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Killing Cardiac Cells

chambers of the heart imageI was in the mall one day and the saleswoman started talking about her health issues. For starters, I am not sure why she entrusted me with this information, but okay. So why is that conversation interesting enough to write about? Well, the lady was 20 years of age and she had undergone several cardiovascular challenges, including a cardiac ablation. I had heard of other people having this procedure done but I had not thought much about it (I looked it up but not in much detail), until I met this young lady. So, I started wondering:

  1. What is the underlying pathology that causes one to need to have the procedure?
  2. What is the average age of patients undergoing the procedure?
  3. What is cardiac ablation?
  4. How commonly is this procedure done?

Cardiac ablation is the use of catheters to target and kill off specific cells within the heart, generally in the atrium. The adult mammalian myocardium has a negligible ability to regenerate once damage has occurred. Thus, rather than undergoing cardiomyogenesis (the formation of myocardium/heart muscles), fibrous tissue is instead formed. This phenomenon raised more questions for me, so I did literature searches…then more literature searches…then read more literature. The more I read, the more I felt I needed to read to understand why cardiologist would choose this procedure. Following a myocardial infarction (heart attack) a significant number of cardiomyocytes die leading to an enhanced inflammatory reaction. This cardiac event results in dead myocardial tissue being replaced with interstitial and perivascular collagen deposition. The presence of fibrosis can lead to pressure overload, increased blood pressure or potentially aortic stenosis. However, a patient that has suffered from myocardial infarction would not be a good candidate for cardiac ablation. So, who would be a good fit to undergo such a procedure? Usually it is a patient exhibiting cardiac arrhythmias, including atrial fibrillation (AF or AFib), supraventricular tachycardia (SVT), and Wolff-Parkinson-White Syndrome (WPW). Because this subject is enormous, I will only focus on AF due to the fact that it is the most common cause of arrhythmias treated with catheter ablation.

Pathophysiology of Atrial Fibrillation
AF is characterized by an abnormal heartbeat (quivering or irregular heartbeat) that causes the heart to ineffectively move blood into the ventricles. The onset of AF could be due to family history (genetics), but controllable risk factors are hypertension and valvular heart disease. The cardiovascular consequence of AF includes: 

  1. Coronary artery disease
  2. Mitral stenosis
  3. Mitral regurgitation
  4. Left atrial enlargement
  5. Hypertrophic cardiomyopathy
  6. Congenital Heart Disease
  7. Cerebrovascular Accident

AF is considered the most common arrhythmic disease and it affects about 4% of the population. The prevalence of AF increase with age (<0.2% under 50 year of age (yoa), 4% are 60-70 yoa, and ~15% >80 yoa), with patients suffering from it has an average age between 75-85 yoa. In the U.S., there was a significant number of deaths (>200,000) resulting from AF in 2015, which is reason enough to pursue aggressive therapies to control this heart rhythm disorder.

Treatment
The European Society of Cardiology (ESC) released guidelines that summarized the current evidence that is available to physicians in selecting the best strategy for managing diseases, taking into consideration the risk-benefit ratio of diagnosis and therapeutic means. The recommended guidelines has shifted to focus on the identification of ‘truly low-risk’ patients (<65 with AF alone that does not need antithrombotic therapy) rather than ‘high-risk’ patients. Based on the earlier guidelines for treating AF, a patient of age >20 would not be considered for ablation therapy, so I wondered…what are the alternative treatments? I found they can either be drugs, such as: 1) Novel oral anticoagulants (blood thinners) fall into two categories (Oral direct factor Xa inhibitors or Oral direct thrombin) and 2) Left atrial ablation—introduced by American College of Cardiology Foundation, American Heart Association, and the Heart Rhythm Society.

To read more about these treatment, please be directed to European Heart Journal for the ESC Guidelines. Here I will focus on cardiac ablation.

Cardiac Ablation
Cardiac ablationThe normal mammalian heart is composed of tight layers of myocytes that are separated by small clefts creating a matrix network. The cardiac matrix network is divided into three constituents. The matrix network is collagen-based and serves as a scaffold for various components of the cell as well as transmission of contractive forces that keep the cells in correct timing with neighboring cells. When the heart undergoes damage, the resulting fibrosis disrupts the coordination of this myocardial excitation-contraction leading to hypertension. Subsequently, loss of collagen impair transduction, which causes the uncoordinated contraction of the cardiac muscle bundles (the quivering or fluttering that is felt with AF) or generation of re-entry circuits (irregular heartbeat).

The ablation process will depend on the patient medical condition, past cardiac history, and the ablation technique chosen. There are several types of catheter ablation

a) Radiofrequency ablation-use radiofrequency generators to deliver a current, in a point by point fashion around the pulmonary vein, creating a circular scar around each vein.

b) Cryoablation—uses a single catheter that travels through the femoral vein in the groin to the left atrium. The balloon end (halo) of the catheter has a refrigerant that freezes the tissue it comes in contact with creating a scar.

c) Surgical ablation—generally used when open heart surgery is being conducted.
          i. Mini Maze-use 3-5 incisions on the front and side of the chest to insert the catheter to freeze/heat cardiomyocytes
          ii. Convergent—uses both surgical and catheter based techniques.

Catheter ablation is generally an outpatient procedure, but it should not be taken lightly. As with most consumers, cost comes to mind. How can cardiologist/electrophysiologist conduct such a procedure in so short of a time and charge so much? The answer is simple. The technology used in ablation is extensive; mapping equipment, cardioverter/defibrillator and catheter, recording apparatus, stimulators, and junction boxes. I am overwhelmed just thinking about it all!

Wrap it up…
Cardiovascular disease is a consequence of a lot of factors. Understanding the various procedures that the cardiologists are explaining can be daunting. Even with the expansive literature that is available it is difficult to determine how a procedure will work for each patient, especially with regard to the side effects. For example, in a 2010 study for rhythmic control (294 patients), there was no significant difference between patients that received the catheter ablation compared to those taking antiarrhythmic drugs as a first line of intervention. Catheter ablation is said to be more effective than antiarrhythmic drugs, but the recurrence of AF is significant during long term follow up. Early recurrence of AF is the best predictor of whether one will have a recurrence later. In an observational study conducted at high volume clinics, there was a 39% hospitalization rate post catheter ablation. However, catheter ablation has been deemed reasonable for first line of therapy for AF when patients have paroxysmal AF and low risk for procedures with complications; which is interesting since the majority of studies are inherently biased toward the experienced centers. It is reasonable to speculate that people, such as the saleswoman in the mall, who visit small low volume clinics, contribute to increased rates of hospitalization rates.

I am, furthermore interested in knowing whether there is a decrease in cardiac output post catheter ablation. If this procedure is killing off specific cells in the heart and leaving scar tissue, what are the downstream effects of this cardiac cell death? Especially in patients that have repeated catheter ablations. If there is a decrease in cardiac output, and the kidney filters 20% of the cardiac output daily, then what effect does cardiac ablation have on the renal system? Could this procedure enhance renal failure? I have had conversations with other people who have had cardiac ablations that later suffered from renal failure necessitating dialysis. Since all conditions are patient specific, there is no evidence that catheter ablation is connected to renal failure to my knowledge, but I wonder if anyone else had that observation.

To sum up the conversation I had with the young lady in the mall. She started her cardiac journey at an early age. She has gone through oral anticoagulant drugs, catheter ablation, and open-heart surgery. By the age of 20, that is a lot for one to have gone through. She was in such distress about having to undergo yet another catheter ablation that she was seeking answers to help her understand what she was going through and how to make informed decisions about her care. How can patients be better educated on what is going on with their bodies when visiting medical professionals? People are told to take responsibility for their care, but what if they do not understand enough to know what to ask?

Anberitha Matthews, PhD is a Postdoctoral Fellow at the University of Tennessee Health Science Center in Memphis TN. She is living a dream by researching vascular injury as it pertains to oxidative stress, volunteers with the Mississippi State University Alumni Association, serves as Chapter President and does consulting work with regard to scientific editing.

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The Lack Of New Drugs For Rhythm Control Of Atrial Fibrillation: A Stagnant Pipeline

“It does not matter how slowly you go as long as you do not stop”
– Confucius
 
Atrial fibrillation (AF) is the most common arrhythmia in the world1. This potentially malignant condition can dramatically raise the risk for stroke. Many patients are symptomatic, and those with congestive heart failure may suffer worse outcomes when afflicted with AF2. Undoubtedly with these patients, avoidance and prevention of AF is desirable. Anticoagulants are a mainstay for stroke prevention, and there are several to choose from. Today my article addresses the rhythm control drugs, or lack of. Here lies the problem: the (few) available oral agents are often not well tolerated, and antiarrhythmic drugs (AAD) are notorious for their potential for adverse effects.
 
Patients nowadays are internet savvy and very commonly will “research” their prescription medications. I cannot even begin to estimate how many patients with highly symptomatic AF I have met who were reluctant or downright refused to take a prescribed antiarrhythmic after reading the potential side effect profile. Amiodarone is one such drug. Largely accepted as effective, many practitioners are wary of long-term use and the development of pulmonary toxicity or hepatic insufficiency although rare. Other agents such as flecainide and propafenone may cause fatigue and dizziness due to bradycardia and ancillary effects. These agents are contraindicated in patient’s structural cardiac abnormalities given concerns for heart failure and risk for ventricular tachycardia.
 
Sotalol, a “potassium” (Ikr) blocker is also a very old drug which needs close monitoring to identify electrocardiographic QT prolongation and the proarrhythmic risk of torsades de pointes, a potentially fatal consequence of inadvertently prolonging ventricular repolarization (more on this below). Dofetilide is another Ikr blocker which functions in similar fashion. The protocol for drug initiation requires mandatory hospitalization for the very same reason I just described.
 
Other agents such as disopyramide and quinidine are rarely used. Dronedarone, a form of “amiodarone light” proved to be largely ineffective and cannot be used in heart failure. Ranolazine, a delayed sodium-blocker is being studied for AF control, but its use outside the treatment for angina is off-label. Unfortunately as a whole, the current available antiarrhythmic arsenal cause electrophysiologic effects on ventricular myocardium. To negate the risks associated with the latter, the ideal AAD would have effects solely on atrial tissue.
 
Catheter ablation for AF has emerged has a viable treatment option for AF. The treatment paradigms generally focus on isolation of the pulmonary veins, and occasionally AF triggers outside these structures. With that being said, AF has proven to be a very formidable problem to treat, and not uncommonly repeat procedures or continued antiarrhythmic therapy is required to achieve a favorable result3. Hence the use of an AAD is done with the purpose of lowering AF burden and frequency.
 
Clinicians who care for AF patients were encouraged when the initial studies of vernakalant were published4. The novel drug prolonged atrial refractoriness by blocking multiple channels, including Ikur. The Ikur channel is found exclusively in the atria which made the availability of such a drug in oral form highly attractive4,5 Finally, an atrial-selective AAD with purportedly a very low risk of torsades de pointes might be available. Unfortunately, during a follow-up trial, ACT V, the trial was stopped due to concerns of drug safety. The FDA required revisions to the study protocol. The sponsor could not agree to those terms, and in March 2012 Merck abandoned development of oral vernakalant. It must be noted that the intravenous form of the drug is available in the European Union6.
 
Vanoxerine, a potent dopamine reuptake inhibitor was being studied in the treatment of cocaine addiction. It also was evaluated for and proved to be unsuccessful in treating Parkinsonism and depression7. However, this agent was observed to prolong ventricular repolarization as evidenced by prolongation of the QT on the surface EKG. This lead to interest as a possible antiarrhythmic. The COR-ART trial published in 2015 suggested a high rate of conversion to sinus rhythm. The medicine was in oral form and generally well tolerated. There were no episodes of torsades de pointes8. However, RESTORE SR, a small randomized trial found the drug to pose a risk for ventricular proarrhythmia in patients with structural heart disease [9]. Out of safety concerns, recruitment was terminated, and the manufacturer, Laguna Pharmaceuticals closed operations10,11.
 
While there continue to be marked improvements in mapping and ablation technologies for AF, clinicians are still left with the same limited medical arsenal. Perhaps greater collaboration and determination among the pharmaceutical industry may lead to finally new medical options for AF.
 
References:

  1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-104
  2. Leong-Sit P, Tang AS. Atrial fibrillation and heart failure: a bad combination. Current Opinion in Cardiology. 2015;30:161–167
  3. Duytschaever M1,2, Demolder A1, Philips T3, Sarkozy A3, El Haddad M1,2, Taghji P1, Knecht S1, Tavernier R1, Vandekerckhove Y1, De Potter T4.PulmOnary vein isolation With vs. without continued antiarrhythmic Drug trEatment in subjects with Recurrent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial. Eur Heart J. 2017 Dec 2. doi: 10.1093/eurheartj/ehx666. [Epub ahead of print]
  4. Torp-Pedersen C, Raev DH, Dickinson G, Butterfield NN, Mangal B, Beatch GN .A randomized, placebo-controlled study of vernakalant (oral) for the prevention of atrial fibrillation recurrence after cardioversion. Circ Arrhythm Electrophysiol. 2011;4:637-43
  5. Camm AJ, Capucci A, Hohnloser SH, Torp-Pedersen C, Van Gelder IC, Mangal B, Beatch GN, AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol. 2011;57:313-21
  6. Camm AJ. The Vernakalant Story: How Did It Come to Approval in Europe and What is the Delay in the U.S.A?Curr Cardiol Rev. 2014; 10:309–314
  7. Preti A. New developments in the pharmacotherapy of cocaine abuse. Addict Biol. 2007;12:133-51
  8. Dittrich HC, Feld GK, Bahnson TD, Camm AJ, Golitsyn S, Katz A, Koontz JI, Kowey PR, Waldo AL, Brown AM. COR-ART: A multicenter, randomized, double-blind, placebo-controlled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm.Heart Rhythm. 2015;12:1105-12
  9. Piccini JP, Pritchett EL, Davison BA, Cotter G, Wiener LE, Koch G, Feld G, Waldo A, van Gelder IC, Camm AJ, Kowey PR, Iwashita J, Dittrich HC. Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR. Heart Rhythm. 2016;13:1777-83
  10. https://www.xconomy.com/san-diego/2015/12/06/heart-drug-safety-concerns-prompt-shutdown-at-laguna-pharmaceuticals/
  11. https://clinicaltrials.gov/ct2/show/NCT02454283

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure.

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Anticoagulation In Dialysis Patients: Clear As Mud

End-stage renal disease (ESRD) is a paradox of both increased ischemic and hemorrhagic stroke risk. Atrial fibrillation is prevalent in up to 27% of the ESRD population and further amplifies the stroke risk. However, while the overall ischemic stroke rate is increased 2.5-fold in ESRD as compared to the general population, the rate of hemorrhagic stroke is increased 5-fold due to a complex milieu that includes uremic platelet dysfunction and exaggerated blood pressure fluctuations on hemodialysis.
 
For over 50 years, warfarin was the only oral anticoagulant available for long-term stroke prevention in atrial fibrillation patients. However, while robust data from randomized controlled trials in the 1980s clearly demonstrated stroke reduction in the general population, we only have observational data in the ESRD population and the evidence here is mixed. Overall, the survival benefit is unclear, and bleeding events are augmented. Warfarin also has the notoriety for increasing the risk of adverse cardiovascular outcomes in the ESRD population. Our group recently published a retrospective analysis of our medical center’s database (spearheaded by medical student extraordinaire Mark Lin) where we noted significantly increased risk of mortality and MI in ESRD patients on warfarin.
 
Over the past decade we’ve seen the emergence of Direct Oral Anticoagulants (DOACs) that include the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors apixaban, rivaroxaban and edoxaban. Apixaban was approved by the FDA in 2014 for use in ESRD patients, a perplexing move that was based on a single phase 1 study that involved eight hemodialysis patients who were given a single dose of the drug.
 
At the #AHA17 scientists and colleagues presented trends from the US Renal Data System database that highlights the remarkable spike in apixaban prescriptions for atrial fibrillation among Medicare beneficiaries on chronic dialysis (Nov 12, 2017 Abstract# 17197). About 26,000 patients were included in the final analysis. Utilization of DOACs rose from 0.16% to 29.16% between 2010-2015 with apixaban accounting for the majority of new DOAC prescriptions (see Figure). 
 
anticoagulant graph Photo credit @JCosinSales
 
Post FDA approval, the observational data has been promising in that apixaban may have lower adverse bleeding rates compared to warfarin. However, a more rigorous pharmacokinetics study published this year in the Journal of the American Society of Nephrology by Mavrakanas et al. raises serious concerns about supratherapeutic blood levels if standard apixaban dosing (5 mg BID) is used in ESRD patients. Until more data is available, the investigators cautioned that apixaban 2.5 mg BID is a more appropriate dosing regimen in dialysis patients.
 
A randomized clinical trial in ESRD patients with atrial fibrillation is currently ongoing that will directly compare apixaban versus warfarin (RENAL-AF). However, given the lack of a placebo control arm, this trial will not address the fundamental unanswered question: Does anticoagulation, period, decrease stroke risk and improve survival in the ESRD population?
 
Nephrologists, who manage heparin anticoagulation during hemodialysis treatments and are most attuned to the bleeding risks in ESRD patients, need to be notified when dialysis patients are initiated on anticoagulation. In this complex and high-risk population, ongoing dialogue between the cardiologist, primary care doc and nephrologist is necessary to weigh the risks/benefits of anticoagulation on a case-by-case basis.

Wei Ling Lau Headshot 

Wei Ling Lau MD is Assistant Professor in Nephrology at the University of California-Irvine, where she studies vascular calcification and brain microbleeds in animal models of chronic kidney disease. She is currently funded by an AHA Innovative Research Grant, and has been a speaker for CardioRenal University and the American Society of Nephrology.