious risk in dialysis patients and the concomitant mortalityrisk with renal dysfunction. The author suggested in retrospectivestudy, no incremental benefit of ICDs in patients with chronickidney disease and perhaps some element of added risk is related tohospitalization. However, this study has several limitations. It isretrospective and many patients received ICDs may have beenperceived to be sicker in some way. Thus care must be taken ininterpretation, but consideration of randomized studies toadjudicate benefit are likely necessary.
Finally, within the realm of devices, we reviewed an article byTayal et al. entitled "Cardiac Resynchronization Therapy inPatients With Heart Failure and Narrow QRS Complexes.' publishingthe Journal of American College of Cardiology last month. Severalparameters have been stressed to identify benefit ofresynchronization therapy in patients with wide QRS include crosscorrelation analysis with tissue doppler imaging. However, manypatients may have evidence in mechanical dyssynchrony even in theabsence of an apparent wide QRS thus Tayal et al. sought toevaluate the benefit of resynchronization therapy amongst 807patients with heart failure and a narrow QRS mean criteria in arandomized study. Of the 807 46% had delayed mechanical activation.Those without delay mechanical activation had underwent westandardization therapy and were associated with worse overalloutcomes likely due to new delayed mechanical activationpotentially related to CRT pacing. These data support the absenceof a role for resynchronization therapy in patients with a narrowQRS. This is expected as resynchronization therapy likely offersthe most benefit in patients with mechanical dyssynchrony thatresults from electrical dyssynchrony.
Since by its very nature resynchronization therapy relies on nonphysiologic cardiac pacing thus compared to normal cardiacactivation the nature of resynchronization pacing isdesynchronization. These data support the absence of a role forresynchronization therapy in patients with heart failure and narrowQRS complexes.
Moving on to cellular electrophysiology we review an article byKozasa et al. published in last month's issue of Journal ofPhysiology entitled 'HCN4 pacemaker channels attenuate theparasympathetic response and stabilize the spontaneous firing ofthe sinoatrial node.' Heart rate is controlled by an interplaybetween sympathetic and parasympathetic components. In turn HCN4abnormalities have been implicated in congenital sick sinussyndrome. The authors sought to clarify the contribution of HCN4 tosinus node autonomic regulation. They created a novelgain-of-function mouse where the HCN4 activity could be modulatingfrom zero to three times normal. They then evaluated ambulatoryheart-rate variability and responsive heart rate to vagus nervestimulation. They found HCN4 over-expression did not increase heartrate, but attenuated heart-rate variability. It also attenuatedbradycardic response to vagus nerve stimulation. Knockdown of HCN4in turn lead to sinus arrhythmia and enhanced parasympatheticresponse. These data suggest HCN4 attenuates sinus node response tovagal stimuli thus stabilizing spontaneous firing of the node. Theclinical application of this remain to be seen but are maybeimportant in that they highlight a mechanism for a heretoforepoorly understood mechanism for how exactly HCN4 abnormalities maylead to sick sinus syndrome.
Within the realm of ventricular arrhythmias we highlighted a numberof articles published this past month. The first article we reviewwas published in last month's issue of JACC clinicalelectrophysiology, entitled characterization of the electrodeatomic substrate and cardiac sarcoidosis: correlation with imagingfindings of scarring inflammation published by [inaudible 00:41:40]et al. In patients with cardiac sarcoidosis one of the questions ishow to define the electronic atomic substrate, particularly beforewe entered the electrophysiology laboratory. Both activeinflammation and replacement fibrosis maybe be seen in patients.The authors evaluated in 42 patients with cardiac sarcoidosis, theassociation between an abnormal electrograms and cardiac imagingfindings including PET and Computed Tomography, as well as CardiacMRI. They noted that amongst these 40 patients, a total of 21,000electrograms were obtained, and a total of 19% of these wereclassified as abnormal. Most of the abnormalities occurred in thebasal paravalvular segments and intraventricular septum. Theyfurther noted that many of these abnormalities in terms ofelectrograms were located outside the low voltage areas,particularly as it relates to fractionation. In about 90% ofpatients they notice late gadolinium enhancements and they notedabnormal FDG uptakes suggesting active inflammation in about48%.
However, it should be noted that only 29 of the 42 patientsunderwent cardiac imaging. Segments with abnormal electrogramstended to have more late gadolinium enhancement evidence scartransmurality, and also they noted that the association of abnormalPET scan did not necessarily occur with abnormal electrograms.Thus, they concluded that in patients with cardiac sarcoidosis andventricular tachycardia pre-procedural imaging with cardiac MRIcould be useful in detecting electroanatomic map abnormalities thatmay in turn be potential targets for substrate ablation. However,they were more likely associated with more scar transmurality andlower degrees of inflammation on PET scanning. These data areimportant in that they highlight potential non-invasive means bywhich to understand where substrate might occur in patients withthe cardiac sarcoidosis. It is well recognized that cardiacsarcoidosis is associated with increased risk of ventriculararrhythmias. These risks have increased ventricular arrhythmias,might be targetable with ablation. Newer therapies might even offernon invasive means by which to perform ablation in patients best.Thus if we could identify non based on mechanisms of identifyingthe substrate, this will be even more critical.
The critical findings of this particular paper lie in noting thatmost of the abnormalities still is in intra ventricular sePtum inbasal segments, and also that it is MRI in late gadoliniumenhancement and associates more with the abnormal electrograms.Interestingly, the absence of inflammation correlating with thepresence of more abnormal electrograms suggests that it is not somuch the act of inflammation as being reflected in the endocardialmap, but the existence of scar.
Next, again within JACC clinical electrophysiology we review anarticle by Porta-Sánchez et al. entitled 'Multicenter Study ofIschemic Ventricular Tachycardia Ablation With Decrement EvokedPotential Mapping With Extra Stimulus.' The authors sought toconduct a multicenter study of decrement evoked potential basefunctional tech ventricular tachycardia substrate modification tosee if such mechanistic and physiologic strategies could result inreduction in VT burden. It is noted that really only a fraction ofthe myocardium in what we presume to be substrate based on thepresence of low voltage areas are actually involved in theinitiation and perpetuation of VT. Thus if we can identify thecritical areas within the presumed substrate for ablation, thiswould be even a better way of potentially honing in on our targets.They included 20 consecutive patients with ischemic cardiomyopathy.During substrate mapping fractionated late potentials were targetedand an extra stimulus was provided to determine which displaydecrements. All patients underwent DEEP focus ablation withelimination being correlated with VT non-inducibility afterradio-frequency ablation. Patients were predominantly male, andthey noted that the specificity of these decrement evokedpotentials to detect the cardiac isthmus for VT was better thanthat of using late potentials alone. They noted 15 of 20 patientswere free of any VT after ablation of these targets over six monthsof follow-up, and there was a strong reduction in VT burdencompared to six months pre ablation.
They concluded that detriment evoked potential based strategiestowards ablation for ventricular tachycardia might identify thefunctional substrate and those areas most critical to ablation.They in turn regarded that by its physiologic nature it offersgreater access to folks to ablation therapies.
This publication is important in that it highlights another meansby which we can better hone in on the most critical regions forsubstrate evaluation in patients with ventricular tachycardia. Thefact is more extensive ablation is not necessarily better and mightresult in increased risk of harm if we think about the potentialeffects of longer ablations or more ablation lesions. Thus if wecould identify ways of only targeting those areas that are mostcritical to the VT circuits, we could perhaps short and ablationprocedural time, allow for novel ways of approaching targetedablation with limited amounts of ablation performed, or perhapseven improve overall VT outcomes by knowing the areas that are mostcritical to ensure adequate ablation therapy provided. However, weneed to understand that this is still a limited number of patientsevaluated in a non randomized manner. Thus whether or not moreextensive ablation performed might have been better is as of yetunclear
Staying within the realm of ventricular tachycardia we review anarticle published in last month's issue of Heart Rhythm byWinterfield et al. entitled the 'Impact of ventricular tachycardiaablation on healthcare utilization.' Catheter ablation of atrialtachycardia has been well accepted to reduce recurrent shocks inpatients with ICDs. However, this is a potentially costlyprocedure, and thus effect on overall long-term health careutilization remains to be seen. The authors sought to evaluate in alarge scale real world retrospective study the effect of VTablation on overall medical expenditures in healthcare utilization.A total 523 patients met study inclusion criteria from the marketscan database. After VT ablation median annual cardiac rhythmrelated medical expenditures actually decreased by over $5,000.Moreover the percentage of patients with at least one cardiacrhythm related hospitalization an ER visit decreased from 53 and41% before ablation respectively, to 28 and 26% after ablation.Similar changes we're seeing in number of all causehospitalizations and ER visits. During the year before VT ablationinterestingly there was an increasing rate of healthcare resourceutilization, but a drastic slowing after ablation.
These data suggests that catheter ablation may lead to reducedhospitalization in overall healthcare utilization. The importanceof these findings lies in understanding why we do the things we do.We can provide a number of therapies to patients, but we seek twodifferent effects. One is the individual effect of improving theirparticular health. The second thing is trying to avoid increasinghealthcare expenditures on a population level and making sureresources are utilized. If we can reduce recurrent hospitalizationsand overall healthcare expenditure in patients by providing atherapy in addition to provide individual benefit, this is theoptimal situation. These data suggests that VT ablation mightprovide such a benefits, that in fact it reduces overall healthcareutilization while improving overall outcomes.
Next and finally within the realm of ventricular arrhythmias, wereview more on the basic side the role of Titin cardiomyopathyleads to altered mitochondrial energetics, increased fibrosis andlong-term life-threatening arrhythmias, published by Verdonschot etal. in last month's issue of European Heart Journal. It is knownnow that truncating Titin variants might be the most prevalentgenetic cause of dilated cardiomyopathy. Thus, the authors soughtto study clinical parameters and long term outcomes related toTitin abnormalities in dilated cardiomyopathy. They reviewed 303consecutive and extensively phenotype dilated cardiomyopathypatients who underwent cardiac imaging, Holter monitoring, andendomyocardial biopsy and in turn also underwent DNA sequencing of47 cardiomyopathy associated genes. 13% of these patients had Titinabnormalities. Over long-term followup they noted that thesepatients had increased ventricular arrhythmias compared to othertypes of dilated cardiomyopathy, but interestingly, they hadsimilar survival rates. Arrhythmias in those Titin abnormalpatients were most prominent in those who were subjected to anadditional environmental trigger, including viral infection,cardiac inflammation, other systemic disease or toxic exposure.They also noted the cardiac mass was relatively reduced in titanadmirable patients.
They felt that all components of the mitochondrial electrontransport chain we're simply up-regulated in Titin abnormalpatients during RNA sequencing and interstitial fibrosis was alsoaugmented. As a result, they concluded that Titin variantassociated dilated cardiomyopathy was associated with an increasedrisk of ventricular arrhythmias, and also with more interstitialfibrosis. For a long time we have reviewed all non ischemiccardiomyopathy as essentially equal. However, more recent data hassuggested that we can actually hone in on the cause. In turn, if wehone in on the cause, we might be able to understand the effects ofspecific therapies for ventricular arrhythmias based on thatunderlying cause. Patchy fibrosis might not be as amenable, forexample, to ablation as discreet substrate that we might see ininfarct related VT. Understanding the relative benefit in veryspecific types of myopathies might hold benefit in understandinghow to, one, risk stratify these patients, and two, understand whattype of therapy, whether pharmacologic or ablative, might result ingreatest benefit to the patients.
Changing gears entirely now to the role of genetics, we reviewmultiple articles in various genetic syndromes published this pastmonth. First, we reviewed an article by Providência et al.published in the last month's issue of heart entitled 'Impact ofQTc formulae in the prevalence of short corrected QT interval andimpact on probability and diagnosis of short QT syndrome.' Theauthors sought to assess the overall prevalence of short correctedQT intervals and the impact on diagnosis of short QT syndrome usingdifferent methods for correcting the QT interval. In thisobservational study they reviewed the sudden cardiac deathscreening of risk factors cohorts. They then applied multipledifferent correction formulae to the ECGs. They noted that theprevalence of individuals with the QTc less than 330 and 320 wasextremely low, namely less than .07 and .02% respectively. Theywere also more frequently identified using the Framinghamcorrection. The different QTc correction formulae could lead to ashift of anywhere from 5 to 10% of individuals in the cohortoverall.
They further noted, that based on consensus criteria, instead of 12individuals diagnosed with short gut syndrome using the Bazettequation, a different number of individuals would have metdiagnostic criteria with other formulae, 11 using Fridericia, 9with Hodges, and 16 using the Framingham equation. Thus, they notedthat overall the prevalence of short QT syndrome exceedingly lowand an apparently healthy adult population. However,reclassification as meeting criteria might be heavily dependent onwhich QT correction formula is used. The importance of thesefindings is that not all QTs are created equal.
Depending on how you compute the QT interval in which formula touse may affect how you actually risk characterize a patient.Unfortunately, these data do not necessarily tell us which is theright formula, but this highlights that it might be relevant to inthe future evaluate the role of different formulae and identifyingwhich is the most necessary to classify a patient.
Moving on to an article published in last month's issue of thejournal of clinical investigation by Chai et al. we review anarticle entitled 'Physiological genomics identifies geneticmodifiers of Long QT Syndrome type 2 severity.' Congenital Long QTSyndrome is a very well recognized, inherited channelopathyassociated life-threatening arrhythmias. LQTS type 2 isspecifically caused by mutations in casein to encoding thepotassium channel hERG. However, even with the mutation not allpatients exhibit the same phenotype. Namely some patients are moreat risk of life threatening arrhythmias in spite of having the samemutation as others who do not exhibit the same severity phenotype.The authors sought to evaluate whether specific modifiable factorswithin the remaining genetic code might be modifying the existingmutation. Thus, they sought to identify contributors to variableexpressivity in an LQT 2 family by using induced pluripotent stemcell derived cardiomyocytes and whole exome sequencing in asynergistic manner.
They found that patients with severely effected LQT 2 displayedprolonged action potentials compare to sales from mildly effectedfirst-degree relatives. Furthermore, stem cells derived frompatients were different in terms of how much L-type calcium currentthey exhibited. They noted that whole exome sequencing identifiedvariants of KCNK17 and the GTP-binding protein REM2 in thosepatients with more severe phenotypes in whom greater L-type calciumcurrent was seen. This suggests that abnormalities or evenpolymorphisms in other genes might be modifying the risk attributedto by mutations in the primary gene. This showcases the power ofcombining complimentary physiological and genomic analysis toidentify genetic modifiers and potential therapeutic targets of amonogenic disorder. This is extraordinarily critical as weunderstand on one level that when we sequence a monogenic disorderthat there might exist variants of uncertain significance, namelythey have not been classified as disease causing, but could be. Inturn, we also recognize that mutations in a family might effectdifferent relatives differently. However, why this is has beenrelatively unclear.
If we can understand and identify those patients who are most atrisk of dangerous abnormal rhythms, this will be useful in how muchto follow them, and what type of therapy to use in them. The factthat other genes might modify the risk even in the absence ofspecific mutations, suggests that novel approaches tocharacterizing the risk might help for the risk modified patientsclassification in general. Clinical use, however, remains to beseen.
Moving on from long QT, we evaluate 'The Diagnostic Yield ofBrugada Syndrome After Sudden Death With Normal Autopsy' noted inlast month's issue of the Journal of American College of Cardiologyand published by Papadakis et al. It is well known, the negativeautopsies are not uncommon in patients, however, families might bewondering how at risk they are. Thus, the authors sought to assessthe impact of systematic ajmaline provocation testing using highright precordial leads on the diagnostic yield Brugada syndrome ina large cohort of Sudden Arrhythmic Death syndrome families.Amongst 303 families affected by Sudden Arrhythmic Death Syndromeevaluation was done to determine whether or not there was a geneticinherited channelopathy cause. An inherited cardiac disease wasdiagnosed in 42% of the families and 22% of relatives Brugadasyndrome was the most prevalent diagnosis overall amongst 28% offamilies. Ajmaline testing was required, however, to unmask theBrugada Syndrome in 97% of diagnosed individuals. Furthermore, theyuse of high right precordial leads showed a 16% incrementaldiagnostic yield of ajmaline testing for diagnosing Brugadasyndrome.
They further noted that a spontaneous type 1 regard or pattern or aclinically significant rhythmic event developed in 17% of theseconcealed regardless syndrome patients. The authors concluded thesystematic use of ajmaline testing with high right precordial leadsincreases the yield of Brugada Syndrome testing in SuddenArrhythmic Death Syndrome families. Furthermore, they noted thatassessments should be performed in expert centers or patients couldalso be counseled appropriately. These findings are important andone of the big questions always becomes how aggressively to testfamily members of patients or of deceased individuals whoexperienced sudden arrhythmic death. Many of these patients havenegative autopsies, and genetic autopsy might not be possible dueto lack of tissue or blood products that can be adequatelytested.
The data here suggest that amongst a group of 303 sudden arrhythmicdeath, families that Brugada Syndrome is by far the most frequentdiagnosis. If an inherited cardiac disease was identified. In turn,it is not ECG alone or echo alone that helps identify them, butrequires drug provocation testing in addition to differentelectrode placements. Whether or not this will consistently offerbenefit in patients in general or my result in overcalling remainsto be seen next within the realm of genetic predisposition.
We view an area where we don't know if there's a geneticpredisposition in article published by Tester et al. entitledCardiac Genetic Predisposition in Sudden Infant Death Syndrome inlast month's issue of the journal of american college ofcardiology. Sudden Infant Death Syndrome is the leading cause ofpost-neonatal mortality and genetic heart diseases might underliesome cases of SIDS. Thus the authors sought to determine thespectrum and prevalence of genetic heart disease associatedmutations as a potential monogenic basis for Sudden Infant DeathSyndrome. They study the largest cohort to date of unrelated SIDScases, including a total of 419 individuals who underwent wholeexome sequencing and targeted analysis for 90 genetic heart diseasesusceptibility genes. Overall, 12.6% of these cases had at leastone potentially informative genetic heart disease associatedvariants. The yield was higher in those mixed European ancestrythan those of European ancestry.
Infants older than four months were more likely to host apotentially informative gene. Furthermore, they noted that only 18of the 419 SIDS cases hold a [inaudible 01:01:26] or likelypathogenic variant. So in other words, only 4% of cases really hada variant that they could say was distinctly pathogenic or likelypathogenic. Thus, overall, the minority of SIDS cases havepotentially informative variant in genetic heart diseasesusceptibility gene, and these individuals were mostly in the 4 to12 month age group. Also, only 4% of cases had immediatelyclinically actionable variance, namely a variant, which is wellrecognized as pathogenic and where we could actually say that aspecific therapy might have had some effect. These findings canhave major implications for how best to investigate SIDS cases infamilies. It might suggest that SIDS cases where the individual wasolder, nearly 4 to 12 months of age might have a greater yield interms of identifying variance.
While this might not affect the deceased in fit, it might affect,families are planning on having another child in whom a variant canbe identified.
Finally, within the realm of genetics, we review an articlepublished in last month's issue of Science Advances by Huang. etal. entitled 'Mechanisms of KCNQ1 Channel Dysfunction in Long QTSyndrome Involving Voltage Sensor Domain Mutations'. Mutations thatinduce loss of function of human KCNQ1 underlie the Long QTSyndrome type 1. While hundreds of mutations have been identifiedthe molecular mechanism by which they result in impaired functionare not as well understood. The authors sought to investigateimpact of 51 specific variants located within the voltage sensordomain and emphasized effect on cell surface expression, proteinfolding, and structure. For each variant efficiency of traffickingof the plasma membrane, impact of proteasome inhibition, andprotein stability were evaluated. They noted that more than half ofthe loss of function mutations were seen to destabilized structureof the voltage sensor domain, generally accompanied bymistrafficking and degradation by the proteasome.
They also noted that five of the folding defective Long QT Syndromemutant sites were located in the S0 helix, where they tend tointeract with a number of other loss of function mutation sites inother segments of the voltage sensor domain. They suggested theseobservations reveal a critical role for the S0 helix as a centralscaffold to help organize and stabilized KCNQ1 overall. They alsonote the importance of these findings is that mutation-induceddestabilization of membrane proteins may be a more common cause ofdisease functioning in humans. The importance of these findingslies in better understanding why specific mutations lead toapparent phenotypes. If we can unDerstand this, we might be able tocharacterize better variants as they appear where pathologiceffects are not as well demonstrated in in vitro assays. Thusvariance of uncertain significance might be more easilyreclassified if we understand why they occur, where they occur, andhow they modulate disease.
Changing gears to our final article of this edition of On the Beatwe delve into the realm of syncope and an article published in lastmonth's issue of Circulation Research by van den Berg. et al.entitled 'Mutations in CYB561 Causing a Novel OrthostaticHypotension Syndrome.' Orthostatic hypotension is a very commonclinical problem, but a very difficult one because we don't totallyunderstand the underlying mechanisms. The authors described tofamilies with four patients in total who experienced severeorthostatic hypotension. They noted that concentrations ofnorepinephrine and epinephrine and these particular patientsrelatively low. They did molecular genetic analysis to determine ifthey could identify an underlying genetic cause. They noted that inthese two families, abnormalities in genes encoding cytochromeCYB561 were present. They in turn sought to understand what themechanism of these specific mutations were. They noted that defectsin the protein led to a shorted ascorbate inside the catecholaminesecretory vesicles linked to a functional dopamine beta hydroxylasedeficiency. Concentration and catecholamines and downstreammetabolites in turn was measured in brain and adrenal tissue inknockout mice for the same gene. The concentration ofnorepinephrine and normetanephrine was known to be decreased inwhole brain homogenates compared with wild type mice.
They intern treated these patients with L-dihydroxyphenylserine,which can be converted directly to norepinephrine to see if thiseffected the phenotype and noted that these patients respondedfavorably. This study is the first one to implicate the cytochromeb561 in orthostatic hypotension diseases. They also suggested themechanism by which this might occur, namely through some degree ofneurotransmitter metabolism. They also suggested treatment in thespecific subtype with L-dihydroxyphenylserine. These findings areimportant in they highlight not all orthostatic hypotension iscreated equal. Namely, some patients with orthostatic hypertensionmight have a discrete phenotype. If we can understand the phenotypeand understand how best to treat it, we might be able to actuallyoffer targeted personalizable therapies. I appreciate everyone'sattention to these key and hard-hitting articles that we have justfocused on from this past month of cardiac electrophysiology acrossliterature. Thanks for listening. Now back to Paul.
Thanks, Suraj. You did a terrific job surveying all journals forthe latest articles on topics of interest to our field. There's notan easier way to stay in touch with the latest advances. Thesesummaries and a list of all major articles in our field each monthcan be downloaded from Circulation Arrhythmia and Electrophysiologywebsite. We hope that you'll find the journal to be the go to placefor everyone interested in the field. See you next month.
