Key Points
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The concept of using cryoenergy to treat medical illness has been present since the dawn of recorded history.
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Specific application of cryoenergy as a therapeutic modality depended on practical application of the Joule-Thomson effect.
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Invasive application of cryotherapy in the heart lagged behind other disciplines because of the relatively recent appreciation of the role of ablating abnormal cardiac substrate to treat arrhythmias.
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The history of cardiac cryotherapy reflects progressively less invasive and more specialized delivery systems.
Robert Slama and colleagues in Paris reported on surgical ablation of the atrioventricular (AV) node in patients with drug-refractory atrial arrhythmias in 1967. Subsequently, Will Sealy at Duke University described successful surgical interruption of a right lateral accessory pathway in a 32-year-old fisherman with Wolff–Parkinson–White syndrome. These publications represent the birth of interventional electrophysiology, providing proof of concept that arrhythmias could be cured or alleviated by destroying cardiac tissue requisite for their clinical manifestation. Soon surgeons, in collaboration with their electrophysiologist colleagues, extended these findings to the management of supraventricular arrhythmias and ventricular tachyarrhythmias. However, incisional approaches to treating arrhythmias required open-heart surgery, typically requiring cardiopulmonary bypass, associated with significant morbidity and mortality. The use of surgical electrocautery, formalin injection, and tissue ligation were all associated with disruption of the normal tricuspid valvular apparatus, ventriculoseptal defects, and injury to the aortic sinuses. Therefore, from the inception of arrhythmia surgery, the search for less invasive approaches and ablative modalities was ongoing.
Although cryoablative approaches were studied during these early years of interventional electrophysiology, radiofrequency became the dominant ablative energy source because of the relative simplicity of radiofrequency-based catheter systems and the discrete targets of arrhythmias being treated. However, the extensive lesion sets associated with atrial fibrillation ablation and substrate-based ablation for scar-mediated ventricular tachycardia (VT) make cryoablation an attractive alternative to heat-based modalities, in that cryoablation may be less likely to cause collateral damage. The feasibility of using cryoablation for this purpose entered the practical realm with the realization that the Joule–Thompson effect could be applied to intravascular catheters to deliver ablative levels of cold energy. This chapter reviews the history of this technologic leap with a view toward providing perspective on the present and future roles of cryoablation in arrhythmia management, which is the topic of the ensuing chapters.
Joule–Thomson Effect
Intravenous catheter-delivered cryoenergy—that is, cold enough to destroy cardiac tissue—was made possible by the practical application of the Joule–Thomson effect, and it represents a fascinating chapter in the history of medicine. The alleviating effects of cryotherapy were appreciated at the dawn of medical history, with reference to the use of cold to treat battlefield injuries present in the oldest known medical document, the Edwin Smith papyrus ( Figure 1–1 ). Writings attributed to Imhotep and his pupils (2600 BC) were discovered on papyrus that was purchased in Luxor in 1862 by Egyptologist Edwin Smith. These writings specify the ingredients of cold compresses (figs, honey, and grease) to be applied to battle injuries. However, the notion that cold energy could be used to destroy diseased tissue required the ability to harness and deliver cryoenergy at extremes of cold far exceeding those of compresses, a notion that would take nearly four millennia to manifest.
During the Industrial Revolution, two major innovations occurred that ultimately set the stage for the modern conception of cryotherapy and ultimately cryocatheter-mediated mapping and ablation. One was the discovery and production of powerful refrigerants. In 1853, James Prescott Joule and Henry Thomson reported that the temperature of a real gas would vary depending on the initial temperature and pressure with expansion at constant enthalpy. Allowing compressed gas to rapidly expand below the gas’s inversion temperature resulted in dramatic cooling caused by loss of kinetic energy. Carl Paul Gottfried von Linde (1842–1934) capitalized on the Joule–Thomson effect to make the first commercially viable refrigerant. Von Linde developed vapor-compression refrigeration machines, the first iteration of which used dimethyl ether as the refrigerant. His apparatus for the liquefaction of air combined the cooling effect achieved by allowing a compressed gas to expand with a countercurrent heat exchange technique that used the cold air produced by expansion to chill ambient air entering the apparatus ( Figure 1–2 ). This gradually cooled the apparatus and air within it to the point of liquefaction.
A system was needed that would allow the storage and transfer of frozen liquefied gases, for refrigerants to be applied medically. This second major innovation came in the form of the vacuum flask invented in 1892 by the Scottish physicist and chemist James Dewar (1842–1923). The thermos consists of a vessel within a vessel separated by a vacuum, the latter preventing heat transfer by conduction or convection, with radiant heat loss being minimized with the use of silver-lined glass. The Dewar flask enabled storage, transfer, and ready access to fluids at temperatures less than −180°C, setting the stage for the medical application of cryogens. An example of an early patented version of a Dewar flask submitted by Reinhold Burger to the U.S. Patent Office in 1907 is shown in Figure 1–3 . With these innovations in place, it was now possible for medical scientists to test the effects of extreme cold on biological tissues.
In the first half of the 20th century, liquid refrigerants were used to destroy tumors and skin lesions by surface application. Refrigerants were applied at temperatures less than −70°C to achieve cell death. In 1961, a handheld cryoprobe that would permit surgical application of cryoenergy was invented through collaboration between the renowned New York City neurosurgeon Irving Cooper, and Arnold Lee, an engineer from the Linde division of Union Carbide Corporation. The handheld cryoprobe design is, in essence, a marriage between the concept of vacuum insulation and the Joule–Thomson effect. The probe consists of a vacuum-insulated cannula that delivers liquid nitrogen to its tip, where it vaporizes, resulting in heat transfer from adjacent tissue. The resultant nitrogen gas is then exhausted from a probe outlet. A thermocouple added to the tip of the cannula generates tip temperatures that can be modulated to reach temperature targets ( Figure 1–4 ). Cooper used this instrument to treat a variety of neurologic diseases including Parkinson’s disease and brain tumors, and ultimately promoted its use in other surgical areas.
The proof of concept for arrhythmia management through surgical incision established by Slama and Sealy soon led to the search for less morbid approaches than open-heart surgery and myocardial incision. The cryoprobe lent itself readily to this search. In 1977, John Gallagher and colleagues at Duke University used a modified version of Cooper’s handheld cryoprobe in the successful ablation of the AV node and left posterior and septal accessory pathways. These reports were also the first to describe cryomapping for the selection of appropriate ablation targets. The effects of myocardial cooling had previously been shown to prolong effective refractoriness leading to reversible block at temperatures around 0°C. The Duke group used this phenomenon intraoperatively to safely map and subsequently ablate a septal pathway. Cooling the probe to 0°C resulted in reversible accessory pathway block while maintaining AV nodal conduction. Subsequent application of cryothermy at −60°C eliminated accessory pathway conduction irreversibly while preserving AV nodal conduction.
These authors also described cryoablation of the AV nodal to achieve definitive rate control in patients with drug-refractory atrial fibrillation. Cryomapping at 0°C in the apex of the triangle of Koch resulted in reversible heart block with a junctional escape rhythm; cryoablation was then effected at −60°C, resulting in irreversible AV nodal block with preservation of a junctional escape. Subsequently, the group at Duke reported the results of AV nodal cryothermal ablation in 22 patients and concluded that the handheld cryoprobe offered a safe, effective alternative to mechanical disruption.
Curing Atrioventricular Node Reentry Tachycardia with Preserved Atrioventricular Nodal Conduction using the Cryoprobe as a “Reversible Knife”
The cryoprobe played a central role in the history leading to selective ablation of AV nodal inputs with preservation of AV nodal conduction in patients with atrioventricular node reentry tachycardia (AVNRT). Before the understanding that dual AV nodal inputs could be selectively targeted for ablation, AVNRT was treated with dissection of the His bundle and/or direct current fulguration of the AV node, committing typically young patients to a lifetime of pacing. In 1979, during routine dissection in the triangle of Koch in a patient with incessant AVNRT, Pritchett and colleagues noted abrupt cessation and subsequent noninducibility of AVNRT with continued AV nodal conduction. This led James L. Cox to a remarkable insight, central to which was the notion of the cryoprobe as a “reversible knife.” Cox construed that somehow during their procedure the operators had inadvertently selectively destroyed an AV nodal input required to sustain reentry. He reasoned that cryoablation could be applied around the body of the AV node such that whenever a given lesion led to heart block, the probe would be irrigated with warm saline to prevent tissue destruction ( Figure 1–5 A ). Lesions not causing heart block would be continued for a minimum of 2 minutes to cause irreversible tissue destruction. Cox used this approach successfully in eight consecutive patients and demonstrated the elimination of dual nodal physiology in each case (see Figure 1–5 B ).
