MECHANISMS OF QT INTERVAL PROLONGATION

TOP ABSTRACT THE PATHOGENESIS OF CARDIAC... MECHANISMS OF QT INTERVAL... DENTAL CONSIDERATIONS WHEN... TREATMENT RECOMMENDATIONS CLINICAL SIGNIFICANCE CONCLUSIONS REFERENCES

Seven genes, LQT1 through LQT7, with more than 300 different types of mutation, have been determined to cause congenital LQTS.⁶ Notably, LQT7 gene mutation has been classified as Andersen’s syndrome, in which periodic paralysis, skeletal developmental abnormalities with facial dysmorphia and QT prolongation are seen.⁷

The pathophysiology of LQTS is attributed to dysfunction in cardiac myocellular ion currents. Mutation in the genes responsible for LQT1, 2 and 4 through 7 originates in potassium ion currents within the myocardial potassium channels. Conversely, LQT3 gene mutation causes impairment of sodium ion currents and resultant delays in ventricular repolarization.⁸ Recent studies suggest that the precipitating factors and subsequent choice of treatment modality are based on the respective LQT gene mutation.

Diagnosis and epidemiology. The International Long QT Syndrome Registry, established in 1979, contains more than 1,200 probands (the first person in a family diagnosed with congenital LQTS) and more than 7,000 associated family members. Congenital LQTS is believed to be present in one of every 5,000 to 10,000 people in the general population, with an estimated prevalence of 30,000 to 60,000 cases in the United States. LQTS is primarily diagnosed in the pediatric population; children account for 50 percent of the registered probands and 40 to 50 percent of the affected family members.⁹ LQTS is suspected when

– unexplained syncope occurs;

– syncope occurs during exertion in the pediatric population;

– a family history of unexplained syncope is reported;

– seizures occur;

– congenital deafness is reported;

– there is unexplained sudden death in people younger than 40 years;

– QT interval prolongation (greater than 440 milliseconds in males and 450 ms in females) is seen on an electrocardiogram.¹⁰

In recent years, studies using the registry have determined that particular cardiac triggering events are linked with specific gene mutations. LQT1-mediated events tend to occur with physical exertion, especially swimming, whereas people with LQT2 gene mutations experience TdP in the presence of acute arousal stimuli such as emotion, stress or the unexpected ringing of an alarm clock. Cardiac events in patients with the LQT3 syndrome occur without arousing stimuli and commonly are seen during rest.^11–14 Therefore, early identification of the respective gene mutation involved in the clinical presentation of LQTS commonly is performed so that the patient and his or her family can be educated regarding the avoidance of the precipitating cardiac factors.

The International Long QT Syndrome Registry reports that patients with LQT1 and LQT2 sustain more frequent cardiac events than those with LQT3, but those with LQT3 are more prone to experience lethal events.¹⁵ The risk of cardiac events remains higher in male probands before puberty; the converse is true in females during adolescence and adulthood.^16,17 Zareba and colleagues⁹ determined that patients with LQT1 are at risk of experiencing cardiac events primarily between the ages of 5 and 15 years, whereas people with LQT2 and LQT3 commonly are symptomatic after 10 years of age. Additionally, first-degree female family members in the registry have been shown to be at higher risk of experiencing cardiac events than males.¹⁸ It is believed that the continued use of this registry-based population will provide cardiac researchers and clinicians with a measure of the current therapeutic outcomes and a guide for further prevention of cardiac events.

Cardiac treatment modalities. There are four main interventions used, alone or in combination, in the prevention of cardiac events (syncope, aborted cardiac arrest, sudden cardiac death) for people with congenital LQTS.^19,20

– pharmacological therapy with beta-blockers;

– implantation of cardiac pacemakers;

– use of implantable cardioverter defibrillators (ICDs);

– performance of left cardiac sympathetic denervation (LCSD).

The clinical success of these treatment modalities for management of LQTS also is related, in part, to the underlying genetic mutation.

Pharmacological treatment with ß-blockers has been shown to be the initial means of preventing life-threatening cardiac events in the majority of people with LQTS. Moss and colleagues²¹ reported a statistically significant reduction in the rate of cardiac events when therapy with ß-blockers is initiated. Priori and colleagues²² found that ß-blockers were less effective in patients with LQT2 and LQT3 than in those with LQT1, as evidenced by cardiac events during therapy in 23, 32 and 10 percent of the respective study populations. Thirty percent of patients receiving ß-blocker therapy continue to sustain cardiac events.²¹

People refractory to therapy with ß-blockers and considered to be at high risk of experiencing recurrent LQTS-mediated cardiac events continue to receive ß-blockers and also are treated with surgical implantation of a cardioverter defibrillator or through LCSD.²³ Implanted cardiac pacemakers are used occasionally if there is an associated sinus bradycardia.²⁴

ICDs are used primarily in conjunction with ß-blocker therapy. ICDs do not minimize the occurrence of TdP in patients with LQTS, but the device terminates life-threatening ventricular tachyarrhythmia and ventricular fibrillation when they occur. A retrospective study by Zareba and colleagues²⁵ found that ICDs reduce the mortality rate of patients at high risk of experiencing LQTS from 16 percent to 1.3 percent when compared with high-risk patients with LQTS who are receiving only ß-blockers. ICDs therefore aim to negate the potential for cardiac arrest or death in these high-risk patients.

Patients at high risk of experiencing LQTS who are highly susceptible to recurrent, frequent tachyarrhythmias—despite ß-blocker therapy—can sustain multiple defibrillation shocks through their ICDs. These patients, in addition to those who continue to sustain recurrent syncopal events, can be treated via surgical ablation of the lower half of the left stellate ganglion and the second (T2) through fourth (T4) portions of the thoracic ganglia. LCSD results in diminished cardiac sympathetic stimulation. This procedure reduces the production of norepinephrine, which leads to a diminished probability of cardiac after-depolarizations and re-entrant arrhythmogenic mechanisms. In a 2004 study, Schwartz and colleagues²⁶ reported that LCSD in selected high-risk patients with LQTS reduced the yearly number of cardiac events per patient by 91 percent. Additionally, the patients in whom LCSD was performed to minimize recurrent ICD shocks experienced a 95 percent decrease in the occurrence of defibrillator discharges.²⁶

Although the previously discussed therapeutic modalities are successful in preventing most cardiac events, the reality remains that LQTS is not a curable condition. People with LQTS must diligently avoid known factors that can trigger life-threatening cardiac arrhythmias.

	DENTAL CONSIDERATIONS WHEN TREATING PATIENTS WITH LQTS

TOP ABSTRACT THE PATHOGENESIS OF CARDIAC... MECHANISMS OF QT INTERVAL... DENTAL CONSIDERATIONS WHEN... TREATMENT RECOMMENDATIONS CLINICAL SIGNIFICANCE CONCLUSIONS REFERENCES

 
Dental procedural stressors. Dental intervention using the current surgical management model is commonly reported to evoke emotional, physical and mental stress in the general population. Psychological stress reported by many patients is centered in the fear of potential pain resulting from anticipated procedures. This fear may be founded in a history of oral or odontopathic pain, reaction to physical stressors during previous procedures or fear of the unknown.^27,28 These emotional and mental stressors can result in alterations of cardiac sympathetic stimulation before dental treatment.^29,30 Additionally, the physical stress of receiving local anesthetic injections with incorporated catecholamines, such as epinephrine, and discomfort and pain resulting from pressure stimuli further exacerbate changes in cardiac homeostasis and physiology. These physical stressors increase sympathetic outflow, with resultant increases in blood pressure and heart rate.^31,32

A study by Ackerman and colleagues³³ suggested that intravascular epinephrine even in low doses can induce QT prolongation and an increased risk of experiencing cardiac events in patients with LQT1. Heart rate variability (HRV), defined as the fluctuation in the R-R interval during a prolonged period, appears to be the indicative marker of cardiac modulation between sympathetic and vagal activity in most patients with cardiac arrhythmia, in whom lowered HRV suggests impending cardiac events.³⁴ However, studies by Perkiömäki and colleagues^35,36 suggest that the incidence of cardiac arrhythmias in people with LQTS is related more to QT variability than to HRV. Also, Paavonen and colleagues³⁷ demonstrated in asymptomatic people with LQTS that physical stress, such as that induced by exercise, produced an adjustment in heart rate similar to that in control subjects. The people with LQTS who had LQT1 and LQT2 genotypes were unable to shorten their QT interval with exertion, which was significantly different from the findings for the control group. It is believed that the psychological stressors that frequently accompany dental interventions can augment the potential for life-threatening cardiac arrhythmias in patients with LQTS.

Oral infections. Patients with LQTS have not been shown to be at a greater risk than the general population of developing systemic infection secondary to oral microorganisms. The current guidelines of the American Heart Association do not recommend that people with cardiac pacemakers or ICDs receive prophylactic antibiotics before undergoing invasive dental treatment.³⁸ There is, however, structural cardiovascular damage secondary to placement of these devices in some cases, coexisting congenital heart disease or medical conditions in which immunosuppression is present that would place these patients at risk of developing subacute bacterial endocarditis.

However, acute oral and odontogenic infections still may become difficult to treat in patients with LQTS. Surgical removal of the infectious source in odontogenic infections is curative, but performance of the necessary surgical intervention might precipitate cardiac events. Patients with odontogenic infection commonly seek dental treatment for acute pain, swelling and constitutional symptoms. In the presence of infection, the heart and the peripheral vasculature are under increased physiological stress secondary to neurohumoral activation. The systemic bacterial challenge is associated with augmented sympathetic outflow that can precipitate cardiac events in patients with LQTS.³⁹ As seen in Box 1, certain antibiotics used for treatment of odontogenic infection may be contraindicated by the drug’s potential to prolong the QT interval in patients with LQTS. In addition, Gabel and colleagues⁴⁰ reported ventricular fibrillation requiring resuscitation secondary to QT prolongation associated with the antibiotic clindamycin. When treating a patient with LQTS, the dentist should consult with the patient’s primary care physician, a cardiac specialist, or both before initiating any treatment or palliative care with antibiotic therapy. Prevention of infection should be a priority in the development of a treatment plan for dental intervention in this patient population.

Medical history verification. Dental practitioners will encounter three types of patients in clinical practice:

– asymptomatic patients with no existing diagnosis of LQTS;

– patients with a history of syncope or seizures and/or a family history of LQTS, syncope, seizures or sudden cardiac death;

– patients with an existing diagnosis of LQTS.

Dental professionals should obtain a comprehensive medical history for all patients in their practice to classify them properly. Clinicians should amend their current review of systems to include a personal and family history of syncope, seizure and sudden cardiac death. Syncope is reported to be a common finding in the adolescent population.⁴¹ Although the majority of these events are benign in nature, a cardiologist should evaluate an adolescent patient with syncope for undiagnosed LQTS.⁴¹ On several occasions, people diagnosed with "epileptic seizures" later have been found to have syncope related to LQTS.^42,43 Therefore, dental practitioners should refer all patients with a positive history of syncope or seizure for cardiac evaluation to rule out LQTS before beginning dental care.

Oral and maxillofacial trauma occurs commonly in the pediatric population and occasionally in adults. The majority of these traumatic events occur in conscious patients with a verifiable history. Patients who have sustained orofacial trauma secondary to syncope, seizure or an unexplained accident should be evaluated by a medical professional for possible LQTS. The International Long QT Syndrome Registry lists many people in whom the diagnosis of LQTS was established after a medical workup that followed a syncopal event. Figure 2 outlines a dental management algorithm for patient classification and subsequent dental intervention.

View larger version (61K): [in this window] [in a new window]   Figure 2. Algorithm for medical history assessment and dental treatment plan for healthy patients and those with suspected or diagnosed long QT syndrome (LQTS). All patients should be questioned for a personal or family history of cardiac events before dental intervention. A multidisciplinary approach to treatment, including consultation with a cardiac specialist and treatment in a hospital setting with chairside monitoring by trained medical professionals, is the appropriate course of action for patients with LQTS.

	TREATMENT RECOMMENDATIONS

TOP ABSTRACT THE PATHOGENESIS OF CARDIAC... MECHANISMS OF QT INTERVAL... DENTAL CONSIDERATIONS WHEN... TREATMENT RECOMMENDATIONS CLINICAL SIGNIFICANCE CONCLUSIONS REFERENCES

At present, the prediction of cardiac events and methods to determine the presence of appropriate early warning signs are poorly elucidated. Dental professionals must be cognizant of potential anxiety and cardiogenic stress in patients with LQTS who are entering the dental environment. Known precipitating factors, such as the stress induced by dental treatment, should not be risked in a location in which advanced cardiac life support (ACLS) is not readily available. Studies in the general population have reported that the sound of a dental handpiece induces an increased level of mental stress and anxiety.^27,28 At present, there is no evidence to refute the potential that auditory arousal reactions in conscious patients with LQTS induced by the use of various dental equipment—including handpieces, dental lasers, air abrasion, amalgamators and curing lights—can precipitate cardiac events. A clinical case report by Homme and colleagues⁴⁴ suggested that the algorithms for management of cardiac arrhythmia, TdP and sudden cardiac death in people with LQTS do not follow traditional guidelines. In fact, use of normal ACLS algorithms with drugs such as amiodarone for cessation of cardiac arrhythmias can be paradoxically injurious to those with LQTS. With this in mind, dental practitioners should exercise extreme caution and care when providing dental care to these patients and should obtain training in the use of ACLS for them.

We, therefore, recommend that dental intervention for patients with LQTS should be provided in an outpatient hospital setting in which cardiac events can be managed rapidly. The use of oral premedication with sedative agents is recommended in the traditional treatment of patients with cardiac arrhythmias.⁴⁵ However, the current lack of effective monitoring devices and evidence-based literature to support anxiolysis protocols for the patient with LQTS argues against its use during dental treatment of conscious patients. Conversely, the use of oral pre-medication and patient isolation in quiet surroundings is recommended by anesthesiologists to reduce anxiety and patient stress in the perioperative period before induction of general anesthetic begins.⁴⁶ According to Miller and colleagues, ⁴⁷ dental devices—including electrosurgical equipment, ultrasonic water baths and ultrasonic periodontal scalers—were shown to provide electromagnetic interference with the normal functioning of implanted cardiac pacemakers. The use of the aforementioned dental devices should be avoided in patients with LQTS who have implanted electrical devices.

The algorithm outlined in Figure 2 suggests that dental treatment of conscious patients with LQTS can be undertaken in a hospital clinical setting when the nature of the dental intervention is minimally invasive. At present, there is no evidence-based dental literature reporting the prevalence of cardiac events during dental care of patients with LQTS in an ambulatory setting. However, the influencing factors of inadequate monitoring, restricted drug usage, demonstrated stress and anxiety in response to even benign stimuli, and potential for cardiac events that can become life-threatening if poorly managed support this recommendation: that for patients with LQTS, all dental interventions in which mental or procedural physical stress is expected and would not be appropriately controlled with anxiolytic protocols should be performed in a hospital operating room with a support team of anesthesiologists and cardiologists. When general anesthesia is the appropriate treatment strategy, the dentist should coordinate preventive, diagnostic and restorative dental regimens—including comprehensive oral examinations, intraoral radiographs, dental prophylaxes, tooth restorations and surgical procedures—with other medical services to prevent the need for multiple visits involving general anesthesia and its inherent risks.

The treatment philosophy that should be undertaken by dental practitioners caring for these patients is one of prevention. In the pediatric population, prevention would be demonstrated by the immediate referral of patients with newly diagnosed congenital LQTS to hospital-based pediatric dentists by their primary care physicians or cardiac specialists. Pediatric dentists should focus on the removal of teeth with uncertain prognoses, the aggressive restoration of carious teeth to minimize recurrent decay, the placement of sealants on all posterior teeth to reduce caries risk, and the prevention of dental trauma through the fabrication of mouth guards. Parents of pediatric patients with LQTS should be educated regarding the paramount role of optimal oral hygiene and diets of low cariogenicity for the reduction of dental caries and as a means of preventing unnecessary dental intervention. In the adolescent and adult population, hospital-affiliated general dentists and other dental specialists should use similar preventive strategies, which can be expanded to include education on smoking cessation, coordinated removal of periodontally involved teeth and avoidance of drugs known to prolong the QT interval.

	CLINICAL SIGNIFICANCE

TOP ABSTRACT THE PATHOGENESIS OF CARDIAC... MECHANISMS OF QT INTERVAL... DENTAL CONSIDERATIONS WHEN... TREATMENT RECOMMENDATIONS CLINICAL SIGNIFICANCE CONCLUSIONS REFERENCES

 
The dichotomy between the risk associated with dental treatment of patients with LQTS and the current lack of evidence-based dental literature on the topic suggests several alternatives:

– that dental professionals are unaware of the physiological and management differences between LQTS-induced cardiac events and those founded in other cardiac arrhythmias;

– dental professionals are aware of how to properly treat patients with LQTS but have not transcribed their clinical experiences for the education of other practitioners;

– patients with LQTS are not seeking dental care because of fear and/or avoidance of the psychological and physical stressors associated with dental care.

All three scenarios are worrisome, because either the patient with LQTS will avoid care until emergent treatment is necessary or an unexpected cardiac event will occur in patients treated by untrained or unaware dental professionals. The result could prove damaging and even fatal in either case. Box 2 provides a list of additional resources pertaining to the diagnosis and treatment of congenital LQTS and contact information for the International Long QT Syndrome Registry. Future studies are necessary to elucidate the incidence of cardiac events during dental treatment in the patient with LQTS and the epidemiology of people with congenital LQTS seeking dental care. One of our purposes in writing this article was to catalyze the publication of clinical practice guidelines for treating such patients by dentistry’s various governing bodies.

	CONCLUSIONS

TOP ABSTRACT THE PATHOGENESIS OF CARDIAC... MECHANISMS OF QT INTERVAL... DENTAL CONSIDERATIONS WHEN... TREATMENT RECOMMENDATIONS CLINICAL SIGNIFICANCE CONCLUSIONS REFERENCES