Cardiac catheterization often requires the use of  fluoroscopy  to visualize the path of the catheter as it enters the heart or as it enters the coronary arteries. The coronary arteries are known as "epicardial vessels" as they are located in the epicardium, the outermost layer of the heart. [ 2 ]  The use of fluoroscopy requires radiopaque contrast, which in rare cases can lead to contrast-induced kidney injury (see  Contrast-induced nephropathy ). People are constantly exposed to low doses of  ionizing radiation  during procedures. [ 3 ]  Ideal table positioning between the x-ray source and receiver, and  radiation monitoring  via  thermoluminescent dosimetry , are two main ways of reducing a person's exposure to radiation. [ 3 ]  People with certain  comorbidities  (people who have more than one condition at the same time) have a higher risk of adverse events during the cardiac catheterization procedure. [ 3 ]  These comorbidity conditions include  aortic aneurysm ,  aortic stenosis , extensive three-vessel  coronary artery disease ,  diabetes , uncontrolled  hypertension ,  obesity ,  chronic kidney disease , and  unstable angina . [ 4 ]


Left heart catheterization (LHC) is an ambiguous term and sometime clarification is required: [ citation needed ]


technique is also used to assess the amount of occlusion (or blockage) in a coronary artery, often described as a percentage of occlusion. A thin, flexible wire is inserted into either the  femoral artery  or the  radial artery  and threaded toward the heart until it is in the ascending  aorta . Radial access is not associated with an increased risk of stroke over femoral access. [ 5 ]  At this point, a catheter is guided over the wire into the ascending aorta, where it can be maneuvered into the coronary arteries through the coronary ostia. [ 4 ]  In this position, the interventional cardiologist can inject contrast and visualize the flow through the vessel. If necessary, the physician can utilize percutaneous coronary intervention techniques, including the use of a  stent  (either bare-metal or  drug-eluting ) to open the blocked vessel and restore appropriate blood flow. In general, occlusions greater than 70% of the width of the vessel lumen are thought to require intervention. However, in cases where multiple vessels are blocked (so-called "three-vessel disease"), the interventional cardiologist may opt instead to refer the patient to a cardiothoracic surgeon for coronary artery bypass graft (CABG; see  Coronary artery bypass surgery ) surgery. [ citation needed ]


Right heart catheterization (RHC) allows the physician to determine the pressures within the heart (intracardiac pressures). The heart is most often accessed via the internal jugular or femoral vein; arteries are not used. Values are commonly obtained for the right atrium, right ventricle, pulmonary artery, and pulmonary capillary "wedge" pressures. Right heart catheterizations also allow the physician to estimate the cardiac output, the amount of blood that flows from the heart each minute, and the cardiac index, a hemodynamic parameter that relates the cardiac output to a patient's body size.  Determination of cardiac output  can be done by releasing a small amount of saline solution (either chilled or at room temperature) in one area of the heart and measuring the change in blood temperature over time in another area of the heart. [ citation needed ]


Right heart catheterization is often done for  pulmonary hypertension ,  heart failure , and  cardiogenic shock . The pulmonary artery catheter can be placed, used, and removed, or it can be placed and left in place for continuous monitoring. The latter can be done an  intensive care unit  (ICU) to permit frequent measurement of the hemodynamic parameters in response to interventions. [ citation needed ]


Parameters obtainable from a right heart catheterization: [ citation needed ]


Coronary catheterization is an invasive process and comes with risks that include stroke, heart attack, and death. Like any procedure, the benefits should outweigh the risks and so this procedure is reserved for those with symptoms of serious heart diseases and is never used for screening purposes. Other, non-invasive tests are better used when the diagnosis or certainty of the diagnosis is not as clear. [ citation needed ]


Indications for cardiac catheterization include the following: [ 6 ]


Right heart catheterization, along with  pulmonary function testing  and other testing should be done to confirm  pulmonary hypertension  prior to having  vasoactive   pharmacologic treatments  approved and initiated. [ 7 ]


Placement of internal  pacemakers  and  defibrillators  are done through catheterization as well. An exception to this is placement of electrodes on the outer surface of the heart (called epicardial electrodes). Otherwise, electrodes are placed through the venous system into the heart and left there permanently. Typically, these devices are placed in the left upper chest and enter the left  subclavian vein  and electrodes are placed in the right atrium, right ventricle, and coronary sinus (for the left ventricle stimulation). [ citation needed ]


Echocardiography  is a non-invasive method to evaluate the heart valves. However, sometimes the valve pressure gradients need to be measured directly because echo is equivocal for the severity of valve disease. Invasive assessment of the valve can be done with catheterization by placing a catheter across the valve and measuring the pressures simultaneously on each side of the valve to obtain the pressure gradient. [ 8 ]  In conjunction with a right heart catheterization, the valve area can be estimated. For example, in  aortic valve area calculation  the Gorlin equation can be used to calculate the area if the cardiac output, pressure gradient, systolic period, and heart rate are known. [ citation needed ]


Evaluation of the blood flow to the lungs can be done invasively through catheterization. Contrast is injected into the pulmonary trunk, left or right pulmonary artery, or segment of the pulmonary artery. [ citation needed ]


Cardiac shunts  can be evaluated through catheterization. Using oxygen as a marker, the  oxygen saturation  of blood can be sampled at various locations in and around the heart. For example, a left-to-right  atrial septal defect  will show a marked increase in oxygen saturation in the right atrium, ventricle, and pulmonary artery as compared to the  mixed venous oxygen saturation  from the oxygenated blood from the lungs mixing into the venous return to the heart. Utilizing the  Fick principle , the ratio of blood flow in the lungs (Qp) and system circulations (Qs) can calculate the Qp:Qs ratio. Elevation of the Qp:Qs ratio above 1.5 to 2.0 suggests that there is a hemodynamically significant left-to-right shunt (such that the blood flow through the lungs is 1.5 to 2.0 times more than the systemic circulation). This ratio can be evaluated non-invasively with  echocardiography  too, however. [ citation needed ]


A "shunt run" is often done when evaluating for a shunt by taking blood samples from  superior vena cava  (SVC),  inferior vena cava  (IVC),  right atrium ,  right ventricle ,  pulmonary artery , and system arterial. Abrupt increases in oxygen saturation support a left-to-right shunt and lower than normal systemic arterial oxygen saturation supports a right-to-left shunt. Samples from the SVC & IVC are used to calculate  mixed venous oxygen saturation . [ citation needed ]


By injecting contrast into the left ventricle, the outline of the ventricle can be measured in both systole and diastole to estimate the  ejection fraction  (a marker of heart function). Due to the high contrast volumes and injection pressures, this is often not performed unless other, non-invasive methods are not acceptable, not possible, or conflicting. [ citation needed ]


Advancements in cardiac catheterization have permitted replacement of heart valves by means of blood vessels. This method allows  valve replacement  without  open heart surgery  and can be performed on people who are high-risk for such a surgery. [ citation needed ]


Catheterization can also be used to perform  balloon septostomy , which is the widening of a  foramen ovale ,  patent foramen ovale  ( PFO ), or  atrial septal defect  ( ASD ) using a  balloon catheter . This can be done in certain congenital heart diseases in which the mechanical shunting is required to sustain life such as in  transposition of the great vessels . [ citation needed ]


Hypertrophic cardiomyopathy  is a disease in which the myocardium is thickened and can cause blood flow obstruction. If hemodynamically significant, this excess muscle can be removed to improve blood flow. Surgically, this can be done with  septal myectomy . However, it can be done through catheterization and by injecting  ethanol  to destroy the tissue in an  alcohol septal ablation . This is done by selected an appropriate septal artery supplying the intended area and, essentially, causing a localized, controlled  myocardial infarction  of the area with ethanol. [ citation needed ]


Complications of cardiac catheterization and tools used during catheterization include, but not limited to: [ citation needed ]


The likelihood of these risks depends on many factors that include the procedure being performed, the overall health state of the patient, situational (elective vs emergent), medications (e.g.,  anticoagulation ), and more. [ citation needed ]


"Cardiac catheterization" is a general term for a group of procedures. Access to the heart is obtained through a peripheral artery or vein. Commonly, this includes the  radial artery ,  internal jugular vein , and  femoral artery / vein . Each blood vessel has its advantages and disadvantages. Once access is obtained, plastic catheters (tiny hollow tubes) and flexible wires are used to navigate to and around the heart. Catheters come in numerous shapes, lengths, diameters, number of lumens, and other special features such as electrodes and balloons. Once in place, they are used to measure or intervene. Imaging is an important aspect to catheterization and commonly includes fluoroscopy but can also include forms of  echocardiography  ( TTE ,  TEE ,  ICE ) and ultrasound ( IVUS ). [ citation needed ]


Obtaining access uses the  Seldinger technique  by puncturing the vessel with a needle, placing a wire through the needle into the lumen of the vessel, and then exchanging the needle for a larger plastic sheath. Finding the vessel with a needle can be challenging and both ultrasound and fluoroscopy can be used to aid in finding and confirming access. Sheaths typically have a side port that can be used to withdraw blood or injection fluids/medications, and they also have an end hole that permits introducing the catheters, wires, etc. coaxially into the blood vessel. [ citation needed ]


Once access is obtained, what is introduced into the vessel depends on the procedure being performed. Some catheters are formed to a particular shape and can really only be manipulated by inserting/withdrawing the catheter in the sheath and rotating the catheter. Others may include internal structures that permit internal manipulation (e.g.,  intracardiac echocardiography ). [ citation needed ]


Finally, when the procedure is completed, the catheters are removed and the sheath is removed. With time, the hole made in the blood vessel will heal.  Vascular closure devices  can be used to speed along hemostasis.


Much equipment is required for a facility to perform the numerous possible procedures for cardiac catheterization.


General: [ citation needed ]


Percutaneous coronary intervention: [ citation needed ]


Electrophysiology: [ citation needed ]


The history of cardiac catheterization dates back to  Stephen Hales  (1677-1761) and  Claude Bernard  (1813-1878), who both used it on animal models. Clinical application of cardiac catheterization begins with Dr.  Werner Forssmann  in 1929, who inserted a catheter into the vein of his own forearm, guided it fluoroscopically into his right atrium, and took an  X-ray  picture of it. [ 9 ]  However, even after this achievement, hospital administrators removed Forssmann from his position owing to his unorthodox methods. [ 9 ]
During  World War II ,  André Frédéric Cournand , a physician at  NewYork-Presbyterian/Columbia , then Columbia-Bellevue, opened the first catheterization lab. In 1956, Forssmann and Cournand were co-recipients of the Nobel Prize in Physiology or Medicine for the development of cardiac catheterization.
Dr.  Eugene A. Stead  performed research in the 1940s, which paved the way for cardiac catheterization in the USA. [ citation needed ]


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 . [ 1 ] [ 2 ] [ 3 ]


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 ). [ 4 ] [ 5 ]  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 MVO 2 ). This may be explained by the beneficial effect the therapy has in improving cardiac efficiency. [ 6 ] [ 7 ] [ 8 ]  A meta-analysis in 2014 [ 2 ]  and an overview of device-based treatment options in heart failure in 2013 [ 9 ]  concluded that cardiac contractility modulation treatment is safe, [ 1 ] [ 9 ]  that it is generally beneficial to patients [ 1 ] [ 9 ]  and that the treatment increases the  exercise tolerance  (ET) and  quality of life  (QoL) of patients. [ 2 ]  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. [ 10 ]


Based on the results of the pivotal FIX-HF-5C trial, [ 11 ]  the FDA approved cardiac contractility modulation therapy for use in the United States on March 21, 2019. [ 12 ]


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, [ 3 ] [ 13 ]  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. [ 1 ] [ 2 ] [ 3 ] [ 14 ]


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. [ 2 ] [ 15 ]


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%. [ 1 ] [ 16 ]


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. [ 3 ] [ 17 ] [ 18 ]


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). [ 19 ]


Cardiac resynchronization therapy (CRT; also known as biventricular pacing) has proven to be an effective treatment in heart failure. [ 20 ]  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  (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. [ 20 ]  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. [ 2 ] [ 15 ] [ 17 ]


Until recently, the only other available device-based treatment was the  left ventricular assist device  (LVAD). LVAD therapy is indicated in patients with severe illness and is associated with several hours of surgery (involving a  cardiopulmonary bypass ). 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  is received. [ 2 ] [ 15 ] [ 17 ]  Current research results suggest that the therapeutic gap described above could now be closed by the cardiac contractility modulation therapy. [ 2 ] [ 15 ] [ 17 ]  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. [ 21 ]


The  guidelines  issued by the  European Society of Cardiology  (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. [ 20 ] [ 22 ]


Cardiac contractility modulation has proven to be effective and safe in randomized controlled trials involving several hundred patients. [ 23 ] [ 24 ] [ 25 ]


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. [ 3 ] [ 17 ]


To date (February 2015), there are at least two meta-analyses studying the efficacy of cardiac contractility modulation therapy on heart failure, [ 2 ] [ 26 ]  a large number of review articles (e.g. [ 3 ] [ 17 ] [ 18 ] [ 27 ] [ 28 ] ) and at least two survey articles on device-based treatments of advanced heart failure [ 1 ] [ 15 ]  which address cardiac contractility modulation. Furthermore, there are more than 70 individual publications focusing specifically on cardiac contractility modulation therapy. [ 29 ]


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. [ 3 ] [ 14 ] [ 17 ]


Giallauria et al. evaluated the three  randomized controlled trials  (RCTs) currently available on cardiac contractility modulation as a treatment for heart failure patients. [ 2 ] [ 23 ] [ 24 ]  The three trials included a total of 641 patients and assessed the effect of cardiac contractility modulation either in comparison to a sham treatment [ 23 ] [ 24 ]  or in comparison to the best medical treatment. [ 25 ]  In contrast to an earlier meta-analysis by Kwong et al. [ 26 ]  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, [ 30 ]  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. [ citation needed ]


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. [ citation needed ]


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. [ 10 ]  Kuschyk et al. evaluated the long-term efficacy and survival of patients with cardiac contractility modulation. [ 10 ]  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 [ 31 ] [ 32 ]  which is based on the records of over 39,000 heart failure patients. Unlike a previous long-term outcome study of cardiac contractility modulation, [ 33 ]  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  (BNP) levels. Mortality rates were significantly lower than predicted at year 1, and lower than predicted but not statistically significant at year 3. [ citation needed ]


Heart failure is a chronic disease that usually progresses gradually. [ 20 ]  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. [ citation needed ]


According to large implanting clinics, after the implantation wound is healed, the lifestyle of a patient is not restricted by the implanted device. [ 34 ]  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. [ citation needed ]


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 . 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. [ 35 ]  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. [ 35 ]  Following these study results the new generation was developed and can now offer cardiac contractility modulation therapy also for patients with atrial fibrillation. [ citation needed ]


Other irregular rhythms, including frequent  premature ventricular contractions  (ventricular extra systoles) or a distinct signal transduction disorder in the heart (untreated  AV block  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. [ 9 ] [ 20 ]


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  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 , for example  VVI pacemakers , in the case of 100% stimulation, are also contraindicated. [ 9 ]


The most frequently encountered adverse events related to cardiac contractility modulation therapy are lead fracture or lead dislodgement. [ 25 ]  Other reported complications include:


These side effects are similar to those that occur with other electrical stimulation therapies, such as pacemakers, CRT devices or ICD devices. [ 30 ]  Furthermore, recorded complications did not differ between patients with activated or deactivated cardiac contractility modulation devices. [ 17 ]


Overall, cardiac contractility modulation treatment was demonstrated to have no negative impact on health markers. [ 17 ]


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.


The  mechanism of action  of cardiac contractility modulation has been subject to continuous research since its initial discovery. Based on  animal testing  and experiments on human myocardial tissue obtained by  biopsies , essential parts of the mechanism of action have been identified. [ 4 ] [ 39 ]  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  and  gene expression , which are typically abnormal in heart failure, improve towards their normal state. [ 39 ]  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. [ 39 ]  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. [ 3 ] [ 4 ] [ 5 ] [ 18 ] [ 40 ] [ 41 ]


Development of cardiac contractility modulation began in the late 1990s. [ 42 ] [ 43 ]  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. [ 44 ] [ 45 ]  In 2001, scientists observed that a similar effect occurs even if the voltage is applied exclusively outside the cardiac muscle cells. [ 46 ]  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. [ 47 ] [ 48 ]


An implantable cardiac contractility modulation device was received by a patient for the first time in 2001. [ 49 ] [ 50 ]  The first study on the therapeutic effects of in humans was presented in 2004. [ 51 ]  To date, more than 3,000 heart failure patients have been treated with cardiac contractility modulation worldwide, [ 13 ]  including 641 patients under the study conditions recommended by the  Cochrane Collaboration  as being necessary for inclusion in a meta-analysis. [ 2 ]  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.


Cardiac magnetic resonance imaging perfusion  ( cardiac MRI perfusion ,  CMRI perfusion ), also known as  stress CMR perfusion , [ 1 ]  is a clinical  magnetic resonance imaging  test performed on patients with known or suspected  coronary artery disease  to determine if there are perfusion defects in the  myocardium  of the  left ventricle  that are caused by narrowing of one or more of the  coronary arteries .


CMR perfusion is increasingly used in cardiac imaging to test for inducible myocardial ischaemia and has been well validated against other imaging modalities such as invasive angiography [ 2 ] [ 3 ]  or FFR. Several recent large-scale studies have shown non-inferiority or superiority to  SPECT  imaging. It is becoming increasingly established as a marker of prognosis in patients with coronary artery disease. [ 4 ] [ 5 ]


There are two main reasons for doing this test: [ citation needed ]


In contrast to the nuclear imaging modalities ( PET  and  SPECT ), CMR perfusion does not involve the use of ionising radiation and can therefore be used multiple times without the risk to the patient of exposure to radiation. [ citation needed ]


It is a non-invasive test, is generally regarded as a safe (see below) procedure and is well tolerated by patients (apart from people with claustrophobia) [ citation needed ]


The majority of scans are performed using a stress/rest protocol using adenosine as the stressor which acts to induce ischaemia in the myocardium by the coronary 'steal' phenomenon. Some centers use inotrope dobutamine to stress the heart and the images are interpreted in a similar fashion to  dobutamine stress echocardiogram . This article concentrates on adenosine stress scans. [ citation needed ]


An intravenous infusion of  adenosine  is given at 140 μg/Kg/min for 3 minutes with continuous heart rate and blood pressure recording to induce  hyperaemia  (normally seen as a drop in systolic blood pressure of 10mmHg or a rise in heart rate of 10bpm). Following this, an intravenous bolus of 0.05 mmol/kg of a  gadolinium  chelate (such as gadodoteric acid) is administered via an antecubital fossa vein on the contralateral arm to the adenosine. [ citation needed ]


Typically, 3 short axis slices, each of 10mm thickness, are acquired per cardiac cycle, at the basal, mid papillary and apical levels of the left ventricle. A single shot prospectively gated, balanced TFE sequence is used with a typical resolution of 2.5 x 2.5mm. The patient is then allowed to rest until the haemodynamic effects of the adenosine have stopped (typically 5 minutes). The same scan protocol is then performed at rest. [ citation needed ]


The images are stored as video files and are analysed on a dedicated workstation. The majority of clinical scans are analysed qualitatively by visually comparing the stress and rest scans in parallel. In a normal scan, the wash in (1st pass) of gadolinium into the myocardium can be seen as the myocardium turning from black to mid grey uniformly throughout the whole of the left ventricle in both the stress and rest scans. In an abnormal scan an area of the myocardium will turn grey slower than the surrounding tissue as the blood (and hence gadolinium) enters more slowly due to a narrowing of the coronary artery supplying it. This is called a perfusion defect and usually represents myocardial ischaemia. It may be seen on both the rest and stress scans in which case it is called a matched perfusion defect and is probably due to an area or scar from a previous myocardial infarction. If it is only seen on the stress scan it is called an area of inducible perfusion defect (ischaemia). The position in the left ventricle of the perfusion defects are described using the AHA 17 segment model. [ 6 ]


Stress CMR cannot be performed on all patients due to the relative or absolute contraindications listed below, this is a problem, especially in patients who either have a pacemaker or severe renal failure. [ citation needed ]


The acquisition of the images is very sensitive to the rhythm of the heart and scans of patients with atrial fibrillation, bigeminy or trigeminy will sometimes be of low quality and may not be interpretable. [ citation needed ]


Due to the high contrast between the blood pool and the myocardium it is common to get what looks like a thin subendocardial area of ischaemia called the  Gibbs artifact , this however, is less common with newer technology allowing higher resolution imaging. [ citation needed ]


In patients who have had a previous myocardial infarction or previous coronary artery bypass surgery, the images may be very difficult to interpret and in such cases, the analysis of the scans is performed with the complement of another imaging modality (such as coronary angiography). [ citation needed ]


It is a non-invasive test as is generally regarded as safe however, there are some patients for whom this is contraindicated and there are a number of potential complications: [ citation needed ]


Contraindications are as follows: [ citation needed ]


It is common for the patient to get a number of mild symptoms when they are given the Adenosine infusion, such as feeling hot and sweaty, short of breath, nauseous and noticing that their heart is beating faster. These, if they occur, resolve rapidly (normally within 60 seconds) after the Adensoine infusion has stopped. [ citation needed ]


There are a number of more serious and much less common side effects, including transient heart block, bronchoconstriction and a 1 in 10,000 risk of  anaphylaxis  caused by the gadolinium contrast agent. These can invariably be successfully treated with no long term side effects. [ citation needed ]


Adenosine infusion is associated with some very rare but very serious side effects, including acute  pulmonary oedema  and  cardiac arrest  (occurring in ≈1 in 1000 patients). [ citation needed ]


Cardioversion  is a  medical procedure  by which an abnormally fast  heart rate  ( tachycardia ) or other  cardiac arrhythmia  is converted to a  normal rhythm  using  electricity  or  drugs .


Synchronized electrical cardioversion  uses a therapeutic dose of  electric current  to the  heart  at a specific moment in the  cardiac cycle , restoring the activity of the  electrical conduction system of the heart . ( Defibrillation  uses a therapeutic dose of  electric current  to the  heart  at a random moment in the  cardiac cycle , and is the most effective resuscitation measure for  cardiac arrest  associated with  ventricular fibrillation  and pulseless  ventricular tachycardia . [ 1 ] )  Pharmacologic cardioversion , also called  chemical cardioversion ,  uses  antiarrhythmia medication  instead of an electrical shock. [ 2 ]


To perform synchronized electrical cardioversion, two  electrode  pads are used (or, alternatively, the traditional hand-held "paddles"), each comprising a metallic plate which is faced with a saline based conductive gel.  The pads are placed on the chest of the patient, or one is placed on the chest and one on the back.  These are connected by cables to a machine which has the combined functions of an  ECG  display screen and the electrical function of a  defibrillator . A synchronizing function (either manually operated or automatic) allows the cardioverter to deliver a reversion shock, by way of the pads, of a selected amount of  electric current  over a predefined number of  milliseconds  at the optimal moment in the  cardiac cycle  which corresponds to the R wave of the  QRS complex  on the  ECG .


Timing the shock to the R wave prevents the delivery of the shock during the vulnerable period (or relative refractory period) of the  cardiac cycle , which could induce  ventricular fibrillation .  If the patient is conscious, various drugs are often used to help sedate the patient and make the procedure more tolerable.  However, if the patient is hemodynamically unstable or unconscious, the shock is given immediately upon confirmation of the  arrhythmia . When synchronized electrical cardioversion is performed as an elective procedure, the shocks can be performed in conjunction with drug therapy until  sinus rhythm  is attained. After the procedure, the patient is monitored to ensure stability of the sinus rhythm.


Synchronized electrical cardioversion is used to treat hemodynamically unstable supraventricular (or narrow complex)  tachycardias , including  atrial fibrillation  and  atrial flutter . It is also used in the emergent treatment of wide complex tachycardias, including  ventricular tachycardia , when a pulse is present. Pulseless  ventricular tachycardia  and  ventricular fibrillation  are treated with unsynchronized shocks referred to as  defibrillation . Electrical therapy is inappropriate for  sinus tachycardia , which should always be a part of the  differential diagnosis .


Various  antiarrhythmic agents  can be used to return the heart to normal  sinus rhythm . [ 3 ]  Pharmacological cardioversion is an especially good option in patients with atrial fibrillation of recent onset. Drugs that are effective at maintaining normal rhythm after electric cardioversion can also be used for pharmacological cardioversion. Drugs like  amiodarone ,  diltiazem ,  verapamil  and  metoprolol  are frequently given before electrical cardioversion to decrease the heart rate, stabilize the patient and increase the chance that cardioversion is successful. There are various classes of agents that are most effective for pharmacological cardioversion.


Class I agents are sodium (Na) channel blockers (which slow conduction by blocking the Na+ channel) and are divided into 3 subclasses a, b and c. Class Ia slows phase 0 depolarization in the ventricles and increases the absolute refractory period.  Procainamide ,  quinidine  and  disopyramide  are Class Ia agents. Class 1b drugs lengthen phase 3 repolarization. They include  lidocaine ,  mexiletine  and  phenytoin . Class Ic greatly slow phase 0 depolarization in the ventricles (however unlike 1a have no effect on the refractory period).   Flecainide ,  moricizine  and  propafenone  are Class Ic agents.
 [ 4 ]


Class II agents are beta blockers which inhibit SA and AV node depolarization and slow heart rate. They also decrease cardiac oxygen demand and can prevent cardiac remodeling. Not all beta blockers are the same; some are cardio selective (affecting only beta 1 receptors) while others are non-selective (affecting beta 1 and 2 receptors). Beta blockers that target the beta-1 receptor are called cardio selective because beta-1 is responsible for increasing heart rate; hence a beta blocker will slow the heart rate.


Class III agents (prolong repolarization by blocking outward K+ current):  amiodarone  and  sotalol  are effective class III agents.  Ibutilide  is another Class III agent but has a different mechanism of action (acts to promote influx of sodium through slow-sodium channels). It has been shown to be effective in acute cardioversion of recent-onset atrial fibrillation and atrial flutter.


Class IV drugs are calcium (Ca) channel blockers. They work by inhibiting the action potential of the SA and AV nodes.


If the patient is stable,  adenosine  may be used for restoration of sinus rhythm in patients with macro-reentrant supraventricular tachycardias. It causes a short-lived cessation of conduction through the atrio-ventricular node breaking the circus movement through the node and the macro-reentrant pathway restoring sinus rhythm.


Cardioversion for restoration of sinus rhythm from an atrial rhythm is largely a scheduled procedure. In addition to cardiology, anesthesiology is also usually involved to ensure comfort of the patient for the duration of the shock therapy. The presence of registered nurses, physician associates, or other medical personnel may also be helpful during the procedure.


Before starting the procedure, the patient's chest and back will be prepped for electrode placement. The skin should be free of any oily substances (e.g., lotions) and hair which may otherwise interfere with adhesion of the pads. [ 5 ]  Once this is complete, the medical team will adhere the pads to the patient using a rolling motion to ensure the absence of air pockets.  (see details on pad placement below) . The anesthesiology team will then administer a general anesthetic (e.g.,  Propofol ) in order to ensure patient comfort and amnesia during the procedure. Opioid analgesics (e.g., Fentanyl) may be combined with Propofol, although anesthesiology must weight the benefits against adverse effects including apnea. [ 6 ]  Bite blocks and extremity restraints are then utilized to prevent self-injury during cardioversion. Once these medications are administered, the  glabellar reflex  or  eyelash reflex  may be used to determine the patient's level of consciousness.


The pads are connected to a machine that can interpret the patient's cardiac rate and rhythm and deliver a shock at the appropriate time. The machine should synchronize ('sync') with the  R wave  of the rhythm strip. Although uncommon, sometimes the machine will unintentionally sync to high amplitude T waves, so it is important to ensure that the machine is synced appropriately to R waves. [ 7 ]  Interpretation of the patient's rhythm is imperative when using cardioversion to restore sinus rhythm from less emergent arrhythmias where a pulse is present (e.g.,  atrial flutter ,  atrial fibrillation ). However, if a patient is confirmed to be in  pulseless ventricular tachycardia  "v-tach" or  ventricular fibrillation  "v-fib", then a shock is delivered immediately upon connection of the pads. In this application, electrical cardioversion is more properly termed  defibrillation . [ 7 ]


Once the machine is synced with the patient's cardiac rhythm, the machine must be charged. To determine the amount of energy (measured in joules "J") the patient requires, many factors are considered. As a rule of thumb, recent-onset atrial arrhythmias require less energy compared to persistent atrial arrhythmias. If the cardiologist suspects that the patient may be less respondent to cardioversion, a higher energy may be utilized. Once the machine is synced and charged, a shock can be delivered to the patient. [ 8 ]


Following electrical cardioversion, the cardiologist will determine if sinus rhythm has been restored. To confirm sinus rhythm, a distinct  P wave  should be seen preceding each QRS complex. Additionally, each  R-R interval  should be evenly spaced. If sinus rhythm is restored, the pads may be disconnected, and any other medical equipment is removed from the patients (e.g., bite blocks, restraints, etc.). The patient will regain consciousness soon thereafter (the effects of Propofol generally last for only 3–8 minutes). However, if the arrhythmia is persistent, the machine may be re-charged to a higher energy level, and the cardioversion attempt may be repeated. It is recommended to wait 60 seconds between subsequent cardioversion attempts, but this amount of time may be adjusted based on the patient and/or provider.


Pad placement for electrical cardioversion a cardiac arrhythmia may be either anterior-posterior or anterior-lateral. In an anterior-posterior setup one pad is placed on the chest and the other pad is placed on the back. In an anterior-lateral setup, one pad is placed on the chest and the other pad is placed along the left midaxillary line. Choosing the right pad placement can be an important aspect when measuring the success of electrical cardioversion. For example, the anterior-posterior pad positioning is commonly used when attempting to restore an atrial arrhythmia as the vector between the pads predominately runs through the atria. The anterior-lateral pad positioning may be used when attempting to restore pulseless ventricular tachycardia or ventricular fibrillation as there may not be enough time or strength to apply an electrode the patient's back.


The anterior pad should be placed inferior to the right clavicle while also being vertically centered over at the level of the right 4th intercostal space. The posterior pad should be placed just lateral to the left side of the spine and vertically centered at the level of T7. [ 12 ] [ 13 ]  The inferior angle of the scapula can be used as a reference for the level of T7.


The anterior pad should be placed inferior to the right clavicle while also being vertically centered over at the level of the right 4th intercostal space. The lateral pad should be placed along the left midaxillary line at the level of the left 5th intercostal space. [ 12 ] [ 13 ]  The left nipple can be used as a reference for the level of the left 4th intercostal space. From here, the midaxillary 5th intercostal space is identified by moving inferiorly one intercostal space and laterally towards the midaxillary line.


Catheter ablation  is a procedure that uses radio-frequency energy or other sources to terminate or modify a faulty electrical pathway from sections of the  heart  of those who are prone to developing  cardiac arrhythmias  such as  atrial fibrillation ,  atrial flutter  and  Wolff-Parkinson-White syndrome . If not controlled, such arrhythmias increase the risk of  ventricular fibrillation  and sudden  cardiac arrest . The ablation procedure can be classified by energy source:  radiofrequency ablation  and  cryoablation .


Catheter ablation may be recommended for a recurrent or persistent  arrhythmia  resulting in symptoms or other dysfunction.  Atrial fibrillation  frequently results from bursts of  tachycardia  that originate in muscle bundles extending from the  atrium  to the  pulmonary veins . [ 1 ]  Pulmonary vein isolation by transcatheter ablation can restore  sinus rhythm . [ 1 ]


Catheter ablation of most arrhythmias has a high success rate. Success rates for WPW syndrome have been as high as 95%  [ 2 ]  For  Supraventricular tachycardia  (SVT), single procedure success is 91% to 96% (95% Confidence Interval) and multiple procedure success is 92% to 97% (95% Confidence Interval). [ 3 ]  For atrial flutter, single procedure success is 88% to 95% (95% Confidence Interval) and multiple procedure success is 95% to 99% (95% Confidence Interval). [ 3 ]  For automatic atrial tachycardias, the success rates are 70–90%. [ citation needed ]  The potential complications include bleeding, blood clots, pericardial tamponade, and heart block, but these risks are very low, ranging from 2.6 to 3.2%.


For non-paroxysmal  atrial fibrillation , a 2016 systematic review compared catheter ablation to heart rhythm drugs. After 12 months, participants receiving catheter ablation were more likely to be free of atrial fibrillation, and less likely to need cardioversion. However, the evidence quality ranged from moderate to very low [ 4 ]  A 2006 study, including both paroxysmal and non-paroxysmal atrial fibrillation, found that the success rates are 28% for single procedures. Often, several procedures are needed to raise the success rate to a 70–80% range. [ 5 ]   One reason for this may be that once the heart has undergone atrial remodeling as in the case of chronic atrial fibrillation patients, largely 50 and older, it is much more difficult to correct the 'bad' electrical pathways. Young people with AF with paroxysmal, or intermittent, AF therefore have an increased chance of success with an ablation since their heart has not undergone atrial remodeling yet. [ citation needed ]  Several experienced teams of electrophysiologists in US heart centers claim they can achieve up to a 75% success rate. [ citation needed ]


Pulmonary vein isolation has been found to be more effective than optimized antiarrhythmic drug therapy for improving quality of life at 12 months after treatment. [ 6 ]


Catheter ablation has been found to improve mental health outcomes in individuals with symptomatic atrial fibrillation. [ 7 ]


A 2018 study showed efficacy of cardiac ablation for treatment of  Premature Ventricular Contraction  as 94.1%. [ 8 ]


Catheter ablation is usually performed by an  electrophysiologist  (a specially trained  cardiologist ) in a  cath lab . [ citation needed ]


Catheter ablation procedure involves advancing several flexible  catheters  into the patient's  blood vessels , usually either in the  femoral vein , internal jugular vein, or  subclavian vein . The catheters are then advanced towards the heart. The catheters have electrodes at the tips that can measure the electrical signals from the heart. These electrodes create a map of the abnormal pathways causing arrhythmias. Then, the electrophysiologist uses the map to identify areas from which abnormal heart rhythms originate. [ 9 ]


Once the abnormal areas are located, catheters are used to deliver energy via local heating or freezing to  ablate  (destroy) the abnormal tissue that is causing the arrhythmia. The energy is applied cautiously to avoid damaging healthy heart tissue. [ 9 ]  Originally, a  DC  impulse was used to create lesions in the intra-cardiac conduction system. [ 10 ]  However, due to a high incidence of complications, widespread use was never achieved.


In contrast to the thermal methods (extreme heat or cold)  electroporation  is being used and evaluated as a means of killing very small areas of heart muscle. The cardiac catheter delivers trains of high-voltage ultra-rapid electrical pulses that form irreversible pores in cell membranes, resulting in cell death of cardiac muscle, while not killing adjacent tissues ( esophagus  and  phrenic nerve ). [ 11 ]  It is thought to allow better selectivity than the previous thermal techniques, which used heat or cold to kill larger volumes of muscle. [ 12 ]


One type of catheter ablation is pulmonary vein isolation, where the ablation is done in the left atrium in the area where the 4 pulmonary veins connect. [ 13 ] [ 14 ]   Radiofrequency ablation for atrial fibrillation can be unipolar (one electrode) or bipolar (two electrodes). [ 15 ]  Although bipolar can be more successful, it is technically more difficult, resulting in unipolar being used more often. [ 15 ]  But bipolar is more effective in preventing recurrent atrial arrhythmias. [ 16 ]


During the procedure, the patient's heart rhythm is monitored continuously. The electrophysiologist can observe changes to the patient's cardiac electrical activity to determine the success of the ablation. If the cardiac rhythm shows no abnormal signals or arrhythmias, the catheters are withdrawn from the heart and the incision is closed.


After catheter ablation the patients are moved to a cardiac recovery unit, intensive care unit, or  cardiovascular intensive care unit  where they are not allowed to move for 4–6 hours.  Minimizing movement helps prevent bleeding from the site of catheter insertion.  Some people have to stay overnight for observation, some need to stay much longer and others are able to go home on the same day. This all depends on the problem, the length of the operation and whether or not  general anaesthetic  was used. [ citation needed ]


Recurrence of atrial fibrillation within three months of an ablation is seen in most patients, but many of those patients become free of atrial fibrillation in the long term. [ 17 ]  For this reason the first three months after an ablation are described as the "blanking period," during which no further intervention is to be attempted. [ 17 ]  Recurrence during the nine months following the blanking period, occurs in 25% to 40% of patients, the variability greatly affected by obesity and the severity of atrial fibrillation before the ablation. [ 17 ]


Some potential complications associated with the procedure include: [ 18 ]


Patients may also experience a return of the arrhythmia after the procedure, requiring them to undergo further treatment. However, in general this procedure is considered a safe, effective, and minimally invasive method to treat arrhythmias. Studies have shown that the overall complication rate of cardiac ablation procedures is about 6%. [ medical citation needed ]


A  catheterization laboratory , commonly referred to as a  cath lab , is an examination room in a hospital or clinic with  diagnostic imaging  equipment used to visualize the arteries of the heart and the chambers of the  heart  and treat any  stenosis  or abnormality found.


Most catheterization laboratories are "single plane" facilities, those that have a single  X-ray  generator source and an  X-ray image intensifier  for  fluoroscopic  imaging. [ 1 ]  Older cath labs used  cine film  to record the information obtained, but since 2000, most new facilities are  digital . The latest digital cath labs are biplane (have two X-ray sources) and use  flat panel detectors . [ 2 ]


Cardiac catheterization laboratories are usually staffed by a multidisciplinary team. This may include a medical practitioner (normally either a consultant  cardiologist  or  radiologist ), cardiac  physiologist ,  radiographer  and  nurse . [ 3 ] [ 4 ]


The consultant cardiologist is responsible for gaining arterial access, inserting a sheath into either the  radial  or  femoral artery , passing a wire and  catheter  into the coronary artery and selectively injecting  contrast media  into the coronary arteries. They then interpret the images taken to ascertain where the narrowed or blocked artery has the problem. They use a variety of techniques and imaging tools to measure the size of things such as balloons and  stents .


Cardiac physiologists usually set up what is known as a  transducer  to monitor pressure in the arteries. They also have a live view of the patients  ECG  so they can tell whether or not there is a problem caused by the insertion of the catheter into the heart to the electrical pathways. [ 5 ] [ 6 ]  The physiologist will also set up a temporary pacemaker if the procedure is an angioplasty or a  percutaneous coronary intervention  (PCI). Finally, they also set up  defibrillators  on to the patient for emergency use if needed. In some locations, some of these responsibilities may be carried out by other personnel, such as trained nurses or technologists. [ 7 ]


Cardiac catheterization  is a general term for a group of procedures that are performed in the cath lab, such as  coronary angiography . Once a catheter is in place, it can be used to perform a number of procedures including  angioplasty , PCI ( percutaneous coronary intervention ) angiography,  transcatheter aortic valve replacement ,  balloon septostomy , and an  electrophysiology study  or  catheter ablation . Devices such as  pacemakers  may be fitted or  rotablation  to remove plaque can be performed. [ 8 ] [ 9 ]


Cellular cardiomyoplasty , or cell-based cardiac repair, is a new potential therapeutic modality in which  progenitor cells  are used to repair regions of damaged or necrotic myocardium. The ability of transplanted progenitor cells to improve function within the failing heart has been shown in experimental animal models and in some human clinical trials. [ 1 ]  In November 2011, a large group of collaborators at Minneapolis Heart Institute Foundation at Abbott Northwestern found no significant difference in  left ventricular ejection fraction  (LVEF) or other markers, between a group of patients treated with cellular  cardiomyoplasty  and a group of control patients. [ 2 ]  In this study, all patients were post MI, post  percutaneous coronary intervention  (PCI) and that infusion of progenitor cells occurred 2–3 weeks after intervention. In a study that is currently underway (February 2012), however, more positive results were being reported: In the SCIPIO trial, patients treated with  autologous  cardiac stem cells post MI have been reported to be showing statistically significant increases in LVEF and reduction in infarct size over the control group at four months after implant. Positive results at the one-year mark are even more pronounced. [ 3 ]
Yet the SCIPIO trial "was recently called into question". [ 4 ] [ 5 ]  Harvard University is "now investigating the integrity of some of the data". [ 4 ]  The Lancet recently published a non-specific ‘Expression of concern’ about the paper. [ 6 ]
Subsequently, another preclinical study also raised doubts on the rationale behind using this special kind of cell, [ 7 ]  as it was found that the special cells only have a minimal ability in generating new cardiomyocytes. [ 8 ]  Some specialists therefore now raise concerns to continue. [ 8 ]


To date, the ideal progenitor cells have not been found or created. With the goal of recreating human tissue, the use of embryonic stem cells (ESC) was the initial logical choice. These pluripotent cells can conceptually give rise to any  somatic cell  line in the human body and while animal studies have shown restoration of cardiac function, immunologic rejection issues and  teratoma  formation have rendered ESC's a high risk. [ 9 ] [ 10 ]


Human-induced pluripotent stem cells (iPSCs) are a cell line derived from somatic cells which have been induced through a combination of  transcription factors . The iPSC line is very similar or identical to ESCs in many regards and also shows great promise in cardiac potential. [ 11 ]  This cell line, however, is also less than ideal in that this cell type has been unable to mature into a  homogeneous  cell culture, making it  immunogenic  and  teratogenic . [ 12 ]
A third cell line that shows great promise and has no known safety concerns is the  adult stem cell  derived from bone marrow or from cardiac tissue explants. It has been shown in several studies that adult stem cells do have cardiogenic potential. [ 13 ] [ 14 ] [ 15 ]


Presently, the success of adult stem cells in regenerating human myocardium is just a fraction of what it could be. Three major challenges have been observed. Adult stem cells exhibit a minimal [ clarification needed ]  commitment to engraft into the damaged myocardium, they have low survival rates and they have limited proliferation. [ 16 ]  The positive effects observed in clinical trials today are a result of the work of donated stem cells that persist in the damaged myocardium for just days to weeks after delivery. Clearly, if cell survival is prolonged, these effects could be greatly enhanced. [ citation needed ]  This is where a majority of research is being done today and several methodologies hold great promise. [ 17 ]
 [ 18 ]


A  coronary catheterization  is a  minimally invasive  procedure to access the  coronary circulation  and blood filled chambers of the  heart  using a  catheter . It is performed for both diagnostic and interventional (treatment) purposes.


Coronary catheterization is one of the several  cardiology diagnostic tests and procedures . Specifically, through the injection of a liquid  radiocontrast agent  and illumination with  X-rays , [ 1 ]  angiocardiography allows the recognition of  occlusion ,  stenosis ,  restenosis ,  thrombosis  or  aneurysmal  enlargement of the  coronary artery   lumens ;  heart chamber  size;  heart muscle  contraction performance; and some aspects of  heart valve  function. Important internal  heart  and  lung   blood pressures , not measurable from outside the body, can be accurately measured during the test. The relevant problems that the test deals with most commonly occur as a result of advanced  atherosclerosis  –  atheroma  activity within the wall of the coronary  arteries . Less frequently,  valvular ,  heart muscle , or  arrhythmia  issues are the primary focus of the test.


Coronary artery  luminal  narrowing  reduces the flow reserve for oxygenated blood to the heart, typically producing intermittent  angina . Very advanced luminal  occlusion  usually produces a  heart attack . However, it has been increasingly recognized, since the late 1980s, that coronary catheterization does not allow the recognition of the presence or absence of coronary  atherosclerosis  itself, only significant luminal changes which have occurred as a result of end stage complications of the  atherosclerotic  process. See  IVUS  and  atheroma  for a better understanding of this issue.


The technique of angiography itself was first developed in 1927 by the Portuguese physician  Egas Moniz  at the  University of Lisbon  for  cerebral angiography , the viewing of brain vasculature by X-ray radiation with the aid of a contrast medium introduced by catheter. [ citation needed ]


Heart catheterization was first performed in 1929 when the German physician  Werner Forssmann  inserted a plastic tube in his  cubital vein  and guided it to the right chamber of the heart. He took an x-ray to prove his success and published it on November 5, 1929, with the title "Über die Sondierung des rechten Herzens" (About probing of the right heart). [ citation needed ]


In the early 1940s,  André Cournand , in collaboration with  Dickinson Richards , performed more systematic measurements of the hemodynamics of the heart. For their work in the discovery of cardiac catheterization and hemodynamic measurements, Cournand, Forssmann, and Richards shared the Nobel Prize in Physiology or Medicine in 1956. The first radial access for angiography can be traced back to 1953, where  Eduardo Pereira [ clarification needed ] , in Lisbon, Portugal, first cannulated the radial artery to perform a coronary angiogram.


In 1960  F. Mason Sones , a pediatric cardiologist at the  Cleveland Clinic , accidentally injected radiocontrast in a coronary artery instead of the left ventricle. Although the patient had a reversible cardiac arrest, Sones and Shirey developed the procedure further, and are credited with the discovery (Connolly 2002); they published a series of 1,000 patents in 1966 (Proudfit  et al. ).


Since the late 1970s, building on the pioneering work of  Charles Dotter  in 1964 and especially  Andreas Gruentzig  starting in 1977, coronary catheterization has been extended to therapeutic uses: (a) the performance of less invasive physical treatment for  angina  and some of the complications of severe  atherosclerosis , (b) treating  heart attacks  before complete damage has occurred and (c) research for better understanding of the pathology of  coronary artery disease  and  atherosclerosis . [ citation needed ]


In the early 1960s, cardiac catheterization frequently took several hours and involved significant complications for as many as 2–3% of patients. With multiple incremental improvements over time, simple coronary catheterization examinations are now commonly done more rapidly and with significantly improved outcomes. [ citation needed ]


Indications for cardiac catheterization include the following:


The  patient  being examined or treated is usually awake during catheterization, ideally with only  local anaesthesia  such as  lidocaine  and minimal general  sedation , throughout the  procedure . Performing the procedure with the patient awake is safer as the patient can immediately report any discomfort or problems and thereby facilitate rapid correction of any undesirable events. Medical monitors fail to give a comprehensive view of the patient's immediate well-being; how the patient feels is often a most reliable indicator of procedural safety. [ citation needed ]


Death,  myocardial infarction ,  stroke , serious  ventricular arrhythmia , and major vascular complications each occur in less than 1% of patients undergoing catheterization. [ 4 ]  However, though the imaging portion of the examination is often brief, because of setup and safety issues, the patient is often in the lab for 20–45 minutes. Any of multiple technical difficulties, while not endangering the patient (indeed added to protect the patient's interests), can significantly increase the examination time. [ citation needed ]


Coronary catheterization is performed in a catheterization lab, usually located within a hospital. With current designs, the patient must lie relatively flat on a narrow, minimally padded,  radiolucent  (transparent to  X-ray ) table. The X-ray source and imaging camera equipment are on opposite sides of the patient's chest and freely move, under motorized control, around the patient's chest so images can be taken quickly from multiple angles. More advanced equipment, termed a bi-plane cath lab, uses two sets of X-ray source and imaging cameras, each free to move independently, which allows two sets of images to be taken with each injection of radio contrast agent . The equipment and installation setup to perform such testing typically represents a capital expenditure of US$2–5 million (2004), sometimes more, partially repeated every few years. [ citation needed ]


During coronary catheterization (often referred to as a "cath" or "cardiac cath" by physicians),  blood pressures  are recorded and  fluoroscopy  ( X-ray   motion picture ) shadow-grams of the blood inside the  coronary arteries  are recorded. In order to create the X-ray pictures, a  physician  guides a small tube-like device called a catheter, typically ~2.0 mm (6-French) in diameter, through the large arteries of the body until the tip is just within the opening of one of the  coronary arteries . By design, the catheter is smaller than the lumen of the  artery  it is placed in; internal (intra-arterial) blood pressures are monitored through the  catheter  to verify that the catheter does not block blood flow (as indicated by "dampening" of the blood pressure). [ citation needed ]


The catheter is itself designed to be  radiodense  for visibility and it allows a clear, watery, blood compatible radiocontrast agent, commonly called an X-ray dye, to be selectively injected and mixed with the blood flowing within the artery. Typically 3–8 cc of the radiocontrast agent is injected for each image to make the  blood flow  visible for about 3–5 seconds as the radiocontrast agent is rapidly washed away into the coronary  capillaries  and then coronary  veins . Without the X-ray dye injection, the blood and surrounding heart  tissues  appear, on X-ray, as only a mildly-shape-changing, otherwise uniform water density mass; no details of the blood and internal organ structure are discernible. The radiocontrast within the blood allows visualization of the blood flow within the arteries or heart chambers, depending on where it is injected. [ citation needed ]


If  atheroma , or  clots , are protruding into the lumen, producing  narrowing , the narrowing may be seen instead as increased haziness within the X-ray shadow images of the blood/dye column within that portion of the artery; this is as compared to adjacent, presumed healthier, less  stenotic  areas.


For guidance regarding catheter positions during the examination, the physician mostly relies on detailed knowledge of internal anatomy, guide wire and catheter behavior and intermittently, briefly uses  fluoroscopy  and a low X-ray dose to visualize when needed. This is done without saving recordings of these brief looks. When the physician is ready to record diagnostic views, which are saved and can be more carefully scrutinized later, he activates the equipment to apply a significantly higher X-ray dose, termed  cine , in order to create better quality motion picture images, having sharper radiodensity contrast, typically at 30 frames per second. The physician controls both the contrast injection,  fluoroscopy  and cine application timing so as to minimize the total amount of radiocontrast injected and times the X-ray to the injection so as to minimize the total amount of X-ray used. Doses of radiocontrast agents and X-ray exposure times are routinely recorded in an effort to maximize safety.


Though not the focus of the test,  calcification  within the  artery  walls, located in the outer edges of  atheroma  within the artery walls, is sometimes recognizable on fluoroscopy (without contrast injection) as radiodense halo rings partially encircling, and separated from the blood filled lumen by the interceding radiolucent atheroma tissue and  endothelial  lining. Calcification, even though usually present, is usually only visible when quite advanced and calcified sections of the artery wall happen to be viewed on end  tangentially  through multiple rings of calcification, so as to create enough radiodensity to be visible on fluoroscopy.


Angiocardiography can be used to detect and diagnose congenital defects in the heart and adjacent vessels. [ 5 ]  In this context, the use of angiocardiography has declined with the introduction of  echocardiography . However, angiocardiography is still in use for selected cases as it provides a higher level of anatomical detail than echocardiography. [ 6 ] [ 7 ]


By changing the diagnostic catheter to a guiding catheter, physicians can also pass a variety of instruments through the catheter and into the  artery  to a  lesion  site. The most commonly used are 0.014-inch-diameter (0.36 mm) guide wires and the balloon dilation catheters. [ citation needed ]


By injecting radiocontrast agent through a tiny passage extending down the  balloon catheter  and into the balloon, the balloon is progressively expanded. The hydraulic pressures are chosen and applied by the physician, according to how the balloon within the  stenosis  (abnormal narrowing in a blood vessel) responds. The radiocontrast filled balloon is watched under  fluoroscopy  (it typically assumes a "dog bone" shape imposed on the outside of the balloon by the stenosis as the balloon is expanded), as it opens. As much  hydraulic  brute force is applied as judged needed and visualized to be effective to make the stenosis of the artery lumen visibly enlarge. [ citation needed ]


Typical normal  coronary artery  pressures are in the <200 mmHg range (27 kPa). The hydraulic pressures applied within the balloon may extend to as high as 19000 mmHg (2,500 kPa). Prevention of over-enlargement is achieved by choosing balloons manufactured out of high tensile strength clear plastic membranes. The balloon is initially folded around the catheter, near the tip, to create a small cross-sectional profile to facilitate passage through luminal stenotic areas, and is designed to inflate to a specific pre-designed diameter. If over-inflated, the balloon material simply tears and allows the inflating radiocontrast agent to simply escape into the blood. [ citation needed ]


Additionally, several other devices can be advanced into the artery via a guiding catheter. These include  laser  catheters,  stent  catheters,  IVUS  catheters,  Doppler  catheter, pressure or temperature measurement catheter and various  clot  and grinding or removal devices. Most of these devices have turned out to be niche devices, only useful in a small percentage of situations or for research.


Stents, which are specially manufactured expandable stainless steel mesh tubes, mounted on a balloon catheter, are the most commonly used device beyond the balloon catheter. When the stent/balloon device is positioned within the stenosis, the balloon is inflated which, in turn, expands the stent and the artery. The balloon is removed and the stent remains in place, supporting the inner artery walls in the more open, dilated position. Current stents generally cost around $1,000 to 3,000 each (US 2004 dollars), the drug-coated ones being the more expensive.


Interventional procedures have been plagued by  restenosis  due to the formation of  endothelial   tissue  overgrowth at the lesion site. Restenosis is the body's response to the injury of the vessel wall from  angioplasty  and to the  stent  as a  foreign body . As assessed in clinical trials during the late 1980 and 1990s, using only balloon angioplasty (POBA, plain old balloon angioplasty), up to 50% of patients developed significant restenosis; but that percentage has dropped to the single to lower two-digit range with the introduction of  drug-eluting stents .  Sirolimus ,  paclitaxel , and  everolimus  are the three drugs used in coatings which are currently FDA approved in the United States. [ citation needed ]  As opposed to bare metal,  drug-eluting stents  are covered with a medicine that is slowly dispersed with the goal of suppressing the restenosis reaction. The key to the success of drug coating has been (a) choosing effective agents, (b) developing ways of adequately binding the drugs to the stainless surface of the  stent  struts (the coating must stay bound despite marked handling and stent deformation stresses), and (c) developing coating controlled release mechanisms that release the drug slowly over about 30 days. One of the newest innovations in coronary stents is the development of a dissolving stent.  Abbott Laboratories  has used a dissolvable material,  polylactic acid , that will completely absorb within 2 years of being implanted. [ citation needed ]


CT angiography  can act as a less invasive alternative to Catheter angiography. Instead of a catheter being inserted into a vein or artery, CT angiography involves only the injection of a CT-visible dye into the arm or hand via an IV line. CT angiography lowers the risk of arterial perforation and catheter site infection. It provides 3D images that can be studied on computer, and also allows measurement of heart ventricle size. Infarct area and arterial calcium can also be observed (however those require a somewhat higher radiation exposure). That said, one advantage retained by Catheter angiography is the ability of the physician to perform procedure such as  balloon angioplasty  or insertion of a  stent  to improve blood flow to the artery. [ 8 ]


Imaging in coronary angiograms is performed via  fluoroscopy  using X-rays, which pose a potential for increasing the patient's risk of  radiation-induced cancer . The risk increases with the exposure time, consisting of 1) time guiding the probe into and out of the heart and 2) time illuminating the contrast agent to perform the angiogram. Absorbed radiation is also a function of  body mass index , with obese patients having twice the dose of normal-weight patients; exposure to the operator was also doubled. [ 9 ]  Coronary angiograms can be done either transradial (through the wrist) or transfemoral (through the groin). [ 10 ]  The transradial route results in somewhat greater patient and operator exposure. Overall, patient exposure can range from 2 millisieverts (equivalent of about 20 chest x-ray plates) to 20 millisieverts. [ 11 ]  For a given patient, exposure can vary within an institution and between institutions by up to 121%. [ 12 ]


Radiation exposure to the operator can be reduced by the use of protective equipment. Exposure to the patient can be reduced by minimizing fluoroscopy time.


The  Cox maze procedure , also known as  maze procedure , is a type of  heart surgery  for  atrial fibrillation .


"Maze" refers to the series of incisions arranged in a  maze -like pattern in the  atria . Today, various methods of minimally invasive maze procedures, collectively named  minimaze procedures , are used.


James Cox  is an American cardiothoracic surgeon. Cox received his medical degree at  University of Tennessee Medical Center  and completed his training in both General and Cardiothoracic Surgery at  Duke University Hospital . Cox and his associates at Duke, and later at  Washington University School of Medicine  developed the "maze" or "Cox maze" procedure, an "open-heart"  cardiac surgery  procedure intended to eliminate  atrial fibrillation  (AF).


Incidence of stroke in patients with AF who are anticoagulated is still around 2-5% per year. The first such procedure was performed by Dr. Cox at St. Louis' Barnes Hospital—now  Barnes-Jewish Hospital —in 1987. [ 1 ]


The intention was to eliminate AF by using incisional scars to block abnormal electrical circuits (atrial macroreentry) that initiate and perpetuate the abnormal electrical waves of AF. This required an extensive series of full-thickness incisions through the walls of both atria, a median sternotomy (vertical incision through the sternum), and cardiopulmonary bypass (heart-lung machine;  extracorporeal circulation ). After the introduction of the initial procedure, a series of improvements were made, culminating in 1992 in the Cox maze III procedure, which is now considered to be the "gold standard" for effective surgical cure of AF. It was quite successful in eliminating AF but had drawbacks as well. [ 2 ]  The Cox maze III is sometimes referred to as the "traditional maze", the "cut-and-sew maze", or simply the "maze." [ citation needed ]  Damiano and colleagues have described a Cox-Maze IV procedure in 2002 in which they modified the Cox-Maze III technique using a combination of bipolar radiofrequency and cryothermal ablation lines. [ 3 ]  Since then, the Cox-Maze IV procedure is the gold standard surgical treatment for AF with conversion to normal sinus rhythm and freedom from AF at 1 year postoperatively of 93%, [ 4 ] [ 5 ]  but the results are institution dependent. [ 6 ]


During the past 10 years, [ when? ]  several energy sources, such as unipolar radiofrequency, bipolar radiofrequency, microwave, laser, high-intensity focused ultrasound, and cryothermia, were incorporated into various devices in order to create some of the lesions of the Cox maze III procedure  without actually cutting into the atrial walls .  Microwave and laser therapy have both been withdrawn from the market, but the other devices continue to be utilized to treat AF surgically. [ citation needed ]


External counterpulsation  therapy  ( ECP ) is a procedure that may be performed on individuals with  angina ,  heart failure , or  cardiomyopathy .


The FDA approved the CardiAssist ECP system for the treatment of angina, acute myocardial infarction and cardiogenic shock under a 510(k) submission in 1980 [ 1 ]   [ failed verification ] Since then, additional ECP devices have been cleared by the FDA for use in treating stable or unstable angina pectoris, acute myocardial infarction, cardiogenic shock, and congestive heart failure. [ 2 ]


Studies have found EECP to be beneficial for patients with erectile dysfunction and some COPD patients. Additionally, improvements in exercise endurance in the non-diseased patient has been found in research studies. [ 3 ] [ 4 ]


Some reviews did not find sufficient evidence that it was useful for either angina or heart failure. [ 5 ] [ 6 ]  Other reviews found tentative benefit in those with angina that does not improve with medications. [ 7 ] [ 8 ]


For  stroke  due to lack of blood flow, a 2012 Cochrane review found significant neurological  improvement, but insufficient evidence to make reliable conclusions. [ 9 ]


External counterpulsation therapy significantly improved the exercise endurance of normal adults, low endurance adults, and COPD patients. [ 3 ]


While an individual is undergoing ECP, they have pneumatic cuffs on their legs and is connected to  telemetry  monitors that monitor heart rate and rhythm. The most common type in use involves three cuffs placed on each leg (on the calves, the lower thighs, and the upper thighs (or buttocks)). The cuffs are timed to inflate and deflate based on the individual's  electrocardiogram . The cuffs should ideally inflate at the beginning of  diastole  and deflate at the beginning of  systole . During the inflation portion of the cycle, the calf cuffs inflate first, then the lower thigh cuffs, and finally the upper thigh cuffs. Inflation is controlled by a pressure monitor, and the cuffs are inflated to about 200  mmHg . [ citation needed ]


Of note, therapies are tailored on an individual basis but beginning regimens tend to include daily one-hour treatments that occur 5 days of the week and last 6–8 weeks with an average overall of 35 hours. [ 10 ]


One theory is that ECP exposes the coronary circulation to increased  shear stress , and that this results in the production of a cascade of growth factors that result in new blood vessel formation in the heart (arteriogenesis and  angiogenesis ). [ 11 ] [ 12 ]


To best understand the pathophysiology of the therapy it is easiest to understand what each step does. To begin with, as the cuffs on each leg inflate, starting at the calf and working up to the upper thighs, blood is propelled back to the heart thereby increasing the venous return or preload. This increase in preload occurs simultaneously with diastole which happens to be the time during the cardiac cycle in which coronary perfusion occurs. So, by increasing the coronary perfusion, you allow more oxygen to perfuse the heart and ultimately generate more collateral circulation without actually increasing the work of the heart. Additionally, cardiac output is increased via the Frank-Starling mechanism secondary to the increased venous return. As the cardiac cycle progresses to systole, the cuffs on the extremities deflate, allowing for the increased cardiac output to adequately perfuse all tissues including the extremities. [ 13 ]


“Heal Your Heart with EECP” by Debra Braverman, MD.


The  handgrip maneuver  is performed by clenching one's fist forcefully for a sustained time until fatigued. Variations include squeezing an item such as a rolled up washcloth. [ citation needed ]


The handgrip maneuver increases  afterload [ 1 ]  by squeezing the  arterioles  and increasing  total peripheral resistance . [ 2 ]


Since increasing afterload will prevent blood from flowing in a normal forward path, it will increase any murmurs that are due to backwards flowing blood. [ 3 ]
This includes  aortic regurgitation  (AR),  mitral regurgitation  (MR), and a  ventricular septal defect  (VSD). [ 4 ]


Mitral valve prolapse : The click and the murmur of mitral valve prolapse are delayed because left atrial volume also increases due to mitral regurgitation along with increased left ventricular volume. [ 5 ]


Murmurs that are due to forward flowing of blood such as  aortic stenosis , and  hypertrophic cardiomyopathy  decrease in intensity. [ 4 ]


The effect of reducing the intensity in forward flowing murmurs is much more evident in aortic stenosis rather than mitral stenosis. The reason for this is that there is a larger pressure gradient across the aortic valve. [ 6 ]  A complementary maneuver for differentiating disorders is the  Valsalva maneuver , which decreases preload. [ 7 ]


Hybrid coronary revascularization  ( HCR ) or  hybrid coronary bypass  is a relatively new type of  heart surgery  that provides an alternative to traditional  coronary artery bypass surgery  (CABG) or  percutaneous coronary intervention  (PCI or PTCA) by combining the two into one operation. It is this combining aspect that " hybrid " refers to. HCR is one of several types of  hybrid cardiac surgery ; it is not to be confused with a  MIDCAB  (minimally invasive direct coronary artery bypass) procedure, which uses the smaller  thoracotomy  incision but does not involve  coronary stenting . [ 1 ]


Hybrid bypass offers all the benefits of a  MIDCAB , although there are some disadvantages.


A 2018 Meta Analysis with over 4000 patient cases found HCR to have significant advantages compared with conventional  CABG . Reduced incidence of  Blood Transfusion , reduced hospital stay duration and reduced  intubation  duration were all reported. In contrast, HCR was found to be  significantly more expensive  compared to CABG. [ 8 ]
However, 2018 guidelines recommend (Level 2B recommendation) that hybrid coronary revascularization may be considered in specific patient subsets at experienced centres. [ 9 ]


The  instantaneous wave-free ratio  ( iFR , sometimes referred to as the  instant wave-free ratio  or  instant flow reserve ) is a  diagnostic tool  used to assess whether a  stenosis  is causing a limitation of blood flow in  coronary arteries  with subsequent  ischemia . iFR is performed during  cardiac catheterisation  ( angiography ) using invasive coronary pressure wires which are placed in the coronary arteries that are to be assessed. Pressure wires are commonly used by  interventional cardiologists  to guide decisions to perform revascularization, either by  stenting  or  bypass surgery .


Coronary artery blockages or stenoses that limit blood flow to the heart muscle can cause  angina  and can be treated by  stenting  or  bypass surgery . Relief of a stenosis by stenting aims to restore vessel patency with improvement in blood flow leading to a reduction in angina symptoms. However, if stenoses are not flow limiting, then they can be safely left alone without stenting or surgery and this help reduce patient's exposure to unnecessary procedures and potential complications. Identifying stenoses that cause flow limitation, or ischaemia, can be done in a variety of ways. Non-invasive tests can include  stress testing  such as exercise electrocardiograms, stress echocardiography, or  perfusion imaging  tests such as  scintigraphy  or  SPECT . Alternatively, invasive tests can be performed at the time of angiography, and these include those that measure coronary flow velocity in the vessel,  CFR  or index flow against pressure gradients such as hyperaemic or basal stenosis resistance (HSR or BSR). More commonly coronary pressure measurements are used as a surrogate for flow measurement and techniques include iFR and  fractional flow reserve  (FFR). Cardiologists use a combination of these investigations together with the patient's history, symptoms and clinical risk factors to decide if a stenosis requires further treatment. An example of use in clinical practice is seen here. [ 1 ]


Instantaneous wave-free ratio is performed using high fidelity pressure wires that are passed distal to the coronary stenosis. iFR isolates a specific period in diastole, called the wave-free period, and uses the ratio of distal coronary pressure (Pd) to the pressure observed in the aorta (Pa) over this period. During this wave-free period, the competing forces (waves) that affect coronary flow are quiescent meaning pressure and flow are linearly related as compared to the rest of the cardiac cycle. [ 2 ] [ 3 ]


When stenoses are flow limiting, Pd and Pa pressures over the wave-free period diverge; a normal ratio is 1.0 and iFR values of below 0.90 suggest flow limitation. iFR can be calculated using dedicated consoles available for medical use and typically uses an average over 5 heart beats but can be performed using a single heart beat. iFR is measured at rest, without the need for pharmacological vasodilators or stressors and compares well to other invasive and non-invasive markers of ischemia or flow limitation. [ 4 ]


A number of studies using the Imperial College developed iFR algorithm have been conducted. [ citation needed ]


The ADVISE study was a proof of concept study that demonstrated that the wave-free period, usually isolated using wave-intensity analysis, [ 5 ]  could be reliably determined using a pressure-only approach. [ 6 ]  This was shown across a variety of stenosis severities and demonstrated that over that specific period in diastole, microcirculatory resistance was the lowest and most stable compared to the rest of the cardiac cycle. During this specific period, pressure and flow are linearly related, allowing pressure-only inferences of transtenotic flow limitation. iFR was compared to the current clinically-used reference standard, FFR, and demonstrated good diagnostic lesion classification. Furthermore, iFR was consistent in utility for the left and right coronary artery, and the wave-free period was stable from beat-to-beat and even in the presence of arrhythmia. The study however was relatively underpowered to determine a clinical cut-point. [ citation needed ]


The ADVISE-Registry was a larger study in which pressure wire data collected from patients undergoing functional assessment for clinical management, was analysed to compare iFR and FFR. [ 7 ]  This study recognised that matching FFR was limited by the capacity of FFR to match itself with repeated measures and accordingly presented per-range agreements. An independent consecutive blinded comparison of iFR and FFR in Asian patients reported similar results. [ citation needed ]


The CLARIFY study was a physiological study in which iFR and FFR were compared to an independent third measure, hyperaemic stenosis resistance (HSR) which uses a combination of pressure and flow assessment to detect ischemia. [ 8 ]  Both measures compared equally well to this flow-based index.  In stenoses classified as ischemic, the wave-free period provided a similar reduction in microvascular resistance as adenosine-mediated hyperaemia over the whole cardiac cycle. [ citation needed ]


The Hybrid iFR-FFR approach has been proposed as method of minimising patient exposure to adenosine or other vasodilators. [ 9 ]  In this approach, an iFR can be measured, and stenoses with an iFR >0.93 may be deferred while those with an iFR <0.86 can be treated by revascularization. Stenoses with an iFR between 0.86-0.93 can undergo an FFR assessment to guide therapy. This range can be changed by the physician according to how closely they want to match an FFR-classification of lesions. Using this typical range, almost 60% of stenoses can be spared from needing vasodilator infusion. [ citation needed ]


ADVISE-II has prospectively assessed the hybrid approach in an independent international multi-centre study which confirmed the findings of the earlier Hybrid analysis. Interim results were reported by Javier Escaned at EuroPCR, the final findings were presented at TCT 2013. [ 10 ]


These findings have been in keeping with an international collaborative study, RESOLVE, which pooled retrospective data from many centres worldwide with independent core-lab analysis of raw pressure traces. [ 11 ]  Conflicting data, when re-analysed using the clinically available iFR-algorithms produced results similar to the ADVISE-Registry and ADVISE Hybrid studies. [ 12 ]


iFR has also been compared to FFR and the resting Pd/Pa ratio in the post-coronary intervention setting. In a manner similar to FFR, iFR can be used to measure the haemodynamic change induced by stent placement and detect the impact of any residual stenoses. [ 13 ]


The ADVISE-in-Practice study reported the first clinical experience of the commercially available iFR console. [ 14 ]  Video examples of iFR technology in clinical use are available here  [1] .


Two outcome studies, DEFINE-FLAIR [ 15 ]  and the iFR-SWEDEHEART [ 16 ]  will assess whether patient outcomes differ if stenoses are treated according to iFR or FFR classification of stenosis severity. DEFINE-FLAIR, which aims to recruit 2500 patients, will be the largest physiological study to date and will provide the first randomised data of the use of iFR and FFR in patients with both stable coronary disease and acute coronary syndromes. It will also provide the first randomised data of the clinical utility of FFR in guiding and deferring coronary intervention outside of the FAME and DEFER studies. Both DEFINE-FLAIR and iFR-SWEDEHEART have harmonised clinical endpoints which will enable combined analysis of over 4500 patients. [ citation needed ]


SYTNAX II is a modern PCI study assessing the clinical utility of stenting three-vessel coronary disease. [ 17 ]  Patients with three-vessel coronary disease whom the Heart Team decide are in equipoise between surgical revascularization or PCI intervention, undergo physiologically guided stenting. The SYNTAX II clinical risk calculator is used to determine equipoise. All major vessels undergo pressure wire assessment using the iFR-FFR hybrid approach, and only those positive for ischaemia undergo stenting. Intravascular ultrasound is used to ensure optimal stent delivery. Clinical outcomes will be compared to a historical surgical cohort from SYNTAX-I study. [ citation needed ]


The instantaneous wave-free ratio can also be calculated on a beat-to-beat basis. If performed during the slow withdrawal of a pressure wire (referred to as 'pullback') under resting conditions, it is possible to plot the change of iFR or trans-stenotic gradient over the wave-free period throughout the vessel. [ 18 ] [ 19 ]  This can help identify focal and diffuse coronary disease potentially amenable to revascularisation. An example of pullback in clinical use can be seen  in this video . The pressure wire data can be co-registered with the angiographic findings to aid ease of interpretation. With mechanised pullback approaches which move the pressure wire at a fixed speed, the physiological length of a stenosis can be determined. With advanced live co-registration this is also feasible with during manual pullback. [ citation needed ]


Advanced computer processing can utilise iFR-pullback data to predict the hemodynamic consequences of performing percutaneous coronary intervention (PCI) to a chosen segment of the coronary vessel. The predicted iFR values produced by the virtual-PCI on the iFR-pullback are closely related to those observed after PCI in the coronary vessel. [ 18 ]  This predictive capacity may provide added advantage to Interventional Cardiologists when assessing multiple coronary stenoses in a single vessel and planning the treatment approach. iFR-pullback technologies are undergoing evaluation in European centres. [ 20 ]


Alternative iFR computation systems have been proposed, for example incorporating part of systole into the definition of diastole and optionally different time-shifts between Pd and Pa signals, [ 21 ]  yielding unsatisfactory results. [ 22 ]  The same datasets reanalysed using the standard algorithms confirm the mainstream findings. [ 11 ]  Various explanations have been proposed. [ 12 ]


A  diagnosis of myocardial infarction  is created by integrating the history of the presenting illness and physical examination with  electrocardiogram  findings and  cardiac markers  ( blood tests  for  heart muscle  cell  damage ). [ 1 ] [ 2 ]  A  coronary angiogram  allows visualization of narrowings or obstructions on the heart vessels, and therapeutic measures can follow immediately. At  autopsy , a  pathologist  can diagnose a  myocardial infarction  based on  anatomopathological  findings.


A  chest radiograph  and routine blood tests may indicate complications or precipitating causes and are often performed upon arrival to an  emergency department . New regional wall motion abnormalities on an  echocardiogram  are also suggestive of a myocardial infarction. Echo may be performed in equivocal cases by the on-call cardiologist. [ 3 ]  In stable patients whose symptoms have resolved by the time of evaluation,  Technetium (99mTc) sestamibi  (i.e. a "MIBI scan"),   thallium-201 chloride  or  Rubidium-82  Chloride can be used in  nuclear medicine  to visualize areas of reduced blood flow in conjunction with physiologic or pharmacologic stress. [ 3 ] [ 4 ]  Thallium may also be used to determine viability of tissue, distinguishing whether non-functional myocardium is actually dead or merely in a state of hibernation or of being stunned. [ 5 ]


According to the WHO criteria as revised in 2000, [ 6 ]  a cardiac  troponin  rise accompanied by either typical symptoms, pathological Q waves, ST elevation or depression or coronary intervention are diagnostic of MI.