Cardiac contractility modulation

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The cardiac contractility modulation or CCM ™ is a technology developed by Impulse Dynamics NV therapy. Patients with moderate to severe heart failure (NYHA class II-IV) and symptoms despite optimal drug therapy can benefit from an improvement in the cardiac output.  The short- and long-term use of this therapy improves the strength of the ventricular contraction and thus the pumping capacity of the heart by modulating (adapting) the myocardial contractility. However, a reduction in overall mortality has not yet been demonstrated using randomized controlled studies.

The cardiac contractility modulation is carried out with the aid of an implanted pacemaker-like device that delivers the NES to the heart muscle in a timed manner in accordance with the electrical  cardiac cycle . Unlike a pacemaker, which delivers an electrical signal with the intention of causing the heart to contract, this therapy uses the NES, which is delivered adapted and synchronized to the electrical action in the cardiac cycle.

In cardiac contractility modulation, the electrical signals are delivered to the heart muscle during the  absolute refractory period of the heart muscle cells . In this phase of the cardiac cycle, electrical signals cannot trigger any movements of the heart muscle ( non-excitatory stimulation ). However, the signals used increase the influx of calcium into the heart muscle cells ( cardiomyocytes ). In contrast to other functional electrostimulative methods for the treatment of heart failure, such as therapy with pacemakers or implantable cardioverter defibrillators (ICD) , cardiac contractility modulation does not have a direct effect on the heart rhythm , but aims at a medium to long-term improvement in cardiac performance from. A summarizing evaluation ( meta-study ) of the available studies from 2014 as well as an overview of the treatment options for heart failure using equipment from 2013 came to the conclusion that the treatment of cardiac contractility modulation is safe, that heart failure patients generally benefit from it and that the therapy increases the load capacity (Exercise tolerance, ET) and can improve the quality of life of patients with certain types of heart failure. In addition, preliminary data show long-term survival that patients who received the treatment, compared to the expected mortality ( mortality ) in a comparable group of patients without cardiac contractility modulation reduced heart failure mortality.

Approval and indication

Admission

Based on clinical studies, the devices are currently approved and available in all EU countries , in Australia , Turkey , India , Hong Kong and in all other countries that use the CE mark for medical devices .

In the USA , cardiac contractility modulation is currently (as of February 2015) not approved for clinical use. However, a study has already started to seek approval from the United States' medical device authority, the FDA .

indication

Phases of heart contraction in sinus rhythm, in the middle of the QRS complex

According to the approval, cardiac contraction modulation is a treatment option for patients aged 18 and over who, despite drug therapy, suffer from symptoms of heart failure due to left ventricular systolic dysfunction (LVSD). The subject of further research is which patient groups benefit in particular from cardiac contractility modulation within the framework of device approval.

Criteria for classifying patients with left ventricular systolic heart failure include: a. the severity of the disease according to functional criteria (NYHA class), the average proportion of the amount of blood in the left ventricle that is ejected during a heartbeat (left ventricular ejection fraction , LVEF) and the duration of the QRS complex in the electrocardiogram curve (EKG) Curve). Cardiac contractility modulation studies were predominantly performed in patients with NYHA class II, III, or IV heart failure who had normal QRS complex duration (QRS duration ≤ 120 ms). The effectiveness of cardiac contractility modulation in patients with early stages of heart failure has not been studied.

According to the subsequent evaluation (subgroup analysis ) of a study, there could be a group of patients who responded better than average to the therapy. These patients were characterized by NYHA class III disease severity and an ejection fraction of the left ventricle (left ventricular ejection fraction) of ≥ 25%.

Although studies on cardiac contractility modulation have so far concentrated on patients with a (normal) QRS duration ≤ 120 ms, the therapy can be used in all patients who meet the indication criteria for cardiac contractility modulation, regardless of the QRS duration. A preliminary study had previously shown that the treatment was effective and safe even in patients who had not previously responded to cardiac resynchronization therapy (CRT).

Therapeutic gap in heart failure treatment

Cardiac resynchronization therapy (Engl. Cardiac resynchronization therapy , CRT, also known as biventricular pacing ) has proven itself in heart failure. To summarize, it is only recommended for patients with preserved sinus rhythm who have a QRS complex ≥ 120 ms wide and additionally a left bundle branch block or, without a left bundle branch block, a QRS complex ≥ 150 ms wide. However, such a prolonged QRS complex is only present in about 30-40% of heart failure patients. In contrast, 60–70% of patients have a normal QRS complex and therefore cannot be treated with cardiac resynchronization therapy. In addition, about 30% of patients eligible for CRT treatment are unresponsive to therapy.

An alternative or supplementary treatment to drug therapy using equipment has only existed in the form of the implantation of an artificial heart (cardiac support system). This is only indicated for seriously ill patients and involves an operation lasting several hours using a heart-lung machine . In heart failure patients, artificial hearts are usually only used to bridge the waiting time before a heart transplant .

Current research suggests that the described therapeutic gap in heart failure treatment could be closed by cardiac contractility modulation. Furthermore, in a long-term study, cardiac contractility modulation was able to halt the prognostically unfavorable increase in QRS duration that often occurs in heart failure in heart failure patients with initially normal QRS duration. This result was taken as confirmation of the safety of the treatment and an indication that patients could benefit from the treatment in the long term. If the QRS-stabilizing effect of the therapy is confirmed in further studies, cardiac contractility modulation would be the first device-based treatment of heart failure that could stop the prognostically unfavorable increase in QRS duration in heart failure.

Guideline recommendations

In the guidelines of the European Society of Cardiology (ESC) from 2016, cardiac contractility modulation is mentioned as a treatment option that should be considered in selected patients with heart failure.

Contraindication

The main contraindications (contraindication) for the treatment of cardiac Kontraktilitätsmodulation is permanent or repeated long-lasting atrial fibrillation or flutter . The signal output of the available systems is calculated and triggered on the basis of the electrical signal of the  atria (atrial signal). In the case of atrial fibrillation or flutter, however, the atrial electrical signal is severely disturbed and therefore no reliable basis for signal calculation. This also applies in the same way to other disturbances that lead to a significant disturbance or the absence of the electrical atrial signal. In the scientific literature, an improved algorithm has therefore already been described as desirable, which would work independently of the electrical signals of the atria. An initial study was also able to show that a modified algorithm can enable the treatment of patients with permanent atrial fibrillation.

Larger deviations from the sinus rhythm, such as those that occur with frequent additional heartbeats (higher-grade extrasystole ) or a pronounced signal transmission disorder in the heart ( AV blockage of more than 300 ms), are also contraindications. With existing left bundle branch block and a width of the QRS complex ≥ 120 ms or without a left bundle branch block with a width of the QRS complex ≥ 150 ms, a CRT using a biventricular pacemaker should be  considered.

Cardiac contractility modulation also cannot be used if the technically required electrodes cannot be positioned in the heart as intended. This can e.g. This could be the case , for example, with an artificial heart valve between the right atrium and right ventricle (artificial tricuspid valve ), the function of which would be impeded by a ventricular electrode , or if - for example, as a result of a thrombosis - the electrodes cannot be passed through the large veins of the upper half of the body to advance to the heart (these restrictions apply equally to pacemaker and ICD treatment, among others). There is also a contraindication for patients with  VVI pacemakers that are 100% stimulated.

Mechanism of action

The mechanism of action of cardiac contractility modulation has been the subject of ongoing research since the treatment was discovered. On the basis of  animal experiments and studies of human heart muscle tissue obtained through biopsies , essential sub-steps of the mechanism of action have been deciphered to this day.

According to current understanding (as of February 2015), the mechanism of action of the cardiac contractility modulation can be summarized as follows: The electrical signals given during the electrical non-excitability of the heart muscle cells (absolute refractory period) cause an increased influx of calcium into the cells. This increases the electrical excitation of the cells. The muscle function is  strengthened . In addition, within minutes there is a change and finally a normalization of the cell metabolism, which is disturbed in heart failure, due to an altered activation of the genetic information of the cell. This beneficial effect initially only occurs in the vicinity of the electrodes, but with increasing duration of use it also spreads to areas of the cardiac muscles remote from the electrodes. There is a remodeling of the damaged cells towards a healthier structure and function. In favorable cases, disease-related changes to the heart chambers can be partially reversed. This process is known as reverse remodeling or re-remodeling.

How the devices work

construction

Cardiac contractility modulation devices are similar in structure to other implantable devices that support electrical cardiac stimulation, such as pacemakers or implantable cardioverter defibrillators (ICD) . The devices consist of four components (as of February 2015):

The cardiac contractility modulation, a possible form of treatment for chronic heart failure, takes place via the implantable pulse generator Optimizer® from Impulse Dynamics.
  • Implantable pulse generator: The pulse generator (implantable pulse generator, IPG) generates the signals. The currently used IPG is somewhat larger in area, but somewhat flatter than a matchbox (approx. 6.5 cm × 4.8 cm × 1.2 cm). The pulse generator, the patient is usually below the right  clavicle implanted under the skin or under the chest muscle ( implanted ) .Dabei may result from the IPG a felt and partially visible also bulging. In 2015, no devices were available that could also take over the functionality of other electrostimulative devices that could be combined with cardiac contractility modulation, such as pacemakers or implantable cardioverter-defibrillators. However, the development of such combination devices has already been suggested in the specialist literature.
  • Electrodes : Current devices for cardiac contractility modulation (as of October 2014) have three standard pacemaker electrodes . These are special medical cables that carry electrical signals from the pulse generator to the heart. The electrodes are below the clavicle in the subclavian vein (subclavian vein) or, more rarely in the axillary ( axillary vein ) or the cephalic vein introduced and via the superior vena cava (superior vena cava) to the right atrium and into the right ventricle (right Ventricle) advanced. The electrode in the right atrium picks up the electrical signals from the atria and sends them to the pulse generator. This calculates the necessary signals and sends them to the heart muscles via the two electrodes in the right ventricle. These chamber electrodes are anchored in the upper or middle area of ​​the heart septum (septum interventriculare), which separates the right from the left heart chamber. The electrodes themselves do not lead to a mechanical change in the blood flow in the heart.
  • Charger : The charger ensures that the implanted pulse generator is supplied with power. Current battery chargers are portable. The patients can therefore move largely freely during the charging process. The charger works  inductively , so it can charge the battery of the IPG through the skin without contact and wirelessly. Charging is carried out independently by the patient at home after a briefing. One charging process supplies the pulse generator with energy for about a week. In this respect, the pulse generator of the cardiac contractility modulation differs from pacemakers and ICD devices, which as a rule do not have a battery charging function, but are surgically exchanged as soon as their battery is exhausted.
  • Programming unit : The programming unit is only available to the doctor and - in the event of technical problems - specially trained technicians for checking the device. With the programming unit, the signal output of the pulse generator can be individually tailored to the needs of the individual patient. Adjustments are possible, among other things, with regard to the signal intensity and the duration of daily use. The programming of the IPG is also done contactless by induction, so it can easily be done through the skin on the implanted device.

Signals

Illustration of a signal

The cardiac contractility modulation works via special electrical signals that are generated by the pulse generator and act on the heart muscle cells during the absolute refractory period. In practice, signals are used today that begin about 30 ms after the start of the QRS complex (normal total QRS duration: ≤ 120 ms). The signal consists of two biphasic deflections with a voltage of ± 7.7 V and a total duration of around 20 ms.

Since the signals are administered to the heart muscle cells during the absolute refractory period, they do not trigger any muscle contractions and also do not activate additional  muscle fibers . Nor is the sequence of electrical and mechanical activation changed in the heart. The signals contain around 500 times more energy than the signals from cardiac pacemakers and can be easily recognized in an electrocardiogram (EKG).

implantation

The implantation of the pulse generator and the electrodes for the treatment of cardiac contractility modulation is carried out using the same procedure that is also used for the implantation of cardiac pacemakers. Corresponding interventions are carried out around 100,000 times a year in Germany and around 1,000,000 times worldwide. The minimally invasive operation takes about 40 minutes and is usually performed under local anesthesia . However, patients should remain sober in order to be able to easily expand the anesthesia and the procedure in the event of complications .

At the beginning of the implantation, the doctor checks the function of the pulse generator and the electrodes. The electrodes are then positioned in the heart. The positioning of the electrodes is checked by means of X-rays and measurement of voltage and current flow (electrode impedance).

Once the electrodes are in position, they are connected to the pulse generator. A pocket to hold the pulse generator is placed under the patient's collarbone. The IPG is inserted and the function is checked again. If the patient also has a pacemaker or implantable cardioverter defibrillator, it is ensured that the signals from the two devices do not interfere with one another. Finally the pocket is sutured and the wound is bandaged. Generally, patients will be monitored for some time to ensure that the device is working properly. Since the device is completely covered by skin after the wound has healed, no further precautions are required with regard to contact with water. The patients can - depending on their state of health - u. a. shower and swim without restriction.

After discharge, treatment is continued by a resident cardiologist. Check-ups take place after a few days, after a few weeks and then according to the cardiologist's assessment.

maintenance

A patient at the weekly shop.

Apart from the regular charging of the device battery (the charging time is approx. 1 hour for one week of operation) and the operational replacement of the battery after the operating time has expired, the devices of the cardiac contractility modulation are maintenance-free. At certain intervals, which are determined by the attending physician, however, the function of the device is checked and, if necessary, the device setting is adjusted by the cardiologist . The battery charger is equipped with a warning function that informs the patient in the event of device malfunctions or other abnormalities such as B. an inadequate signal to see the doctor.

Interactions with other electrostimulative treatments

Interfering interactions between cardiac contractility modulation and other electrostimulative treatment methods have not been observed to date. Studies have shown that the therapy can easily be carried out in parallel to a pacemaker and / or CRT treatment with or without simultaneous cardioverter-defibrillator treatment, without impairing the individual therapies. Based on these results, some medical professionals have already called for the development of combined devices for cardiac contractility modulation and cardioverter-defibrillator devices in order not to burden patients with combined therapy with multiple electrostimulative devices and implantation operations.

Regulation and assumption of costs

Treatment for cardiac contractility modulation is usually recommended by a cardiac specialist. The implantation is usually carried out by an interventional cardiologist. In Germany, Switzerland, Austria and Italy, the costs of treatment are covered in full by both health insurance companies and private health insurance companies.

Treatment effectiveness

Cardiac contraction modulation has been shown to be effective and safe in randomized controlled trials with several hundred participants.

The type and scope of therapy have been the subject of numerous studies. Although various individual publications and one of two meta-studies award the efficacy and extensive potential for the treatment of heart failure, the medical evaluation of the efficacy of the method has not yet been completed. So far (as of February 2015) there have been at least two meta-studies on the effectiveness of cardiac contractility modulation in heart failure, a large number of review articles on therapy (e.g.) and at least two reviews on the use of apparatus-based treatments for advanced heart failure that deal with cardiac contractility modulation . In addition, there are more than 70 individual publications that focus on therapy.

Further randomized controlled studies on the effect of cardiac Kontraktilitätsmodulation on the progression ( progression ) of heart failure have been initiated and is currently recruiting patients. Scientists point out that a similar study situation also existed at the beginning of the introduction of the now established CRT treatment, and advocate making the cardiac contractility modulation available to suitable patients before the corresponding studies are completed.

Meta-studies

Giallauria, Vigorito, Piepoli, Coats 2014: Giallauria, Coats and other colleagues evaluated the three randomized controlled trials (RCT) available to date for the treatment of heart failure patients with cardiac contractility modulation. The three studies included a total of 641 patients who rated the effect of the therapy either in comparison to a sham treatment or in comparison to an optimal drug therapy. In contrast to an earlier meta study by Kwong and colleagues, they did not evaluate the study data on the basis of the summary results, but on the basis of the individual treatment results of the 641 patients included.

They came to the conclusion that cardiac contractility modulation improves important markers of cardiac output. This includes the so-called maximum oxygen uptake in the heart and lungs (recorded by means of a cardiopulmonary stress test: peak VO 2 or pVO 2 ), which indicates a longer survival of the disease, and the result of the so-called 6-minute walk test . The quality of life of the patients, as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ), was also significantly improved. However, both meta-studies called for additional and more extensive randomized controlled studies in order to better assess the effect of cardiac contractility modulation.

Giallauria et al. highlight the success and further potential of cardiac contractility modulation. It is particularly pointed out that the therapy could possibly close the existing therapeutic gap in heart failure treatment - according to the results of the studies so far.

Long-term survival studies

So far (as of February 2015) the effects of the therapy on the long-term mortality of heart failure patients have not yet been investigated in randomized controlled studies. However, some preliminary results from single-center studies have been published.

Kuschyk et al. investigated the long-term efficacy and survival rate of heart failure patients who received cardiac contractility modulation. Their study enrolled 81 patients with NYHA class II, III, and IV disease severity over an average observation period of 3 years. The analysis compared the observed mortality with the predictions of the meta-analysis Global Group in Chronic Heart Failure (MAGGIC) model, which is based on the analysis of the medical records of 39,000 heart failure patients. In contrast to an earlier long-term study of the success of cardiac contractility modulation, the significance of the study by Kuschyk et al. not restricted by too great a heterogeneity of the patient group.

Based on the long-term observation, the study came to the result that the cardiac contractility modulation the quality of life, physical exercise capacity, the NYHA class (disease severity), the left ventricular ejection fraction (LVEF) and the brain natriuretic peptide (BNP; a hormone that is active when stretching secreted by myocardial cells). The observed mortality of the patients treated with the therapy was found to be significantly lower after one year than expected based on the MAGGIC data. A similar trend was also evident three years after the start of the study, but did not reach any significance.

Individual studies

Frequently cited studies on cardiac contractility modulation include: a .:

  • FIX-HF-3 (Stix et al. 2004): This study was the first extensive test of the therapy on humans. 25 patients were included in the prospective study. The results showed that the electrical signals could improve systolic function and clinical parameters.
  • USA FEASIBILITY RCT FIX-HF-5-I (Neelagaru et al. 2006): This investigation was a prospective, double-blind, prospective feasibility and safety study conducted in the USA and enrolling 49 patients. The study provided basic data on the safety of the therapy.
  • Butter et al. 2007: This prospective short-term therapy study on 9 patients and 6 dogs showed that the function of the left ventricle can be improved by cardiac contractility modulation without increasing the oxygen consumption of the heart muscle.
  • Nagele et al. 2008: In this study, the therapy was used as an additional measure in patients who had not responded to CRT treatment (CRT non-responders). The research showed that the treatment improved the resilience and quality of life of CRT non-responders.
  • EUROPEAN RCT FIX-HF-4 (Borggrefe et al. 2008): This prospective double-blind crossover study enrolled approximately 160 patients and provided the first definitive evidence for the safety and effectiveness of the cardiac contractility modulation devices. The term crossover means that the study participants went through both treatment options with cardiac contractility modulation to be compared for the same period of time. The effect of cardiac contractility modulation on quality of life and exercise tolerance was comparable to that of CRT.
  • FIX-HF-9 (Yu et al. 2009): This clinical investigation was a prospective, double-blind long-term study on 30 patients. She showed that cardiac contractility modulation led to an improvement in the function of the left ventricle and to remodeling pathological changes in the heart (reverse remodeling).
  • USA RCT FIX-HF-5-II (Kadish et al. 2011): 428 patients were recruited for this prospective randomized study. The results showed that cardiac contractility modulation is safe, increases the maximum oxygen consumption in the cardiopulmonary stress test - peak VO 2 (pVO 2 ) - which is  prognostically indicative of lower disease severity and mortality and is an indicator of longer patient survival, and increases quality of life , recorded via the Minnesota Living With Heart Failure Questionnaire (MLWHFQ), improved in the target group.
  • Abraham et al. 2011: This study was a retrospective subgroup analysis of the data from the FIX-HF-5-II study (see above). The study identified a subgroup of patients in whom cardiac contractility modulation led to a significant improvement in the anaerobic threshold and other parameters. This subgroup was characterized by a normal QRS time, symptoms corresponding to NYHA class III and a left ventricular ejection fraction (LVEF)> 25%.

Side effects

The most common side effect observed in cardiac contractility modulation is the breakage or displacement of the electrodes.

In addition, the following occurred:

These side effects do not differ from those that occur with electrostimulative treatment procedures (cardiac pacemakers, other CRTs, ICDs). Furthermore, there was no difference between activated and deactivated treatment devices with regard to side effects. Overall, no negative effects of the treatment on health markers could be proven statistically.

Treatment in everyday life

General

Heart failure is a chronic disease that usually progresses in its course. The affected patients experience different courses and complaints of varying severity. The cardiac contractility modulation is aimed at medium to long-term treatment success over the course of weeks and months. Accordingly, affected patients have to adapt permanently to a life with the treatment.

According to information from large implantation clinics, everyday life with cardiac contractility modulation after the wound has healed is hardly different from life before implantation. Leisure time, travel, hobbies and sex life can continue unchanged. If the therapy responds, however, there is a possibility that the patient will experience improved resilience in these activities.

Precautions

Metal detectors at Berlin-Schönefeld Airport
  • Electromagnetic fields: Strong electromagnetic fields can temporarily disrupt the function of the device. After the interfering signals have subsided or if the distance is sufficient, the device will in most cases resume normal function. The electromagnetic fields from household appliances are generally considered to be harmless.
  • Mobile phones: A safety distance of 10-15 cm is recommended between the device and mobile phones. Other than that, there are no restrictions on the use of cell phones.
  • Security checks: full-body metal detectors , such as those used B. are used at airports, usually do not affect the function of the device. Nevertheless, there are often warnings for people with pacemakers and defibrillators. In these cases, patients are advised to present their device ID. The control is then mostly carried out with handheld devices or by manual scanning. During the check, however, the hand-held devices must not be passed over the implant several times in quick succession, as this can lead to functional failures.
  • Sports: In most cases, all sports that involve increased stress on the arms or chest area, such as exercise, are no longer possible. B. strength and martial arts, but also tennis. Due to the increasing water pressure, diving is only permitted up to a diving depth of 5 m.
  • Magnetic resonance imaging (MRI, magnetic resonance imaging): Patients with implanted electrostimulative devices for cardiac contractility modulation, cardiac pacemakers or ICDs must not be examined using magnetic resonance imaging.

history

The development of cardiac contractility modulation began in the late 1990s. Investigations on individual myocardial cells using the  patch-clamp technique had already shown in 1969 that an electrical voltage applied by electrodes between the cell interior and the cell exterior during the absolute refractory period of the cell resulted in an increased influx of calcium through the cell membrane of myocardial cells and improved shortening ( Contraction ) of the muscle cell. In 2001 it was possible to prove that a corresponding effect also occurs when the voltage is applied exclusively outside the heart muscle cells. In addition, it was observed that therapeutically useful effects on the heart muscle also occurred when the electrical signals not only reached individual cells, but were also emitted over a large area by means of macroscopic electrodes, such as those used in pacemakers. By applying suitable signals during the absolute refractory period of the heart muscle cells, the contractility of both healthy and damaged hearts could be improved.

The first treatment of a human with cardiac contractility modulation took place in 2001. The first study on therapeutic effects in humans was presented in 2004. To date (as of February 2015) more than 2,000 devices have been implanted worldwide, including 641 patients under study conditions that, according to the recommendations of the Cochrane Collaboration, qualitatively met the requirements for inclusion in a meta-study .

See also

Web links

Individual evidence

  1. ^ William T. Abraham, Karl-Heinz Kuck, Rochelle L. Goldsmith, JoAnn Lindenfeld, Vivek Y. Reddy: A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation . In: JACC: Heart Failure . tape 6 , no. 10 , October 2018, p. 874–883 , doi : 10.1016 / j.jchf.2018.04.010 ( elsevier.com [accessed on November 3, 2019]).
  2. ↑ a b c d e f g h W.T. Abraham, SA Smith: Devices in the Management of Advanced, Chronic Heart Failure . In: Nat Rev Cardiol . 10, No. 2, February 2013, pp. 98-110. doi : 10.1038 / nrcardio.2012.178 . PMID 23229137 . PMC 3753073 (free full text).
  3. ↑ a b c d e f g h i j k l m F. Giallauria, et al .: Effects of cardiac contractility modulation by non-excitatory electrical stimulation on exercise capacity and quality of life: an individual patient's data meta-analysis of randomized controlled trials . In: Int J Cardiol . 175, No. 2, August 2014, pp. 352-357. doi : 10.1016 / j.ijcard.2014.06.005 . PMID 24975782 .
  4. ↑ a b c d e f g h i j k l M. Borggrefe, D. Burkhoff: Clinical effects of cardiac contractility modulation (CCM) as a treatment for chronic heart failure . In: Eur J Heart Fail . 14, No. 7, July 2012, pp. 703-712. doi : 10.1093 / eurjhf / hfs078 . PMID 22696514 .
  5. ↑ a b C. Butter, et al .: Cardiac Contractility Modulation Electrical Signals Improve Myocardial Gene Expression in Patients With Heart Failure . In: J Am Coll Cardiol . 51, No. 18, May 2008, pp. 1784-1789. doi : 10.1016 / j.jacc.2008.01.036 . PMID 18452785 .
  6. ↑ a b c C.M. Yu, et al .: Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling . In: JACC Cardiovasc Imaging . 2, No. 12, December 2009, pp. 1341-1349. doi : 10.1016 / j.jcmg.2009.07.011 . PMID 20083066 .
  7. ↑ a b c T. Tönnis, K.-H. Kuck: Therapy of chronic heart failure through cardiac contraction modulation (CCM) possibilities and study overview . In: heart . 36, No. 7, October 2011, pp. 600-607. doi : 10.1007 / s00059-011-3510-z . PMID 21912910 .
  8. ↑ a b c d J. Kuschyk, S. Roeger u. a .: Efficacy and survival in patients with cardiac contractility modulation: Long-term single center experience in 81 patients. In: International journal of cardiology. [electronic publication before printing] January 2015, ISSN  1874-1754 , doi: 10.1016 / j.ijcard.2014.12.178 , PMID 25662055 .
  9. ↑ a b c d J. Kuschyk: The special value of cardiac contractility modulation in device therapy . In: Heart Medicine . 2014.
  10. ↑ a b c d clinicaltrials.gov
  11. ↑ a b c d e f g h i j K.-H. Kuck, et al .: New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association . In: Europace . 16, No. 1, January 2014, pp. 109–128. doi : 10.1093 / europace / eut311 . PMID 24265466 .
  12. ↑ a b W.T. Abraham, et al .: Subgroup Analysis of a Randomized Controlled Trial Evaluating the Safety and Efficacy of Cardiac Contractility Modulation in Advanced Heart Failure . In: J Card Fail . 17, No. 9, September 2011, pp. 710-717. doi : 10.1016 / j.cardfail.2011.05.006 . PMID 21872139 .
  13. ↑ a b c d e f g h D. Burkhoff: Does Contractility Modulation Have a Role in the Treatment of Heart Failure? . In: Curr Heart Fail Rep . 8, No. 4, December 2011, pp. 260-265. doi : 10.1007 / s11897-011-0067-3 . PMID 21656201 .
  14. ↑ a b c d e f g h i j k l C. Butter: Improving left ventricular contractility through stimulation in the absolute refractory period. Cardiac contractility modulation. . In: Herzschr Elektrophys . 22, No. 1, March 2011, pp. 27-33. doi : 10.1016 / j.jacc.2008.01.036 . PMID 21365468 .
  15. ^ A b H. Nagele, S. Behrens, C. Eisermann: Cardiac contractility modulation in non-responders to cardiac resynchronization therapy . In: Europace . 10, No. 12, December 2008, pp. 1375-1380. doi : 10.1093 / europace / eun257 . PMID 18776196 . Retrieved October 11, 2014.
  16. ↑ a b c d J.JV McMurray, et al .: ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 . In: European Heart Journal . 33, No. 14, 2012, pp. 1787-1847. doi : 10.1093 / eurheartj / ehs104 . PMID 22828712 . Retrieved October 10, 2014.
  17. ↑ a b S. Röger, et al .: Long term impact of cardiac contractility modulation on QRS duration . In: J Electrocardiol . August 2014. doi : 10.1016 / j.jelectrocard.2014.08.011 . PMID 25201417 .
  18. ^ Acute and Chronic Heart Failure. Retrieved November 22, 2017 .
  19. ↑ a b c S. Röger, et al .: Cardiac contractility modulation: first experience in heart failure patients with reduced ejection fraction and permanent atrial fibrillation . In: Europace . April 2014. doi : 10.1093 / europace / euu050 . PMID 24706089 .
  20. ↑ a b A.R. Lyon, MA Samara, DS Feldman: Cardiac contractility modulation therapy in advanced systolic heart failure . In: Nat. Rev. Cardiol. . 10, No. 10, October 2013, pp. 584-598. doi : 10.1038 / nrcardio.2013.114 . PMID 23939481 .
  21. ↑ M. Imai, et al .: Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure . In: J Am Coll Cardiol . 49, No. 21, May 2007, pp. 2120-2128. doi : 10.1016 / j.jacc.2006.10.082 . PMID 17531662 . Retrieved October 11, 2014.
  22. ↑ K.-H. Kuck, et al .: EHRA White Book 2014 Archived from the original on December 17, 2014. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: The EHRA White Book . August, p. 203. Retrieved November 6, 2014. @1@ 2Template: Webachiv / IABot / www.escardio.org
  23. ^ HG Mond, A. Proclemer: The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009 - a World Society of Arrhythmia's project . In: Pacing Clin Electrophysiol . 34, No. 8, August 2011, pp. 1013-1027. doi : 10.1111 / j.1540-8159.2011.03150.x . PMID 21707667 .
  24. ^ Living With Your Pacemaker . Tips by the American Heart Association
  25. ↑ a b J. Kuschyk, S. Röger, M. Borggrefe: Cardiac contractility modulation for the treatment of symptomatic heart failure . In: The cardiologist . 8, No. 5, October 2014, pp. 407-414. doi : 10.1007 / s12181-014-0595-7 .
  26. ↑ a b Announcement of the launch of the OPTIMIZER IVs CCM device on Implantable-Device.com
  27. ↑ a b c S.B. Neelagaru, et al .: Nonexcitatory, cardiac contractility modulation electrical impulses: Feasibility study for advanced heart failure in patients with normal QRS duration . In: Heart Rhythm . 3, No. 10, October 2006, pp. 1140-1147. doi : 10.1016 / y.hrthm.2006.06.031 . PMID 17018340 .
  28. ↑ a b c d M. Borggrefe, et al .: Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure . In: Eur Heart J . 29, No. 8, April 2008, pp. 1019-1028. doi : 10.1093 / eurheartj / ehn020 . PMID 18270213 . Retrieved October 16, 2014.
  29. ↑ a b c d A. Kadish, et al .: A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure . In: Am Heart J . 161, No. 2, February 2011, pp. 329-337. doi : 10.1016 / y.ahy.2010.10.025 . PMID 21315216 .
  30. ↑ a b J.S. Kwong, JE Sanderson, CM Yu: Cardiac contractility modulation for heart failure: a meta-analysis of randomized controlled trials . In: Pacing Clin Electrophysiol . 35, No. 5, September 2012, pp. 1111-1118. doi : 10.1111 / j.1540-8159.2012.03449.x . PMID 22734676 .
  31. ↑ J. Kuschyk, M. Borggrefe: Electrical therapy of heart failure . In: Cardio up . 9, No. 1, 2013, pp. 37-56. doi : 10.1055 / s-0032-1326192 . Retrieved November 6, 2014.
  32. ^ Search for the search term "Cardiac Contractility Modulation" in the title of publications in the Pubmed database, carried out on October 16, 2014.
  33. ↑ a b S. Pakarinen, L. Oikarinen, L. Toivonen: Short-term implantation-related complications of cardiac rhythm management device therapy: a retrospective single-center 1-year survey . In: Europace . 12, No. 1, January 2010, pp. 103-108. doi : 10.1093 / europace / eup361 . PMID 19914920 . Retrieved November 6, 2014.
  34. ↑ SJ Pocock, et al .: Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies . In: Eur Heart J . 34, No. 19, May 2013, pp. 1404-1413. doi : 10.1093 / eurheartj / ehs337 . PMID 23095984 . Retrieved February 20, 2015.
  35. ↑ “MAGGIC” Heart Failure Risc Calculator (heart failure risk 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
  36. ^ T. Schau, et al .: Long-term outcome of cardiac contractility modulation in patients with severe congestive heart failure . In: Europace . 13, No. 10, April 2011, pp. 1436-1444. doi : 10.1093 / europace / eur153 . PMID 21712286 . Retrieved February 20, 2015.
  37. ↑ AJS Coats, LG Shewan: Inconsistencies in the development of the ESC Clinical Practice Guidelines for Heart Failure . In: Int J Cardiol . 168, No. 3, October 2013, pp. 1724-1727. doi : 10.1016 / j.ijcard.2013.05.045 . PMID 23735338 .
  38. ↑ a b G. Stix, et al .: Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure . In: Eur Heart J . 25, No. 8, April 2004, pp. 650-655. doi : 10.1016 / y.ehj.2004.02.027 . PMID 15084369 . Retrieved October 10, 2014.
  39. ↑ C. Butter, et al .: Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption . In: J Card Fail . 13, No. 2, March 2007, pp. 137-142. doi : 10.1016 / j.cardfail.2006.11.004 . PMID 17395055 .
  40. ↑ a b Information from the Kerckhoff Clinic on everyday life with pacemakers and defibrillators ( memento of the original from December 7, 2014 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (Due to the similarity of the devices, the information given also applies to patients with CCM devices) @1@ 2Template: Webachiv / IABot / www.kerckhoff-klinik.de
  41. ↑ a b Pacemaker and device distance . German Heart Foundation; accessed on February 10, 2015
  42. ↑ With a pacemaker on vacation . German Heart Foundation; accessed on February 10, 2015
  43. ↑ Pacemaker and sport . German Heart Foundation; accessed on February 10, 2015
  44. ↑ T. Dill: Contraindications to magnetic resonance imaging Archived from the original on April 2, 2015. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Heart . 94, No. 7, July 2008, pp. 943-948. doi : 10.1136 / hrt.2007.125039 . PMID 18552230 . Retrieved February 22, 2015. @1@ 2Template: Webachiv / IABot / www.rad.pitt.edu
  45. ↑ Patent for CCM: Apparatus and method for controlling the delivery of contractility modulating non-excitatory signals to the heart
  46. ↑ S. Mohri, et al .: Cardiac contractility modulation by electric currents applied during the refractory period Archived from the original on August 14, 2017. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Am J Physiol Heart Circ Physiol . 282, No. 5, May 2002, pp. H1642-H1647. doi : 10.1152 / ajpheart.00959.2001 . PMID 11959626 . Retrieved October 9, 2014. @1@ 2Template: Webachiv / IABot / ajpheart.physiology.org
  47. ^ H. Antoni, R. Jacob, R. Kaufmann: Mechanical response of the frog and mammalian myocardium to changes in the action potential duration by constant current pulses . In: Pflugers Arch . 306, No. 1, 1969, pp. 33-57. PMID 4975967 .
  48. ↑ EH Wood, RL Heppner, S. Weidmann: Inotropic effects of electric currents. I. Positive and negative effects of constant electric currents or current pulses applied during cardiac action potentials. II. Hypotheses: calcium movements, excitation-contraction coupling and inotropic effects. . In: Circ Res . 24, No. 3, March 1969, pp. 409-445. doi : 10.1161 / 01.RES.24.3.409 . PMID 5766519 . Retrieved October 9, 2014.
  49. ↑ a b D. Burkhoff, et al .: Electric currents applied during the refractory period can modulate cardiac contractility in vitro and in vivo . In: Heart Fail Rev . 6, No. 1, January 2001, pp. 27-34. PMID 11248765 .
  50. ^ HN Sabbah, et al .: Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure . In: Heart Fail Rev . 6, No. 1, January 2001, pp. 45-53. PMID 11248767 .
  51. ↑ C. Pappone, et al .: Electrical modulation of cardiac contractility: clinical aspects in congestive heart failure . In: Heart Fail Rev . 6, No. 1, January 2001, pp. 55-60. PMID 11248768 .
  52. ↑ C. Pappone, et al .: Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy . In: Am J Cardiol . 90, No. 12, December 2002, pp. 1307-1313. PMID 12480039 .