Cellular Mechanism and Pathophysiology of ARVC

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)

ARVD/C refers to a genetically heterogeneous group of cardiomyopathies characterized by progressive degeneration and fibrofatty infiltration of the right ventricular myocardium . Patients are prone to ventricular tachycardia, right heart failure, and sudden death . Mutations in genes encoding for the desmosomal proteins plakoglobin , desmoplakin , and plakophilin-2  have been shown to cause ARVD/C. The molecular mechanisms of arrhythmias in ARVD/C are poorly understood. ARVD2, caused by mutations in the ryanodine receptor (RyR2), is clinically different from other forms of ARVD/C in that ventricular arrhythmias are stereotypically effort-induced .In ARVD2 the leaky ryanodine receptor results in cytosolic Ca²⁺ overload and, consequently, in delayed afterdepolarizations triggering arrhythmias, and may overlap with CPVT.

ARVC occurs in ∼1 in 5,000 individuals and primarily affects adults (Basso et al., 2009). However, ARVC is also an important cause of death among young people, accounting for ∼20% of deaths occurring in individuals under 30 years old (Shen et al., 1995). ARVC is inherited in an autosomal-dominant or recessive pattern in 50% of cases often with incomplete penetrance, so unknown genetic or environmental modifiers are predicted (Basso et al., 2009).

Mutations in proteins that comprise the cardiac desmosome, a junctional complex that mechanically couples neighboring cardiomyocytes to coordinate contractile activity, account for most inherited cases of ARVC (Yang et al., 2006). Disruptions in desmosome stability cause structural and functional alterations and are associated with cardiomyocyte apoptosis (Yamaji et al., 2005). Adipose and fibrotic tissue that replace cardiomyocytes are a hallmark of ARVC, primarily in the right ventricle; however, left ventricular involvement is common in later stages of the disease (Corrado et al., 1997). The right ventricle enlarges as myocyte loss progresses, causing a reduction in blood volume pumped from the heart and arrhythmias.

 A). The action potential of atrial and ventricular myocytes consists of 4 phases (upper part), to which specific ion flows contribute (middle). The long plateau phase (3) and a stable resting phase (4) are characteristic for myocyte action potential. The corresponding electrocardiographic ventricular activity is shown below. Early afterdepolarizations occur during phase 2 / 3 of the action potential, before the ongoing action potential has reached phase 0 (B). Delayed afterdepolarizations occur during phase 4 of the action potential, before the action potential has reached phase 0 (C).

 On the cellular level, three distinct entities causing tachyarrhythmias can be distinguished: automaticity, triggered activity and reentry. One or a combination of these mechanisms occurs in inherited arrhythmias. AP action potential, HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, ARVD/C arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Displayed are transverse tubules of two neighboring cardiomyocytes with the ion channels localized on the sarcolemma of cell 1 and the connecting gap junction connexins to the sarcolemma of cell 2. Shown are the pore regions of the ion channels (α-subunits) through which ions flow across the plasma membrane, and the cytoplasmic β-subunits. Within each subunit, the encoding gene is displayed in italics, the protein in normal font. Differences in disease status are indicated in a box next to the currents. Intranuclear proteins and genes might also interact with ion channels and/or gap junction proteins. Disturbed calcium handling within the sarcomere or sarcoplasmic reticulum underlies distinct arrhythmia causing diseases.

The figure illustrates the location of several intercalated disc proteins associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Each grey line is a cell membrane, and the area in-between is the cell-to-cell contact area. APC = adenomatous polyposis coli (a tumor suppressor gene that provides a platform for the beta-catenin destruction complex [BDC]); Axin = also part of the BDC that regulates stability of the β-cat in Wnt-signaling pathway; β-cat = beta-catenin; CDH = cadherin; CK1 = casein kinase 1 that targets β-cat for phosphorylation; DSC = desmocollin; DSG = desmoglein; DSP = desmoplakin; Dvl = disheveled [a cytoplasmic protein involved in canonical and noncanonical Wnt-signaling pathways]; GSK3β = glycogen synthase kinase 3 beta and known to phosphorylate β-cat; JUP = junction plakoglobin; LRP5/6 = low-density lipoprotein receptor–related proteins 5 and 6 (transmembrane receptors involved with receptor-mediated endocytosis and transduction of canonical Wnt signals); NF2 = neurofibromin 2 (an upstream molecule of Hippo signaling pathway also known as Merlin [acronym for Moesin-Ezrin-Radixin-like protein], which is a tumor suppressor); PKP-2 = plakophilin-2; PKCα = protein kinase C alpha; Wnt = after Drosophila melanogaster wingless gene.

Arrhythmogenic right ventricular cardiomyopathy (ARVC)

An introduction to ARVC or arrhythmic cardiomyopathy

• A problem with the proteins that hold heart muscle cells together causes these cells to be lost and replaced by fibrous scar tissue and fatty cells, causing the ventricle walls to become thin.
• ARVC can affect the electrical activity of the heart and causes arrhythmias.
• As ARVC affects both the right and left ventricle it is also known as arrhythmic cardiomyopathy.

What is ARVC?

Arrhythmogenic right ventricular cardiomyopathy, or ARVC, is a type of cardiomyopathy that affects
the ventricles (lower pumping chambers) of the heart and causes arrhythmias (abnormal heart rhythms). It affects the right ventricle, and often also affects the left ventricle. For this reason it is sometimes called arrhythmic cardiomyopathy (as the main symptoms are arrhythmias). It doesn’t affect the atria (upper chambers) of the heart.

The structure of the heart, showing the atria and ventricles

In ARVC there is a defect in the proteins that join the cells of the heart muscle (myocytes) together. This means that the proteins do not develop properly and cannot keep the muscle cells together. When this happens the muscle cells detach and die, the area of the heart becomes inflamed, and the lost cells are replaced with fibrous scar tissue and fat deposits. This affects the structure of the heart muscle, and it becomes thin and stretched. This causes two main problems:

• the electrical pathways through the heart that coordinate the heart beat may be affected, causing arrhythmias; and
• the thin walls of the ventricles of the heart are unable to pump blood as effectively as normal.

What causes ARVC?

ARVC is often a genetic condition (caused by an altered or ‘mutated’ gene) and can be inherited (passed from parent to child). However, the genetics of ARVC are complicated.

ARVC is often ‘autosomal dominant’. This means that the mutated gene is found on one of the non-sex
chromosomes (called the autosomes). A child of an affected parent will have a 50% chance of inheriting the gene mutation. In some cases it is ‘recessive’ (and it therefore only develops into the
condition if both parents pass on the gene). 

Who gets ARVC?

ARVC is rare compared to some other types of cardiomyopathy (such as dilated and hypertrophic
cardiomyopathy). Around 1 in 10,000 people are thought to have ARVC, although it is likely that there
are more people living with the condition than this figure suggests.

What are the symptoms of ARVC?

ARVC can be a progressive condition, and symptoms may become worse over time. The symptoms are
related to the electrical activity of the heart as well as the structure of the heart and how well it pumps.
Symptoms can include the following.

• Palpitations (feeling your heart beating too fast, too hard or like it is ‘fluttering’) – this is caused by
  arrhythmias (when the electrical messages which control the heart’s rhythm are disrupted).
• Light-headedness and fainting (loss of consciousness) – reduced oxygen levels or blood flow to the brain, due to arrhythmias, can cause light-headedness or dizziness and, in some cases, loss of consciousness.
• Swollen legs, ankles and tummy – build-up of fluid in the tissues, because the heart isn’t pumping
  effectively, can cause swelling (called ‘oedema’).
• Breathlessness (or dyspnoea) – fluid builds-up around the lungs, making it harder to breathe. Due to the effect of ARVC on the electrical signalling the in the heart, it often causes arrhythmias.

As ARVC affects the electrical signalling the in the heart, it often causes arrhythmias.

Arrhythmias

Arrhythmias are caused by the disruption of the normal electrical signalling in the heart that controls the heart beat. This disruption causes a change in the heart’s rhythm, which means it beats too fast, too slow or erratically. Types of arrhythmias that can happen in ARVC include the following.

• Atrial fibrillation (AF) – caused by disruption of the electrical messages that normally cause the heart muscle to contract. In AF the atria beat very quickly and are uncoordinated. This can make the flow of blood around the atrium ‘turbulent’, and the heart less efficient at pumping out blood. AF can cause palpitations and increase the risk of blood clots forming, which can increase the risk of a stroke. 
• Ventricular premature beats (VPB) – this is an extra heart beat that happens when electrical impulses start in one of the ventricles, and it contracts before it receives the normal signal via the atria. ARVC can sometimes cause an increase in the number and frequency of these extra beats.
• Ventricular tachycardia (VT) – VT starts due to abnormal electrical activity in the ventricles, where
  the heart contracts abnormally quickly (over 100 beats per minute). It can lead to loss of consciousness.
• Ventricular fibrillation (VF) – the contraction of the ventricles is uncoordinated, and they ‘quiver’ rather than contract normally, so blood is not pumped out of the heart effectively. This condition is
  life-threatening and requires urgent treatment with a defibrillator (see treatment below).

What are the complications of ARVC?

ARVC can be very serious as it can cause complications.

• Heart block – where the normal electrical activity that controls the heart beat is slowed or stopped, and stops the heart contacting normally. Heart block might require a pacemaker if the heart is unable to keep a normal rhythm.
• Heart failure – when the heart is not working effectively and it ‘fails’ to pump enough blood, at
  the right pressure, to meet the body’s needs. It describes a collection of symptoms caused by a
  heart that is struggling to work effectively, such as weight gain (due to fluid retention), shortness of
  breath, a cough, oedema, palpitations, dizziness and tiredness.
• Sudden cardiac death (SCD) – this can happen due to dangerous arrhythmias, such as ventricular
  fibrillation (VF), where the contraction of the ventricles is uncoordinated, and they ‘quiver’ rather
  than contracting normally, so blood is not pumped out of the heart effectively. Although it is relatively
  rare, if VF is not controlled (using a defibrillator to shock the heart back into normal rhythm), it can
  cause the heart to stop beating (a cardiac arrest).

How is ARVC diagnosed?

ARVC can be difficult to diagnose as the changes in the heart can be subtle and the fat deposits can
be hard to see. Because the heart chambers can become enlarged, it is sometimes misdiagnosed as
dilated cardiomyopathy.

• Medical history – to look at symptoms and whether other family members have this condition (as it can be genetic).
• Physical exam – to see what physical symptoms, if any, are happening.
• ECG (electrocardiogram) – this looks at the electrical activity of the heart and whether arrhythmias
  (abnormal heart rhythms) are happening. A ‘signal -averaged ECG’ might be used to look for particular electrical signals that are common to ARVC. An ECG might also be done during exercise.
• Echo (echocardiogram) – this is a type of ultrasound scan, which uses sound waves to create echoes when they hit different parts of the body. This looks at the structure of the heart and how it is working. 
• Exercise tests – these are tests done during exercise, such as on an exercise bike or a treadmill, to look at how the heart works during exertion (where it is under increased pressure to work) and measure oxygen consumption during exercise.
• Holter monitoring – this is when an ECG is recorded over a period of time (such as a few days), while carrying on with normal activities. The ‘holter’ is a ECG device which is worn on the waist or in a pocket which makes it possible to move and walk around.
• Electrophysiology study (EPS) – this test involves having a long tube called a catheter inserted into
  a blood vessel and fed up to the heart. Electrical signals are sent through the catheter to the heart
  which makes it beat at different rates, which is recorded. This can be used to find where in the
  heart arrhythmias are starting (and can be used to identify treatment options).
• Implantable loop recorder – this is a small device, implanted under the skin, that records the electrical activity of the heart to identify any arrhythmias. Implantable loop recorders can be in place for up to a couple of years, if this is helpful.
• MRI (magnetic resonance imaging) scan – this scan produces high quality images and is used to look at the structure of the heart and blood flows through it.
• Radionuclide test and CT test – this involves having a radioactive dye (called a contrast dye) injected into a blood vessel. A CT scan, which uses x-rays, is done to produce images of the heart. The dye helps to see the structure of the heart and how blood flows around it.

How is ARVC treated and managed?

Although there is no cure for ARVC, treatments are used to reduce and control symptoms, and reduce the risk of complications. Treatment focuses on improving the pumping of the heart, controlling arrhythmias and reducing the risk of cardiac arrest.

Medication and devices

• ACE inhibitors (angiotensin-converting enzyme inhibitors) – relax the smooth muscle around the
  blood vessels to reduce the workload on the heart, and reduce the volume of the blood, making it
  easier for the heart to work. 
• Anti-arrhythmic medication – reduces abnormal heart rhythms and helps to control the normal
  rhythm.
• Anticoagulants (blood thinners) – may be used in people with arrhythmias to reduce the risk of blood clots forming, which could lead to a stroke.
• Angiotensin II Receptor Blockers (ARBs) – dilate (enlarge) the blood vessels which helps to reduce
  blood pressure and may be used if the person is not able to tolerate ACE inhibitors. 
• Beta-blockers – reduce the rate and force of the heart’s contraction, by reducing stimulation of
  adrenalin (which would normally make the heart beat faster).
• Diuretics (water tablets) – reduce the build-up of fluid on the lungs or the ankles by encouraging the kidneys to get rid of water as urine. 
• Pacemaker – may be recommended for people who have heart block (which makes the heart
  rate slow down). Pacemakers control the electrical signalling of the heart to keep a normal heart rhythm.
• Cardioversion – this is a when an electric shock is given to the heart to try and control arrhythmias,
  most commonly atrial fibrillation, and put the heart back into a normal rhythm. This is similar to what an ICD does (see below) but is a procedure done in hospital.
• Catheter ablation – this uses radio waves to treat areas of the heart where the electrical pathways
  cause arrhythmias. It stops the transmission of electrical signals that affect the normal heart rhythm.
• ICDs (implantable cardioverter defibrillator) – this may be recommended due to the risk of life-threatening arrhythmias. ICDs detect and correct any dangerous arrhythmias which could otherwise lead to a cardiac arrest.

Lifestyle management

In addition to medication and devices, there may be ways to reduce the effect of ARVC through lifestyle. The following are examples of what might help.

• Healthy eating – a balanced diet can help to keep a healthy weight, which will reduce the impact on the heart as well as helping with general health.
• Keeping a healthy weight – as this can help to reduce any extra pressure on the heart and lungs.
• Minimise alcohol – alcohol can raise your heart rate and increase blood pressure. You may not need to completely avoid it, but keeping within recommended guidelines can reduce any potential affects.
  The Chief Medical Officer reviewed these guidelines in 2016.
• Minimise caffeine – caffeine can raise your heart rate and increase blood pressure. As everyone is
  different in how they react to it, you might like to talk to your specialists about how to manage your caffeine intake.
• If you smoke – stopping smoking is important to help your overall health as well as your heart and
  lung function (as it can reduce oxygen levels in the blood as well as narrowing blood vessels). Your GP or an NHS stop smoking service may be able to help.

A note on exercise

Although exercise is often recommended for people with a heart condition, it can trigger arrhythmias and heart failure symptoms, and can be dangerous if the condition is unstable. Exercise for people with ARVC needs to be considered carefully, and be part of a discussion between the individual and their cardiologist or specialist nurse.

Cardiac Devices and Infection

Current practice guidelines

Cardiovascular device therapy has become increasingly commonplace and is now applied not only to patients with manifest rhythm disturbances but also in anticipation of events such as implantable cardioverter-defibrillators (ICDs) for primary prevention, and for improvement in cardiac function in the absence of cardiac arrhythmia (cardiac resynchronization therapy, or CRT.) Approximately 400,000 cardiac devices are implanted yearly in the U.S., and it is estimated that more than 3 million patients have implanted devices.

Presently, one of the most vexing and morbid complications of device therapy is the development of infection. The incidence of device infection is low but has increased.

"Until 2004, the rate of infection was constant at approximately 1.5 percent per year, but then it steadily increased to a rate of 2.5 percent per year as reported in 2008," according to Larry M. Baddour, M.D., chair of the Division of Infectious Diseases at Mayo Clinic in Rochester, Minn. This increase coincides with the expanded use of ICDs and CRT and is likely related to longer procedure times, the increased bulk of larger generators and multiple leads, all undermining wound and skin integrity.

Other factors known to be associated with the risk of device infection include:

• Chronic renal insufficiency
• The presence of chronic intravenous lines (including dialysis catheters)
• Chronic anticoagulation
• Multiple device leads (≥ 3)
• Number of device-related procedures (≥ 3)
• Immunosuppression, either related to an underlying disease process or therapy with corticosteroids

Early device reoperation (especially within days) is associated with the greatest risk of infection, increasing it by fifteenfold. Also contributing are the increasing longevity of patients with devices and the subsequent need for generator replacement and lead revision.

Appropriate antibiotic prophylaxis at the time of device procedure is a crucial step in device infection prevention. In most centers, cefazolin is administered one hour prior to device placement and is continued for less than 24 hours. In contrast, there are no data to support secondary prophylaxis for patients with devices who undergo dental and other invasive procedures and, therefore, it is not recommended.

Pocket infection

In the majority of patients (60 percent), a device infection will involve the device pocket. "The most obvious sign is a pocket abscess, but the presenting symptoms may be subtle, such as pocket erythema, induration or pain," says Michael J. Osborn, M.D., electrophysiologist at Mayo Clinic in Rochester. "The latter symptom should not be overlooked, as pocket pain persisting for more than a few days postprocedure or developing after a symptom-free period is extremely unusual and should be vigorously evaluated."

A draining sinus is a very common manifestation of pocket infection. Those that develop shortly after a device procedure may represent stitch abscesses, which may respond to antibiotics and careful removal of protruding suture material. Any more aggressive therapy should be avoided.

A chronic draining sinus, especially one that develops late after a procedure, is worrisome. If the sinus has clear communication with the pocket or if more pronounced pocket erosion occurs, the entire pocket should be considered contaminated, and the device and leads should be removed. If there is no clear communication with the pocket, a trial of appropriate antibiotic therapy is reasonable as long as there are no signs of systemic infection, such as:

• Chills
• Fever
• Valve or lead endocarditis seen on an echocardiogram

If the sinus does not heal or recurs after therapy, the device should be managed as an infection.

In about 40 percent of patients, bloodstream infection occurs as the only sign of device infection. Bloodstream infection due to staphylococci or relapsing bloodstream infection should prompt concern for device infection, even when the pocket site appears normal.

"Echocardiography should be done to determine if there is evidence for complicating valve infection. The finding of a mobile mass on an intracardiac lead is much less reliable as a sign of lead infection, as many leads develop an irregular fibrinous coating over time in noninfected patients," says Dr. Osborn. Device infection requires complete system removal for attempted cure. Antibiotic therapy without complete device and lead removal is associated with an increase in 30-day mortality.

Mortality risk

Despite proper therapy, there is still a significant mortality risk with infection, especially when associated with staphylococcal bacteremia. The in-hospital mortality rate following successful extraction of an infected system ranges from 3 to 11 percent with a posthospital (up to two-year) mortality rate of 10 to 20 percent. The risk of death is two to three times higher in patients with staphylococcal bacteremia compared with infection limited to the pocket. This significant mortality risk is related to the virulence of the organism and also frequently to delays in delivery of appropriate therapy because of slow recognition of the infection, delays in device removal and attempts at more conservative therapy.

"Patients with devices who present with staphylococcal bacteremia have a high incidence of associated device infection and should be evaluated promptly by physicians with expertise in infected device removal," says Dr. Baddour. In contrast, patients with gram-negative bacteremia have associated device infection much less frequently and, as a result, device removal can be delayed to allow assessment of appropriate antibiotic therapy if there is no other evidence of device infection. Obvious signs of pocket site infection, lead endocarditis, valve endocarditis, or relapsing or sustained bloodstream infection despite antibiotic therapy should be managed aggressively with complete device removal.

Stepwise approach to management of suspected cardiovascular implantable electronic device infection.

The Heart Rhythm Society and American College of Cardiology have established appropriateness criteria for lead extraction in patients with infections based on prior experience managing patients in a more conservative fashion. Complete extraction is recommended in any definite device infection:

• Valve or lead endocarditis
• Bloodstream infection and associated pocket infection (abscess erosion or chronic draining sinus)
• An occult gram-positive bacteremia

Extraction is reasonable in patients with persistent gram-negative bacteremia. Extraction is not recommended when there is no clear evidence of pocket infection or in the rare patients who have a significant underlying morbidity that would preclude aggressive therapy.

Management can be complicated and outside the scope of this review, but a few general principles to remember:

• Treatment involves both antibiotics (empiric choice is generally Vancomycin for coag negative staph and MRSA coverage) and consideration of device explantation, including the leads.
• Removing the device (i.e. pacemaker/ICD without the leads) is generally fairly safe and straightforward.  On the other hand, removing the transvenous leads is technically more challenging, and carries the risk of vascular and cardiac injury. This is because over time, the leads get partially endothelialized and incorporated into the wall of the heart by connective tissue.  This is good for protecting against infection but makes it tricky to remove.  There is more of a risk of damage with ICD leads vs pacemaker leads since ICD leads are larger and have more components, like coils.
• Generally, whenever there is evidence that the device pocket or leads are infected, the entire device including the leads should be explanted.  For staph aureus bacteremia without an alternative source, the entire device should be explanted.  For other bacteremias without an alternate source and that persists/recurs despite abxs, the entire device should be explanted. 
• Of course, you must take into account the patient’s comorbidities, the indication for the pacemaker/ICD, and overall goals of care, especially in a patient such as in our case.

Lead extraction

There is a standard approach to lead extraction in patients with infection. Blood cultures are obtained when a diagnosis of device infection is suspected. The pocket is opened and inspected. If there is obvious infection, the pocket is extensively debrided, and tissue is sent for microbiologic studies. The leads are dissected free of all fibrous material within the pocket and from the sleeves that anchor them to the pectoralis muscle. Stylets are inserted, and extraction by traction is attempted.

If this approach is not entirely successful, the proximal portions of the leads are amputated, and a locking stylet is inserted into the lead and advanced under fluoroscopic control to the distal tip of the lead and locked in place. Traction is attempted again, and if not successful, a powered sheath (typically a laser sheath) is advanced over the lead to the first area of resistance or binding scar. The laser is activated until the fibrous tissue is ablated, and the sheath is then advanced to the next area of binding scar, with the process repeated until the lead is freed and removed from the heart. The extracted device and leads are sent for microbiologic studies.

Power extraction tools have improved the rate of successful lead removal. In the past 20 years at Mayo Clinic in Rochester, 97.3 percent of all leads have been completely removed. Approximately 1 percent of leads have been incompletely removed, leaving a very small segment firmly attached to the endocardium. In 1.5 percent of patients, leads could not be removed transvenously and required surgical intervention.

"Virtually all leads that have been in place for less than five years have been completely removed successfully," says Dr. Osborn. "For leads that have been in place for more than five years, the success rate for complete lead removal is approximately 92 percent."

The rate of potentially life-threatening complications, however, remains between 2 and 3 percent. These complications include:

• Innominate vein or superior vena cava laceration
• Cardiac perforation
• Requirement for emergent (rescue) surgery
• Pericardial effusion requiring intervention
• Blood loss requiring transfusion
• Deep venous thrombosis
• Tricuspid valve damage resulting in significant regurgitation
• Ventricular arrhythmias requiring intervention
• Pulmonary embolism
• Cerebrovascular accident
• Transient respiratory failure
• Transient renal failure
• Axillary or subclavian venous bleeding requiring surgical intervention

Laceration of the superior vena cava accounts for more than 60 percent of procedural mortality. Cardiac perforation and consequent emergent surgery accounts for the majority of the other deaths.

http://circ.ahajournals.org/content/121/3/458.full