Cardiac contractility modulation is a therapy 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. 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.

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 contractions, hence this type of stimulation is known as a non-excitatory stimulation. However, the electrical signals increase the influx of calcium ions into the cardiac muscle cells (cardiomyocytes). In contrast to other electrical stimulation treatments for heart failure, such as pacemaker therapy or implantable cardioverter defibrillators (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 (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.

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.

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%.^{[citation needed]}

Based on the results of clinical trials, cardiac contractility modulation devices are approved and available for clinical use in all European Union countries and in Australia, Turkey, India and Hong Kong, as well as in other countries that recognize CE marking for medical devices.^{[citation needed]}

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.

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 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%.