cardiac contractility modulation
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Cardiac contractility modulation is a
therapy A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...
which is intended for the treatment of patients with moderate to severe heart failure ( NYHA class II–IV) with symptoms despite optimal medical therapy who can benefit from an improvement in cardiac output. The short- and long-term use of this therapy enhances the strength of ventricular contraction and therefore the heart's pumping capacity by modulating (adjusting) the
myocardial contractility Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of t ...
. This is provided by a pacemaker-like device that applies non-excitatory electrical signals adjusted to and synchronized with the electrical action in the
cardiac cycle The cardiac cycle is the performance of the human heart from the beginning of one heartbeat to the beginning of the next. It consists of two periods: one during which the heart muscle relaxes and refills with blood, called diastole, following ...
. In cardiac contractility modulation therapy, electrical stimulation is applied to the cardiac muscle during the absolute refractory period. In this phase of the cardiac cycle, electrical signals cannot trigger new
cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
contractions, hence this type of stimulation is known as a non-excitatory stimulation. However, the electrical signals increase the influx of
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s into the cardiac muscle cells (
cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...
). In contrast to other electrical stimulation treatments for heart failure, such as pacemaker therapy or
implantable cardioverter defibrillator An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion and pacing of the h ...
s (ICD), cardiac contractility modulation does not directly affect cardiac rhythm. Rather, the aim is to enhance the heart's natural contraction (the native cardiac contractility) sustainably over long periods of time. Furthermore, unlike most interventions that increase cardiac contractility, cardiac contractility modulation is not associated with an unfavorable increase in oxygen demand by the heart (measured in terms of Myocardial Oxygen Consumption or MVO2). This may be explained by the beneficial effect the therapy has in improving cardiac efficiency. A meta-analysis in 2014 and an overview of device-based treatment options in heart failure in 2013 concluded that cardiac contractility modulation treatment is safe, that it is generally beneficial to patients and that the treatment increases the exercise tolerance (ET) and
quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
(QoL) of patients. Furthermore, preliminary long-term survival data shows that cardiac contractility modulation is associated with lower long-term mortality in heart failure patients when compared with expected rates among similar patients not treated with cardiac contractility modulation.


Medical uses


FDA approval

Based on the results of the pivotal FIX-HF-5C trial, the FDA approved cardiac contractility modulation therapy for use in the United States on March 21, 2019.


FDA indication

The FDA approved the OPTIMIZER Smart System, which delivers cardiac contractility modulation therapy, as indicated to improve 6-minute hall walk distance, quality of life, and functional status of NYHA Class III heart failure patients who remain symptomatic despite guideline directed medical therapy, who are in normal sinus rhythm, are not indicated for cardiac resynchronization therapy, and have a left ventricular ejection fraction ranging from 25% to 45%.


CE mark

Based on the results of clinical trials, cardiac contractility modulation devices are approved and available for clinical use in all
European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been de ...
countries and in Australia,
Turkey Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula in ...
,
India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
and
Hong Kong Hong Kong ( (US) or (UK); , ), officially the Hong Kong Special Administrative Region of the People's Republic of China (abbr. Hong Kong SAR or HKSAR), is a city and special administrative region of China on the eastern Pearl River Delta i ...
, as well as in other countries that recognize
CE marking On commercial products, the letters CE (as the logo ) mean that the manufacturer or importer affirms the good's conformity with European health, safety, and environmental protection standards. It is not a quality indicator or a certificatio ...
for
medical device A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assura ...
s.


CE indication

Based on the approval of cardiac contractility modulation devices, the therapy is a treatment option for patients that are at least 18 years old who suffer from heart failure symptoms due to left ventricular systolic dysfunction (LVSD) despite adequate medical treatment. Further clinical research are under way to identify which patient group within the scope of the device approval benefits most from cardiac contractility modulation treatment.clinicaltrials.gov Announcement of a study that will further investigate safety and efficacy of CCM devices
/ref> Criteria for the classification of patients with left ventricular systolic heart failure include the severity of the disease based on functional parameters (NYHA classification), the average percentage of blood volume ejected by the left ventricle with each heart beat (left ventricular
ejection fraction An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...
or LVEF) and the duration of the QRS complex seen in the electrocardiogram (ECG). Most clinical studies on cardiac contractility modulation therapy have involved heart failure patients who were classified initially as NYHA Class II, III or IV and had a normal QRS duration (QRS duration ≤ 120 ms). The efficacy of cardiac contractility modulation on patients in an earlier stage of heart failure has not yet been studied. A subsequent evaluation study (subgroup analysis) has already suggested a particular patient group that responds exceptionally well to cardiac contractility modulation therapy. The patients were characterized by a disease severity of NYHA class III and a left ventricular ejection fraction of ≥ 25%. Although studies on cardiac contractility modulation therapy have focused on patients with a normal QRS duration (i.e. ≤ 120 ms), it is possible to use the therapy in patients who meet the treatment indication but who do not have a normal QRS duration. A preliminary study has previously shown that cardiac contractility modulation may be safe and effective in such patients who have not responded to cardiac resynchronization therapy (CRT).


Therapeutic gap

Cardiac resynchronization therapy (CRT; also known as biventricular pacing) has proven to be an effective treatment in heart failure. However, CRT is generally recommended exclusively for patients with a preserved sinus rhythm and a prolonged QRS complex (≥ 120 ms) who also suffer from
left bundle branch block Left bundle branch block (LBBB) is a conduction abnormality in the heart that can be seen on an electrocardiogram (ECG). In this condition, activation of the left ventricle of the heart is delayed, which causes the left ventricle to contract late ...
(LBBB), or for patients without left bundle branch block but who have a preserved sinus rhythm and a QRS complex with a width of ≥ 150 ms. However, only 30-40% of all heart failure patients show such a prolonged QRS complex, and therefore the 60-70% of patients who have a normal QRS complex cannot be treated with CRT. In addition, around 30% of the patients eligible for CRT treatment do not respond to CRT. Until recently, the only other available device-based treatment was the
left ventricular assist device A ventricular assist device (VAD) is an electromechanical device for assisting cardiac circulation, which is used either to partially or to completely replace the function of a failing heart. The function of a VAD differs from that of an artifici ...
(LVAD). LVAD therapy is indicated in patients with severe illness and is associated with several hours of surgery (involving a
cardiopulmonary bypass Cardiopulmonary bypass (CPB) is a technique in which a machine temporarily takes over the function of the heart and lungs during surgery, maintaining the circulation of blood and oxygen to the body. The CPB pump itself is often referred to as a ...
). It is usually considered as a therapy providing a "bridge to transplant" for heart failure patients classified as NYHA class IV, and is intended to support heart function until a
heart transplant A heart transplant, or a cardiac transplant, is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease when other medical or surgical treatments have failed. , the most common procedu ...
is received. Current research results suggest that the therapeutic gap described above could now be closed by the cardiac contractility modulation therapy. Additionally, a long-term study showed that the cardiac contractility modulation was able to stop the common and prognostically unfavorable long-term prolongation of QRS duration in heart failure patients. This result was interpreted as signaling the safety of the treatment and as an indicator that patients could benefit from cardiac contractility modulation therapy in the long term. If the QRS-stabilizing effect were to be confirmed in further studies, the cardiac contractility modulation would become the first device-based treatment for heart failure with the potential to halt QRS prolongation, a factor associated with a poor prognosis.


Recommendations

The
guidelines A guideline is a statement by which to determine a course of action. A guideline aims to streamline particular processes according to a set routine or sound practice. Guidelines may be issued by and used by any organization (governmental or pri ...
issued by the
European Society of Cardiology The European Society of Cardiology (ESC) is an independent non-profit, non-governmental professional association that works to advance the prevention, diagnosis and management of diseases of the heart and blood vessels, and improve scientific un ...
(ESC) in 2016, mention cardiac contractility modulation therapy as a therapy option to be considered in selected group of patients with HF. Mostly these guidelines are endorsed by national cardiac societies in individual countries within the European Union.


Efficacy

Cardiac contractility modulation has proven to be effective and safe in randomized controlled trials involving several hundred patients. The nature and extent of the effect of cardiac contractility modulation have been the subject of numerous investigations. Although various individual publications, as well as one of two meta-analyses, have presented the efficacy and significant potential of cardiac contractility modulation in the treatment of heart failure, medical evaluation of the therapy efficacy is not yet complete. Scientists point out, however, that this was also the case for CRT therapy when it was first introduced, advocating the provision of cardiac contractility modulation to suitable patients before further studies are completed. To date (February 2015), there are at least two meta-analyses studying the efficacy of cardiac contractility modulation therapy on heart failure, a large number of review articles (e.g.) and at least two survey articles on device-based treatments of advanced heart failure which address cardiac contractility modulation. Furthermore, there are more than 70 individual publications focusing specifically on cardiac contractility modulation therapy.Research of th
Pubmed data base
for the search term "Cardiac Contractility Modulation" in the title of publications performed on Oct 16, 2014
Further randomized controlled trials studying the effect of cardiac contractility modulation on the progression of heart failure have been initiated and are currently (as of February 2015) recruiting patients.


Meta-analyses

Giallauria et al. evaluated the three
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s (RCTs) currently available on cardiac contractility modulation as a treatment for heart failure patients. The three trials included a total of 641 patients and assessed the effect of cardiac contractility modulation either in comparison to a sham treatment or in comparison to the best medical treatment. In contrast to an earlier meta-analysis by Kwong et al. the study did not evaluate the data based on summarized results alone, but on the basis of the individual data sets of the 641 enrolled patients. The study concluded that cardiac contractility modulation significantly improved important markers of cardiac performance. These included the maximal oxygen uptake (peak VO2 or pVO2 – measured by ventilatory parameters during a cardiopulmonary exercise test), which is indicative of improved survival, and the 6-minute walk test. The quality of life of participating patients, measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ), also improved significantly. However, both meta-analyses demanded additional and larger randomized controlled trials in order to evaluate the effect of the therapy more precisely. Giallauria et al. describe the success of cardiac contractility modulation and the further potential of the therapy. Particular emphasis is given to the possibility that cardiac contractility modulation therapy may close the therapeutic gap in heart failure treatment if previous study outcomes are confirmed.


Long-Term Survival Studies

As of February 2015, the effect of cardiac contractility modulation therapy on the long-term mortality rates of heart failure patients has not been studied in a randomized controlled trial. Some preliminary single-center studies have been reported though. Kuschyk et al. evaluated the long-term efficacy and survival of patients with cardiac contractility modulation. Their analysis included 81 patients with a disease severity of NYHA class II, III or IV and a mean follow-up of around 3 years. The analysis compared the observed mortality rate with the prediction of the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) model"MAGGIC" Heart Failure Risc Calculator according to Pocock et al. ''Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies'', Eur Heart J (2013) 34(19) 1404-1413 (linked above)
/ref> which is based on the records of over 39,000 heart failure patients. Unlike a previous long-term outcome study of cardiac contractility modulation, this study was not limited by a widely heterogeneous group of patients. Following long-term observation, the study concluded that cardiac contractility modulation improved quality of life, exercise tolerance, NYHA class, left ventricular ejection fraction (LVEF) and
brain natriuretic peptide Brain natriuretic peptide 32 (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. Along with NT-proBNP, BNP is one ...
(BNP) levels. Mortality rates were significantly lower than predicted at year 1, and lower than predicted but not statistically significant at year 3.


General

Heart failure is a chronic disease that usually progresses gradually. The rate of progression and the degree of symptoms of the disease varies between different patients. Cardiac contractility modulation therapy aims to treat heart failure through a medium- to long-term treatment, over the course of weeks and months. According to large implanting clinics, after the implantation wound is healed, the lifestyle of a patient is not restricted by the implanted device.Tips by the American Heart Associuation "Living With Your Pacemaker"
/ref> Leisure, travel (by car, train, ship or plane), hobbies and sex life will not be restricted. The patient may perceive an improved capacity for these activities and overall enhanced performance and exercise capacity in response to the actual therapy.


Contraindications

In the past, the most important contraindication in cardiac contractility modulation treatment was permanent and long-standing persistent atrial fibrillation. The signal application in current cardiac contractility modulation devices was timed and triggered according to the electrical activity of the
atrium Atrium may refer to: Anatomy * Atrium (heart), an anatomical structure of the heart * Atrium, the genital structure next to the genital aperture in the reproductive system of gastropods * Atrium of the ventricular system of the brain * Pulmona ...
. In atrial fibrillation, electrical activity in the atrium is severely disturbed and is therefore not a reliable basis for the triggering of cardiac contractility modulation signals. This also applies to other diseases involving severe disturbance in electrical atrial sensing. Requests have been raised in scientific literature for an improved cardiac contractility modulation algorithm which would allow the therapy to be delivered independently from any atrial signal. A pioneering study had shown that an improved cardiac contractility modulation algorithm could make the therapy an effective treatment for patients with persistent atrial fibrillation. Following these study results the new generation was developed and can now offer cardiac contractility modulation therapy also for patients with atrial fibrillation. Other irregular rhythms, including frequent premature ventricular contractions (ventricular extra systoles) or a distinct signal transduction disorder in the heart (untreated
AV block Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoa ...
of more than 300 ms), may represent contraindications. CRT treatment should be considered in lieu of cardiac contractility modulation in patients with left bundle branch block (LBBB) and a QRS duration of over 120 ms, or when the QRS duration is greater than 150 ms and independent of LBBB. As with conventional pacemaker therapy, the cardiac contractility modulation device cannot be implanted if the leads cannot be positioned appropriately in the heart. In cases where there is an
artificial heart valve An artificial heart valve is a one-way valve implanted into a person's heart to replace a heart valve that is not functioning properly ( valvular heart disease). Artificial heart valves can be separated into three broad classes: mechanical he ...
between the right atrium and ventricle (a mechanical prosthetic tricuspid valve), the valve function could be greatly affected by the ventricular leads. In some instances it may be impossible to guide the leads through the main veins in the upper half of the body to the heart due to
venous thrombosis Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, for example VVI pacemakers, in the case of 100% stimulation, are also contraindicated.


Side effects

The most frequently encountered adverse events related to cardiac contractility modulation therapy are lead fracture or lead dislodgement. Other reported complications include: * Infection and bleeding at the IPG implantation site * Accumulation of fluid in the pericardium (
pericardial effusion A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...
) These side effects are similar to those that occur with other electrical stimulation therapies, such as pacemakers, CRT devices or ICD devices. Furthermore, recorded complications did not differ between patients with activated or deactivated cardiac contractility modulation devices. Overall, cardiac contractility modulation treatment was demonstrated to have no negative impact on health markers.


Precautions

Similarly to patients with other electrical stimulation devices, patients with a cardiac contractility modulation device must follow certain precautions arising from the device implantation and its function. * Electromagnetic fields: Strong electromagnetic fields can interfere with the function of the device. Most interference will lead to inhibition of cardiac contractility modulation signal delivery. Once away from the field, the device will resume its normal function in most cases. The electromagnetic fields of household appliances are usually considered harmless.Safety recommendations of the American Heart Association for patients with artificial pacemakers
/ref>Safety recommendations of the American Heart Association for patients with implantable cardioverter defibrillators (ICDs)
/ref> * Mobile phones: Similarly to other electrical stimulation devices, such as pacemakers, aside from a recommended safety distance of 10–15 cm (4-6 inches) between the device and mobile phones, there are no restrictions on the use of mobile phones. * Security checks: Full body or hand-held metal detectors, such as those used at airport security controls, do not usually affect the function of the device. However, where such detectors are used there are often signs warning people with cardiac pacemakers and defibrillators, and cardiac contractility modulation patients are therefore advised to present their device ID. In these cases, the security check will typically continue with the use of a hand-held metal detector or by physical inspection. * Sports: All sports associated with increased stress on the arms or the chest, such as body building, martial arts or tennis, are usually not permitted. Diving is only permitted up to a depth of 5 meters due to the high pressure at greater depth. * Magnetic Resonance Imaging (MRI): Similarly to other electrical stimulation devices, such as pacemakers, cardiac contractility modulation therapy is a contraindication for MRI, a medical imaging technique.


Mechanism of action

The
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
of cardiac contractility modulation has been subject to continuous research since its initial discovery. Based on
animal testing Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
and experiments on human myocardial tissue obtained by
biopsies A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
, essential parts of the mechanism of action have been identified. According to current understanding (as of February 2015), the mechanism of action of cardiac contractility modulation may be summarized in the following manner: The signals applied during the electrical non-excitatory state of the cardiac muscle cells (the absolute refractory period) cause an increase in myocyte calcium in the cytosol during systole. This increases the muscle contraction strength. Additionally, within minutes, cell
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
and gene expression, which are typically abnormal in heart failure, improve towards their normal state. This beneficial effect occurs initially only in the area adjacent to the electrodes, but with time also spreads to remote areas of the cardiac muscle. Cardiac contractility modulation therefore restores the structure and function of damaged cells back towards their normal state. In some cases, disease-related changes in the ventricular heart structure can be partially reversed by cardiac contractility modulation through a process known as reverse remodeling of the heart.


History

Development of cardiac contractility modulation began in the late 1990s.Patent for CCM: ''Apparatus and method for controlling the delivery of contractility modulating non-excitatory signals to the heart''
/ref> Studies on individual cardiac muscle cells using a patch-clamp technique had already shown, in 1969, that a voltage applied during the absolute refractory period through leads between the interior of the cell and its outside environment increased the calcium influx through the cell membrane and improved the contraction of cardiac muscle cells. In 2001, scientists observed that a similar effect occurs even if the voltage is applied exclusively outside the cardiac muscle cells. 8/sup> Additionally, it was observed that therapeutically useful effects on the cardiac muscle were achieved if the electrical signals were applied not only to single cells but to large areas using larger leads, as used in conventional cardiac pacemakers. The contractility of both a healthy heart and a damaged heart could be increased through application of appropriate signals during the absolute refractory period of the cardiac muscle cells. An implantable cardiac contractility modulation device was received by a patient for the first time in 2001. The first study on the therapeutic effects of in humans was presented in 2004. To date, more than 3,000 heart failure patients have been treated with cardiac contractility modulation worldwide, including 641 patients under the study conditions recommended by the
Cochrane Collaboration Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profess ...
as being necessary for inclusion in a meta-analysis. Cardiac contractility modulation device implantation was first successfully done in India in Royal Hospital, Trivandrum, Kerala, under the leadership of Dr. C. Bharath Chandran. Advocate Harishankar was the first person in India to get the cardiac contractility modulation device implanted.


See also

*
Heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
*
Cardiac cycle The cardiac cycle is the performance of the human heart from the beginning of one heartbeat to the beginning of the next. It consists of two periods: one during which the heart muscle relaxes and refills with blood, called diastole, following ...
* Heart failure *
Artificial cardiac pacemaker An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart ei ...
*
Implantable cardioverter-defibrillator An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion and pacing of the h ...
* NYHA classification * Cardiac resynchronization therapy


References


External links


Current assessment of new device therapies for heart failure by the European Heart Rhythm Association (EHRA) – includes Cardiac contractility modulation
{{DEFAULTSORT:Cardiac contractility modulation Cardiac procedures