Ambulatory patients with a left ventricular assist device (LVAD) are increasing in number, and so is their life expectancy. Thus, there is an increasing need for care of these patients by non-LVAD specialists, such as providers in the emergency department, urgent care centers, community-based hospitals, outpatient clinics, etc. Non-LVAD specialists will increasingly come across LVAD patients and should be equipped with the knowledge and skills to provide initial assessment and management for these complex patients. These encounters may be for LVAD-related or unrelated issues. However, there are limited data and guidelines to assist non-LVAD specialists in caring for these complex patients. The aim of our review, targeting primary care providers (both inpatient and outpatient), general cardiologists, and other providers is to describe the current status of durable LVAD therapy in adults, patient selection, management strategies, complications and to summarize current outcome data. Heart failure (HF) affects an estimated 6.5 million people in the United States currently. Optimal medical ,2 and reOver the past decade, the use of LVADs has increased significantly. In the United States, approximately 421 isolated LVAD implants were performed in 2008. A total of 2118 LVADs were implanted in 2017, which is a significant increase from only 459 implants in 2008. There was a steady increase in the number of LVADs implanted from 2008 to 2015, peaking at 2754 devices annually. Since 2016, the INTERMACS Database reported a decline in annual LVAD volume, related in part to a number of patients who received non-FDA-approved pumps as part of the MOMENTUM 3 clinical trial or a delay in enrollment of patients during contractual negotiations in 2017 between STS and participating hospitals . So far,In 1963, Drs. Michael DeBakey and Domingo Liotta implanted the first LVAD in a patient who suffered a cardiac arrest after an aortic valve replacement surgery . The patFirst-generation pulsatile LVADs were volume-displacement pumps, using a diaphragm and unidirectional valves to mimic the pulsatile cardiac cycle through diastolic filling and systolic emptying of the device. However, these devices were large, noisy and had limited durability due to multiple mechanical parts that were subject to wear and tear .To overcome the limitations of pulsatile-flow (PF)-LVADs with respect to mechanical wear and to permit application to smaller recipients, the field focused on development of continuous-flow (CF) LVADs. CF-LVADs have a smaller profile with a single moving part . They have significantly improved durability, reliability, reduced noise emission and reduced incidence of adverse events. There are currently three such durable  LVADs approved for adults by the U.S. Food and Drug Administration (FDA): the HeartMate II , the HeartWare ventricular assist device system (HVAD) , and the HeartMate 3 .The contemporary LVADs are all continuous-flow pumps. They vary in design but have the same basic components. The components of an LVAD system are depicted in A surgically tunneled cable, called a driveline, connects the pump to an external control unit, which operates and monitors the function of the pump. The driveline usually exits the body through the abdominal wall. The external controller is connected to a power source, which may be batteries; or a power module which is plugged into an AC wall source when the batteries are charging. Batteries usually last up to 12 h, allowing the patient to ambulate freely untethered. The remaining battery life is displayed on the external controller. The external controller also displays other parameters describing pump function, such as the LVAD speed, flow, power and pulsatility index in the Heartmate devices (explained in detail below).Most pumps are now designed to be contact-free, without mechanical bearings and an impeller suspended using magnetic and/or hydrodynamic systems. The presence of mechanical bearings is thought to predispose to formation of thrombi on the metal. Thrombus formation leads to further propagation of the thrombus by leading to friction and, therefore, increasing heat and turbulence. The pump in the HVAD device uses a layer of blood to lift the rotor, known as hydrodynamic levitation. In the Heartmate 3, the motor is suspended magnetically without any mechanical bearings.In addition to being frictionless due to the absence of mechanical bearings, the HeartMate 3 LVAD also has wide blood-flow passages to reduce shear stress and an intrinsic pulse (~20/min) by transiently decreasing the impeller speed. These design changes are engineered to reduce stasis, minimize destruction of red blood cells, avert thrombosis, and thus improve hemocompatibility. Current trends in the evolving technology of LVADs are focusing on generating pulsatility, further miniaturization, total implantability and remote monitoring.Present day LVADs, both axial and centrifugal, continuously empty blood from the LV into the systemic circulation. The rotor or impeller within the pump propels blood by spinning at a high speed. Blood flow is proportional to the pump speed, though the relationship is not linear. The speed at which the LVAD pump operates, is essentially the only parameter that can be set by the provider. The LVAD speed is selected at rest to ensure adequate left ventricular unloading. Inadequate LV unloading may result in pulmonary edema and heart failure, while excessive unloading could lead to what are called suction events, resulting in hypotension and arrhythmias. Blood flow through the LVAD is proportional to the motor current or power consumption. Therefore, the blood flow is estimated based on the power consumption and is also displayed on the external controller. However, since it is an estimated value, it may be inaccurate, especially in cases of hemodynamic derangements, such as aortic insufficiency or pump thrombosis.Continuous-flow pumps do not typically generate a pulse; however, the interaction with the native ventricular function leads to phasic changes in blood flow through the LVAD. This fluctuation is termed pulsatility index for the HeartMate devices and is displayed as a waveform for HVAD. Typical values for pump parameters are mentioned in While patients are still distinguished by upfront strategy of BTT or DT, there is significant dual crossover that occurs once they are on LVAD therapy. For example, some patients may develop contraindications to transplantation while waiting for transplant on LVAD support. Conversely, many patients have co-morbidities that may be reversible  after a more prolonged period of hemodynamic support with an LVAD. In addition, many patients eligible for transplantation simply never receive an organ because of the relative shortage of suitable donors. These issues have recently raised the question of whether categorization as BTT or DT remains clinically meaningful.LVEF < 25%NYHA IIIb–IV symptoms for at least 45 of the last 60 daysRefractory heart failure symptoms despite optimal medical and device therapyPeak VO2 < 14 mL/kg/minContinued need for IV inotropic therapy due to symptomatic hypotension, worsening end organ function, or persistent pulmonary edemaIV inotropic medication use for ≥14 daysIntra-aortic balloon pump support for ≥7 daysIndications for durable mechanical support are generally derived from inclusion criteria used in the clinical trials leading to FDA approval. The criteria generally reflect end-stage heart failure, but are somewhat subjective. These criteria include:Recent cancer is not an absolute contraindication for LVAD implant, unlike for heart transplantation. Psychosocial evaluation is important for selection of candidates who may achieve good outcomes. Studies have documented that social network and even marital status are important factors in achieving good outcomes with LVAD therapy .The challenge is in identifying patients who have advanced heart failure, but not decompensated to the degree of declining despite inotropic and/or temporary mechanical support. Early referral is key to ensuring good outcomes post durable mechanical support.Long-term outcomes for patients on LVAD support continue to improve. The most recent INTERMACS data reports overall survival for patients on CF-LVAD at 1, 3 and 5 years of 83%, 63%, and 46%, respectively . More coAs the volume of LVAD patients has increased, a model of “shared care” has emerged, wherein care of the LVAD patients is shared between the implanting center and a community-based, non-implanting site ,29. ThisAt this time, the greatest value of such a model is in providing routine, ambulatory care. This includes routine LVAD care, assessing device function, driveline evaluation, anticoagulation management, routine laboratory testing and cardiac rehabilitation. Non-LVAD related medical problems, such as diabetes, can also be managed at these sites. Though the implanting center will remain the primary contact for emergencies, it may become necessary for the patient to be stabilized locally prior to transfer. In such cases, the shared care sites can be extremely valuable due to their knowledge of LVADs and of the patient’s history. The implanting center should be contacted as soon as possible in case of emergencies and management should be done in consultation with an LVAD specialist. Unique aspects of the patient evaluation include assessment for normal LVAD function, and for common (sometimes occult) complications.The history should include recent device parameters and alarms, symptoms of driveline infection such as discharge and redness, heart failure symptoms, ICD shocks, and signs of hemoglobinuria  that could herald development of LVAD thrombosis. History of overt bleeding, particularly melena, should be elicited, because bleeding from arteriovenous malformations in the gastrointestinal tract is a frequent complication.Continuous flow devices greatly alter the physical exam in supported patients. This can be challenging to clinicians and first responders in assessing these patients. Patients supported by a CF-LVAD frequently have no palpable pulse (or sometimes faint and intermittent pulse) and blood pressure (BP) may not be measurable by auscultation. Heart sounds are obscured by the hum of the device. Additionally, high placement of the external driveline can impede examination of the liver and assessment of hepatic congestion.Underlying heart rate and rhythm are best assessed by electrocardiogram (ECG) or telemetry. BP is best estimated manually using a Doppler ultrasound probe and sphygmomanometer  . A DopplOn cardiac auscultation, the “hum” of an LVAD should be appreciated, which is important if there is any concern for pump dysfunction, since the hum can vary depending on pump stress or pump stoppage. Another important element of the physical exam for specialists (or for shared care centers) in mechanical device patients is assessment of the percutaneous driveline or lead for infection or damage. If there is a high level of suspicion for infection and LVAD specialists are not available, direct inspection of the driveline site for erythema, swelling, and/or purulent discharge can be performed. This should be performed wearing masks and sterile gloves to avoid transmitting infections to the percutaneous driveline site. It is important to stabilize and anchor the driveline to avoid trauma and potential infection. Any signs of infection, the implanting LVAD center should be notified urgently.Percutaneous lead damage is a frequent cause for device exchange. The driveline should be inspected for tears in the outer casing or tears at the connecting sites, which can expose the internal wires. Repair of the driveline with safety clamps or reinforcement with tape may occasionally be needed, and should be performed only by a trained specialist and/or engineer. An ECG should be obtained to evaluate the heart rate and rhythm. A high index of suspicion is appropriate in patients presenting with vague symptoms since sustained ventricular tachycardia or ventricular fibrillation in a patient supported by a VAD may present with vague symptoms. Sustained (particularly incessant) ventricular arrhythmias generally precipitate worsening right-sided HF and, therefore, require prompt attention .Shared care physicians who have undergone training (by the implanting LVAD team) and have the appropriate equipment may wish to interrogate the device controller for proper function, especially if there is any clinical change or suspicion of device malfunction. This is generally performed by the LVAD team, however. For all current devices, alarm alerts can be reviewed along with flow estimates, pump power, and pump speed. Normal ranges for device operating parameters have been described previously in this article. Alarms are displayed on the system controller display screen. The system controller also has audio warnings depending on the severity and type of alarm. When an alarm occurs, some information to help troubleshoot and resolve the issue are also displayed on the screen. Some examples of common system controller alarms are:“Low flow”The display will state to call the hospital contact. This warning suggests that the pump flow is estimated to be <2.5 Lpm. Ensure the driveline is intact, connections are secure, the controller is connected to a power source and the batteries have enough charge if the patient is on batteries. Assess the patient for causes of low flow such as hypertension (particularly in the case of HeartMate 3), significant volume loss, right-sided heart failure and pump thrombosis.Hazard alarm: Flashing red heart or batteryThis warning suggests that there is a mechanical, electrical or software issue with the system.Advisory: Flashing yellow wrench or diamond“VAD stopped”The display will state to connect the driveline or change the controller. Ensure the driveline is intact, connections are secure, the controller is connected to a power source and the batteries have enough charge if the patient is on batteries. Assess for other causes of VAD dysfunction, including pump thrombosis.“Critical battery”It indicates less than 5 min of battery remaining. Immediately replace the existing batteries with fully charged ones, or switch to the Power Module.High priority: Flashing red triangle“High watt”The display will state to call for medical assistance. This suggests that the pump has exceeded the high power alarm threshold. This could be due to a variety of causes, such as pump thrombosis, or an electrical malfunction and requires evaluation by a VAD specialist.Medium priority: Flashing yellow triangleLow priority: Solid yellow triangleIf an LVAD patient presenting to a community-based practice or hospital is noted to have alerts or alarms, the implanting center should be notified. The LVAD team can assist with troubleshooting in case of an emergency. All patients are provided with contact information and on-call numbers for their respective center. Most centers also label the LVAD equipment with the on-call number. Laboratory tests that are particularly relevant for patients with an LVAD are evaluation for anemia, anticoagulation goals and hemolysis. Coumadin is recommended for all LVADs and thus the international normalized ratio (INR) should be checked frequently. Plasma-free hemoglobin >40 mg/dL is very specific for evidence of hemolysis; while lactate dehydrogenase (LDH) has greater sensitivity . LDH 2.5Echocardiography is crucial for the assessment of LVAD patients, including assessment of right and left ventricular function, filling pressures, inflow cannula position, orientation, and even obstruction, and adequacy of LV unloading. In addition, echocardiography can assess the presence and degree of aortic valve opening, which can aid in blood pressure assessment and interpretation. Periodic imaging at regular intervals is helpful for detecting complications such as aortic insufficiency. Echocardiography is also indicated if there are device alarms or signs or symptoms suggestive of LVAD dysfunction. Speed modifications with simultaneous echocardiographic imaging can help diagnose and troubleshoot various causes of LVAD dysfunction, as well as be useful for optimization of speed . GuideliThe LVAD inflow cannula and outflow graft can be extremely well imaged by contrast-enhanced gated CT scan. The images can be diagnostic for cannula malposition and outflow graft narrowing, kinking, or thrombosis . Of noteMedical management of LVAD patients includes HF therapy, management of hypertension, and other concurrent conditions.Components of HF therapy are similar to those used generally in systolic HF. Diuretics are used to treat volume overload. Angiotensin converting enzyme inhibitor or angiotensin II receptor blocker and/or beta blocker may be used to treat hypertension. Aldosterone antagonist may be used to reduce the need for potassium repletion in patients with preserved renal function. For patients with CF-LVADs, the ISHLT guidelines recommend a mean arterial BP goal of ≤80 mmHg . HF mediThe majority of the patients with an LVAD already have a pre-existing ICD. Concurrent ICD and LVAD therapy is feasible and safe, but the existing data on mortality benefit of ICDs in patients with CF-LVADs is inconsistent, with analysis of the UNOS registry data not showing a reduction in mortality with ICDs . In patiThe clinical benefit of a wireless implantable hemodynamic monitoring system (CardioMEMS) in patients with LVADs is being studied in the Intellect2 and HEMO-VAD studies ,45. Anal® (aspirin plus extended-release dipyridamole) or daily aspirin 81 mg plus clopidogrel 75 mg. The goal INR in clinical trials and from the manufacturers for all the currents LVADs is 2.0 to 3.0 [Patients supported by LVADs should be treated with anticoagulant and antiplatelet agents to reduce the risk of thrombotic complications, such as device thrombosis and embolic stroke. Since these patients are also at risk for bleeding events, anticoagulation should be carefully monitored and adjusted. . The dev0 to 3.0 . This ma0 to 3.0  and a laDirect oral anticoagulants should be avoided in patients with LVADs. A higher rate of thromboembolic events on dabigatran led to early termination of a randomized controlled trial of dabigatran versus vitamin K antagonists in LVAD patients . Low-molLiving with an LVAD requires adjustments to certain daily activities. Driveline care is of utmost importance. Since the source of LVAD infections is skin flora, ensuring sterility at the driveline exit site and aseptic precautions during dressing changes are essential for reducing the risk of infection. Measures such as ensuring hand hygiene, wearing sterile gloves, using antiseptic cleansing solutions around the driveline exit site, and use of sterile dressing material are important for prevention of infection. Many centers use standardized kits for inpatient dressing changes, as well as for home driveline maintenance. Patients and their caregivers are trained on driveline dressing change practices. Preventing wear and tear of the driveline, particularly at the exit site, and avoiding bends and kinks are also important to reduce the risk of infection. Patients are advised to limit exposing the driveline as much as possible. The number of people performing driveline care, dressings and assessment should be limited. Only the LVAD nurse/coordinator, surgeon if needed, and the patient or caregiver should assess the driveline and perform dressing changes. Patients should maintain a program of oral health care including regular professional care, the regular use of manual or powered toothbrushes, dental floss, and other plaque-removing devices to reduce the risk of infection.Care should be taken during daily activities to avoid damage to external connections, for instance, patients may have to change the way they sleep so as to avoid lying on the LVAD and pulling the driveline or connections. Taking a shower is not permitted initially, but once the incisions are healed, it may be allowed at the discretion of the implanting center. A special shower bag is provided so the equipment does not get wet. Initially, post implant physical activity may be limited due to deconditioning; however, once stable, exercise as tolerated should be encouraged. The only restrictions include swimming and contact sports. Driving with an LVAD is safe for stable patients and can be resumed 3 months after LVAD implantation, once the incision has healed, after careful patient assessment. A survey of 390 LVAD patients showed that 90% felt that their driving capabilities were perfect or adequate . Once thPatients with LVADs often require routine noncardiac procedures. These procedures should be carefully coordinated with an LVAD specialist, especially for recommendations regarding periprocedural management of antiplatelet therapy and anticoagulation. In addition, BP monitoring and management is paramount. There is an increased risk of bleeding, intraoperative hypotension, and a higher risk for acute kidney injury when these patients undergo noncardiac surgery . HoweverWhile survival has improved with CF-LVADS, the adverse event profile remains high. At 1 month post-implant, nearly 30% and at 1 year, almost 80% of patients, require readmission . The comDue to the presence of a percutaneous driveline exiting the skin, infections remain the Achilles heel of LVADs. Recent implantation of the first-in-man totally implantable LVAD aims to minimize this risk . ISHLT cDifferent techniques, largely limited to single-center experiences, have been shown to reduce infection rates and there is no universal protocol. Risk factors for driveline infection include trauma to the driveline exit site , youngerStaphylococcus aureus. Gram-negative organisms like Pseudomonas spp. and Enterobacteriaceae, and fungal infections can also occur. Surgical evaluation for debridement of the driveline exit site may be needed depending on the extent of the infection, and should be performed by a surgical team with LVAD experience. Infectious diseases consultation may be needed, particularly in the case of polymicrobial infections or multidrug-resistant organisms. If bacteremia or sepsis are present, a chest and abdomen CT, transthoracic and even transesophageal echocardiogram should be obtained to evaluate for the source of the infection . There is an emerging role for PET imaging with F-18 labeled fluoro-2-deoxyglucose [Driveline drainage culture and blood cultures should be obtained, and imaging may be needed as well. It is important to note that driveline site assessment and obtaining specimens of the drainage should only be performed by members of the LVAD team (or designated shared care centers) in order to limit the number of times and the number of people to whom the driveline is exposed. Culture of any drainage is recommended. Abnormal swelling of the region surrounding the driveline site should be assessed by imaging studies  to assess the presence, extent, and appearance of any fluid collections . Blood cyglucose . VAD infSome studies have shown that LVAD infections adversely affect survival after adjusting for age and comorbidities . One proGI bleed is one of the most frequent complications after LVAD implant and the most common reason for hospital readmission. It is triggered by the use of antiplatelet and anticoagulant therapy. Additionally, CF-LVADs can cause acquired von Willebrand factor deficiency due to the high shear stress imposed by the LVAD motor, resulting in breakdown of large von Willebrand factor multimers. Also, continuous flow physiology and dysregulation of angiogenic factors have been shown to lead to development of arteriovenous malformations (AVMs) in the gastrointestinal tract, nasopharynx, brain, and other tissues . Most patients present with melena, fatigue or dyspnea due to anemia or asymptomatic decline in hemoglobin picked up on routine evaluation. The initial assessment includes ensuring hemodynamic stability and transfusing blood products if needed . Antiplatelet agents and anticoagulants are usually held and active reversal of INR is not needed, unless there is life-threatening hemorrhage, such as an intracranial hemorrhage. Decisions on blood transfusion and holding antiplatelet and antithrombotic agents should be made by the specialist LVAD team. Reversal of INR should only be performed by the specialist LVAD team. As the source of the GI bleed is most frequently AVMs, endoscopy is the diagnostic and therapeutic modality of choice. Endoscopic options for diagnosis include upper endoscopy, colonoscopy, video capsule endoscopy, and deep small bowel enteroscopy . Since AVMs can be located throughout the GI tract, a combination of endoscopic techniques may be necessary. At many institutions, deep small bowel enteroscopy is the initial modality since AVMs are frequently located in the jejunum. The diagnostic and therapeutic yield of endoscopy remains high, with many patients undergoing repeated interventions . For rapLong-term pharmacologic therapy may be considered in select patients with recurrent GI bleeding. Drugs that are used are octreotide, a somatostatin analog, thalidomide, which is an antiangiogenic agent, and danazol . In thesThe reported prevalence of ventricular arrhythmias following LVAD implant varies from 22% to 59% . They caMany LVAD patients can tolerate ventricular tachycardia (VT) or even ventricular fibrillation for hours or even days due to the continuous hemodynamic support provided by the LVAD, although some patients can present with “low flow” alarms due to an unsupported and failing right ventricle. In case of hemodynamic compromise, cardioversion can be safely performed, although external defibrillator pads should not be placed directly over the pump. Once the patient is stabilized, the causative mechanism for the arrhythmia should be evaluated. There can be several etiologic mechanisms, such as, suction events, myocardial scar related VT and apical inflow cannula related VT. A suction event occurs when the LV is excessively emptied, leading to myocardial tissue abutting the inflow cannula. This could be due to dehydration, extremely high speed or inflow cannula malposition . In thisLVAD malfunction due to technical failure is rare with the current generation of devices. These devices are much more durable than the prior pulsatile LVADs. The current devices can fail or malfunction due to tissue ingrowth or thrombus formation. Electric malfunction of internal components is rare, but can be life threatening. A technical fault with the external components, such as the controller, batteries, driveline and the connections can occur, and can, generally, be resolved by replacing the component. The initial evaluation involves assessing the hemodynamic stability of the patient. Auscultation, although limited, can help determine if the pump is on or off. Then ensure the device connections are secure, review LVAD function and alarms, ensure the batteries are charged or that the controller is connected to a power source. Assess the driveline for fractures and signs or wear and tear. The LVAD team should always be contacted if there is suspicion of an LVAD-related issue. Involving an LVAD technician or engineer can be very helpful. The device manufacturers can also be contacted via telephone. Thrombosis can occur in any component of the LVAD and patients are at risk of experiencing thromboembolic events such as stroke as well. Factors that predispose to the development of thrombosis are inadequate anticoagulation or antiplatelet therapy, interruption of anticoagulation, atrial fibrillation, concomitant infection, low pump speed and mechanical issues like stenosed or kinked outflow and inflow cannula malposition. HeartMate II has higher rates of device malfunction compared with HVAD   or HeartPump thrombosis should be suspected if there is evidence of hemolysis and/or suboptimal pump performance. Patients can present with asymptomatic hemolysis, hemoglobinuria, changes in LVAD performance like high power or low flow alarms, heart failure symptoms or even cardiogenic shock and multiorgan failure. Echocardiographic ramp studies  may be hNeurologic complications are the leading cause of mortality, accounting for 19% of deaths following CF-LVAD implant, primarily from hemorrhagic and ischemic strokes . Most isIn the ENDURANCE Trial, the HVAD cohort had a higher incidence of stroke (29.7% vs. 12.1%) at 2 years post-implant . Post hoEarly diagnosis and immediate assessment are critical, and if applicable, the stroke team should be activated, anticoagulation held and CT head without contrast should be performed emergently. In case of hemorrhagic stroke, neurosurgical consultation should be obtained and reversal of anticoagulation with vitamin K, fresh frozen plasma and/or prothrombin protein complex should be considered in consultation with an LVAD specialist. In case of suspected ischemic/embolic stroke, CT angiogram of the head and neck should be performed and endovascular thrombectomy should be pursued if patients are candidates. Hemorrhagic strokes can also occur as a result of rupture of mycotic aneurysms, which are known to be associated with bacteremia associated with LVAD or driveline infection . p < 0.001), based on data from the HeartMate II BTT Trial [The vast majority of VADs are isolated to the LV due to poor outcomes in those that need biventricular VAD support. Thus, one can have continued heart failure post-LVAD due to either right ventricular (RV) failure or due to inadequate unloading of the LV by the device or biventricular failure. Acute or early RV failure post-LVAD implantation has a reported incidence of 10% to 44% and can lead to longer hospital length of stay and higher perioperative mortality ,73. EvenTT Trial . Late orTT Trial . The pat2. LVAD interrogation may demonstrate low flow. Acute RV failure is managed with diuretics, inotropes, pulmonary vasodilators and even a temporary right ventricular assist device in severe cases. Chronic RV failure management is challenging, and management is focused on diuresis, and consideration for heart transplantation if the patient is a candidate. Decreasing the LVAD speed may help. Palliative care consultation may be beneficial in refractory cases, who are not eligible for transplant. When a patient with an LVAD presents with heart failure, assessment should be directed towards gauging whether there are right-sided signs like elevated jugular venous pressure, ascites, pedal edema or left-sided findings like orthopnea, paroxysmal nocturnal dyspnea, or both. Echocardiogram and invasive hemodynamic assessment should be obtained to confirm the diagnosis. In RV failure, echocardiogram will generally reveal a small, underfilled LV, enlarged RV with reduced systolic function, dilated inferior vena cava, tricuspid regurgitation. Right heart catheterization findings include elevated right atrial pressure > 18 mmHg, low pulmonary capillary wedge pressure ≤ 18 mmHg and a low cardiac index < 2.0 L/min/mIn patients presenting with left-sided heart failure, assess for hypertension, LVAD dysfunction , aortic insufficiency and inadequate LV unloading. Treatment is directed towards the underlying etiology. Systemic vasodilators are preferred for treatment of hypertension. Management of aortic insufficiency is challenging: diuresis, inotropic support and LVAD speed increase may help temporize the situation. Transcatheter aortic valve replacement has been performed at a few centers with mixed results. If volume overload is due to inadequate LV unloading, a dilated LV, significant mitral regurgitation, aortic valve opening with each beat can be seen on echocardiogram. Increasing the LVAD speed may result in resolution of the symptoms. In the event of an emergency, patients with LVADs should be taken to their respective VAD center. If a patient with an LVAD is brought to a non-VAD center, it is imperative that emergency medical services providers also bring all the LVAD-related equipment, including back-up and spare components , since it will be necessary to support the patient and may be helpful in troubleshooting the issue. If the patient is being transported to a non-VAD center, a potential VAD center should be immediately notified for medical assistance and potential transfer as soon as possible. The patient’s LVAD center and personnel should also be promptly notified. Oftentimes, family members of patients with an LVAD are trained in emergency procedures, and if feasible, they should be transported with the patient. Code status information, particularly in patients with a DT LVAD, should be identified and the patient’s wishes respected. Care for an unresponsive LVAD patient is challenging due to several different reasons. Their unique physiology alters basic physical examination findings, which makes assessing their perfusion status difficult. In addition, assessing the LVAD for function is essential and consideration of LVAD-related complications as possible etiologic mechanisms for the patient’s deterioration is needed. Also, there has been debate in the past regarding the role for chest compressions in patients with an LVAD, which has led to varying and, on occasion, conflicting instructions being given to personnel involved in emergency care. Guidelines for cardiopulmonary resuscitation (CPR) in adults with LVADs were published in 2017 by the American Heart Association (AHA) . For theAssess responsiveness. If there is no response, call for help.2 should be monitored.Check if the patient is breathing and assist ventilation as needed with supplemental oxygen, airway adjuncts and intubation, as deemed necessary. End-tidal CODetermine if adequate perfusion is being maintained by assessing mental status, skin color, temperature and capillary refill. It is important to remember that LVAD supported patients may not have a palpable pulse or recognizable BP with an automatic machine, even with adequate perfusion.Assess if the LVAD is working by auscultating for an LVAD hum over the precordium. If there is a mechanical hum, then the device is likely working effectively. Ensure connections to the controller are secure, and ensure power supply is adequate.If the VAD is not functioning, and MAP is ≤ 50 mmHg, then chest compressions and rescue breaths should be initiated per the basic life support protocol. If a connection issue is identified, then the connection should be reestablished, provided the period of LVAD discontinuation is known to be less than 30 minutes. If there has been a prolonged period of LVAD discontinuation, thrombus formation is likely and restarting the device could result in a fatal embolism.If the LVAD is not functioning, and no connection problems are identified, a system controller change-out may be required. This should only be done by a trained provider or caregiver. Family members are trained to make this controller change.If the LVAD is still not functioning, chest compressions should be continued, defibrillation and medications should be administered per the advanced cardiac life support algorithms. Temporary mechanical support, including extracorporeal membrane oxygenation may be needed.ETCO2 < 20 mmHg, external chest compressions are indicated. If the LVAD is functioning, only gentle compressions are required, as only RV compressions are needed (the LVAD will continue to provide systemic flow). With an arterial line, the compressions can be adjusted as needed to maintain a perfusing arterial pressure. Overly vigorous chest compressions should be avoided, particularly in the early postoperative phase, as there is risk of dislodging the device and causing myocardial injury and hemorrhage. Defibrillation and medications should be administered per the advanced cardiac life support algorithms.If the LVAD is functioning, but the patient is unconscious with MAP ≤ 50 mmHg or PIf the LVAD is functioning and both respirations and perfusion appear adequate and the patient is unconscious, assess for causes of unconsciousness like stroke, coma , or sedation.It is reasonable to provide standard post-cardiac arrest care, including targeted temperature management and early percutaneous coronary intervention, when indicated. Of note, patients with an LVAD need adequate anticoagulation, which may be difficult to monitor during therapeutic hypothermia.In all hypotensive patients with an LVAD, an arterial catheter should be placed as soon as possible in either the radial or femoral position. Ultrasound guidance should be used. Continuous BP monitoring is essential as it is the only reliable means to monitor for adequate perfusion in these patients. Approach to the management of an unresponsive LVAD patient is depicted in the form of a flowchart in If available, point of care echocardiography should be performed. It is non-invasive, easy and quick to perform and can provide real-time information about the LVAD performance and complications like RV dysfunction, suction and cardiac tamponade. The number of ambulatory LVAD patients is rising and their life expectancy is improving, as well owing to improvements in technology and management. Non-LVAD specialists are increasingly encountering LVAD patients in a variety of clinical settings and, therefore, should be well prepared to perform the initial assessment and provide management for these complex patients. Also, as this therapy becomes more widely available, and adverse events reduce, joint management between the implanting centers and providers in the community will also become increasingly prevalent.


Patient remained asymptomatic from birth until 16 years of age, when he started toshow progressive fatigue at exertion, with the use of anti-congestive medicationsuch as furosemide, enalapril, spironolactone, and carvedilol, in addition towarfarin. The diagnosis of heart disease characterized by heart murmur was attainedin the first month of life.2: 89%.Physical examination: good overall status, eupneic, acyanotic, normal pulses in the 4limbs. Weight: 63 kg, Height: 171 cm, right upper limb blood pressure: 130/90 mmHg,HR: 63 bpm, Sat Oth left intercostal space inthe anterior axillary line and diffuse, with systolic impulses in the left sternalborder. Hyperphonetic heart sounds, with irregular splitting of the second heartsound. Moderate intensity ejection systolic murmur at the left upper sternal borderwith systolic thrill and holosystolic murmur ++/4 at the lower sternal border and atthe tip with diastolic murmur ++/4. The liver was palpable 4 cm from the costalborder and lungs were clear.Precordium: apex beat was palpable at the 6Electrocardiogram: Sinus rhythm and signs of left-chamber overload,with a narrow QRS of 0.87 ms (AQRS = +110°), a positive T wave in V1 (AT =+10°), and an enlarged P wave in II, III and in F (AP = + 60°) (= + 60°) .Chest x-ray: Significantly increased cardiac area on account of theright arch with double contour and left ventricular arch (CTI = 0.69). Increasedpulmonary vascular network and bulging middle arch  and interventricular (22 mm), and posterior deviation of theinfundibular septum with pulmonary subvalvular stenosis. Pulmonary trunkdilatation was observed, and the mitral valve showed double dysfunction. Theleft ventricle (LV) was dilated, with an ejection fraction of 54%. Maximumpressure gradient LV-PT = 58 to 77 mmHg. (77 mmHg. .Magnetic Resonance Image (MRI): Same findings observed in theechocardiogram.Cardiac catheterization: RV = LV: 110 mmHg; PT: 48 mmHg; PVR: 1.3 UWand SVR: 35.9 UW and Qp/Qs: 5.3/ L.Laboratory findings: Hg: 19.3, Hct: 59%, uric acid: 9.5.Clinical Diagnosis: Type II B tricuspid atresia with extensiveseptal defects and moderate infundibulum-pulmonary valve stenosis, mitralinsuficiency, maintaining pulmonary hyperflow and high arterial saturation,undergoing natural evolution until adulthood.Clinical Reasoning: There were clinical elements leading to adiagnosis of cyanogenic congenital heart disease with marked clinicalrepercussion, with pulmonary hyperflow. Tricuspid atresia or double LV inflowtract with mild to moderate pulmonary stenosis due to limitation of pulmonaryflow, in the presence of auscultation characteristic of associated pulmonarystenosis. The electrocardiogram emphasized LV overload, compatible with theabove diagnoses. Echocardiogram and MRI highlighted the diagnostic elements ofthe defect.Differential Diagnosis: Other cyanogenic heart diseases withpulmonary hyperflow should be recalled with the same pathophysiological picture.Among them, left atrioventricular valve atresia in the presence of awell-developed LV and any other heart disease accompanied by right ventricularhypoplasia.Clinical Conduct: Taking into account the harmonized pulmonary andsystemic flows over time, with no signs of hypoxemia and / or heart failure andin the presence of good physical tolerance, the clinical expectant managementwas considered.Comments: It is known that the different types of tricuspid atresia,whether with pulmonary flow limitation or not, has an unfavorable evolution,with signs of hypoxia or heart failure as early as in the first days of life,which progressively worsens over the first months, until the end of the firstyear of life. Therefore, the need for surgical intervention in this period. Itcan be affirmed that cases with tricuspid atresia and a mild repercussion whoremain asymptomatic until adulthood are rarely identified.1 In this circumstance, they maynot require early surgical intervention. Thus, it is important to emphasize thatthese patients require a stringent and thorough evaluation, in order to be ableto determine the most correct conduct for the infant, whether expectant orsurgical intervention. This decision becomes even more difficult in adulthood,since heart failure that is observed at a later period, with myocardialdilatation and hypertrophy, and even with cardiac function preservation, is aparameter for an indefinite conduct, given the greater surgical risks in thisage group. We did not find reports in the literature that were similar to thecase described herein.


In patients with left ventricular (LV) dysssynchrony, contraction that doesn’t fall into ejection period (LVEj) results in a waste of energy due to inappropriate contraction timing, which was now widely treated by cardiac resynchronization therapy(CRT). Myocardial Contraction Efficiency was defined as the ratio of Efficient Contraction Time (ECTR) and amplitude of efficient contraction (ECR) during LVEj against that in the entire cardiac cycle. This study prospectively investigated whether efficiency indexes could predict CRT outcome.Our prospective pilot study including 70 CRT candidates, parameters of myocardial contraction timing and contractility were measured by speckle tracking echocardiography (STE) and efficiency indexes were calculated accordingly at baseline and at 6-month follow-up. Primary outcome events were predefined as death or HF hospitalization, and secondary outcome events were defined as all-cause death during the follow-up. 16-segement Standard deviation of time to onset strain (TTO-16SD) and time to peak strain (TTP-16SD) were included as the dyssynchrony indexes.P < 0.05) and maximum longitudinal strain (MLS)  were the two independent predictors for CRT response, Both TTO-16SD and TTP-16SD failed to predict outcome. Patients with poorer myocardial contraction efficiency and better contractility are more likely to benefit from CRT.According to LV end systolic volume (LVESV) and LV eject fraction(LVEF) values at 6-month follow-up, subjects were classified into responder and non-responder groups, ECR (OR 0.87, 95%CI 0.78–0.97, STE can evaluate left ventricular contraction efficiency and contractility to predict CRT response. When analyzing myocardial strain by STE, contraction during LVEj should be highlighted. Randomized controlled trials have demonstrated that cardiac resynchronization therapy (CRT) is an effective therapy for patients suffering from heart failure refractory to medical therapy with widened electrocardiographic QRS complexes and reduced ejection fraction (EF) , 2. CurrObservational studies suggested that mechanical rather than electrical dyssynchrony can predict the CRT outcome . NeverthEj, the myocardial contraction will directly contribute to changes of LV volume and can be regarded as an effective contraction. The ratio of time and amplitude of contraction during LVEj against those throughout the cardiac cycle reflects the contraction efficiency. The current study hypothesized that low contraction efficiency indicated a high contractile reserve. Patients with low contraction efficiencies are more likely to respond to CRT.speckle tracking echocardiography (STE) is widely used to assess both timing and amplitude of myocardial contraction and has been proved to be superior to TDI in ultrasonic angle dependency, signal-to-noise ratio, and its ability to detect viable versus scarred myocardium Fig. a 14–17]–1714–17]The prospective pilot and observational study involved patients referred to our department for CRT implantation from January 2013 to December 2015. The inclusion criteria were as follows: (1) congestive heart failure patients remained symptomatic in New York Heart Association class (NYHA) III or stable class IV, despite optimal pharmacological therapy; (2) left ventricular ejection fraction ≤35%; (3) QRS duration ≥120 ms. The exclusion criteria were: (1) atrial fibrillation (AF); (2) previously implanted pacemaker; (3) recent cardiac event (< 3 months after an acute coronary syndrome or cardiac surgery); or (4) poor acoustic window or failure to undergo implantation of a biventricular device due to anatomic constraints. Then, patients with a reduction≥15% in LVESV together with a rise of ≥10% in LVEF at the 6-month follow-up were defined as CRT responders. The remaining ones were considered as non-responders. Primary outcome events were predefined as death or HF hospitalization, and secondary outcome events were defined as all-cause death during the follow-up. Thirty healthy subjects with normal physical and laboratory conditions served as control group.A complete standard echocardiography examination, including gray-scale images for 2D strain analysis (mean frame rate 64 ± 11 frames/s) was performed the day before CRT implantation using a VIVID E9 imaging system . Offline analyses were conducted with a standard imaging software (EchoPac BT12 GE-Vingmed). The LV end-systolic volume, LV end-diastolic volume and LVEF were calculated by the biplane Simpson’s rule .Ej)  Fig. c. SpecklMaximum longitudinal strain (MLS):Sum of the absolute value of maximum positive strain and maximum negative strain throughout the whole cardiac cycle.Effective Contraction (EC):Longitudinal myocardial shortening occurs within left ventricular ejection.All time-related indexes were corrected by R-R interval and indicated as a percentage of the cardiac cycle to avoid the influences by heart rate variation.Time to the onset of contraction (TTO):The time interval from the beginning of QRS to the point when a certain myocardial segment starts to contract, followed by strain curve with a declining trend.Time to Peak Strain (TTP):The time interval between the beginning of QRS and the lowest point of the strain curves.Total contractile time (TCT):Total time spent when maximum longitudinal strain occurred.Effective contractile time (ECT):Ej when longitudinal shortening occurred.The sum of time spent during LVEj and throughout the whole cardiac cycle.Contractile efficiency indexes were evaluated by the comparison of contractile patterns within LVRatio of effective contraction (ECR):Ratio of effective contractile time (ECTR):Standard deviation of 16 segments’ time to onset of contraction (TTO-16-SD):On apical four chamber view (A4C), apical two chamber view (A2C) and apical three chamber view (A3C), TTO results of 6 segments were obtained separately. TTO of apical septum on A4C and apical anterior septum on A3C were averaged to calculate that of apical septum; while TTO of apical inferior wall on A2C and apical posterior wall on A3C were averaged to calculate apical septum and apical inferior, and thus we can get TTO results of 16 segments in all. The standard deviation of the 16 segments’ TTOs was calculated to evaluate the synchronism of the start of contraction.Standard deviation of 16 segments’ time to peak strain (TTP-16-SD):TTP results of 16 segments was measured and calculated like TTO results. The standard of the 16 segments’ TTPs was calculated to evaluate the synchronism of the end of contraction.STE parameters including EC, ECT, ECR, ECTR, MLS, TTO and TTP of thirty randomly selected examinations (20 pre-implant patients and 10 controls) were re-evaluated by the original observer and a second independent observer. The intra-observer and inter-observer reproducibility were evaluated by Bland-Altman method comparison and intra-class correlation coefficient (ICC) , 24.Continuous variables are expressed as mean ± SEM. Baseline categorical data were compared by means of the Fisher’s exact test. The comparison between two groups was performed by unpaired t-test and that among three groups by One-way ANOVA.p value < 0.05 was considered significant. All analyses were carried out with use of the SPSS software .Based on the hypothesis that CRT response would be strongly associated with the contraction pattern within left ventricle ejection  and its relation to that of the cardiac cycle , bivariable logistic regression was used to testify the ability to predict CRT response. Based on previous reports of the associations between mechanical synchrony and CRT outcomes , TTO, TTOf the 81 patients enrolled, 11 patients were excluded because of atrial fibrillation (7%), previously implanted pacemaker (2%), poor image qualities (2%) or unsuccessful implantation due to anatomic constraints (1%). Accordingly, 70 patients with complete baseline data were included. 49 subjects were male and 21 were female with a mean age of (62 ± 10) years. Eight cases suffered from ischemic heart disease. Five cases (7%) died before 6-month follow-up, who were considered as non-responders. The Responder and the Non-responder group showed comparable age, gender composition, QRS duration, etiology, NYHA functional class and LVEF. However, a significantly larger LV volume was observed in the Non-responder group and a significantly higher TTO dyssynchrony index was seen in the responder group .ECT of both Non-responder and Responder groups decreased significantly compared with that of the control group. That is to say the time of contraction during left ventricle ejection period decreased in both patient groups and thus their left ventricles had less time to pump forward blood into the systemic circulation. TCT of the Responder group was longer than that of the Control group. It was very likely a compensation pattern occurred in the Responder group. A longer TCT can to some degree extended ECT. However, a shorter ECT with a longer TCT in the Responder group would inevitably make them exhibiting the worst ECTR which was defined as ECT/TCT. Similarly, the Control group exhibited the best ECTR, followed by that of the Non-responder.Obviously, timing of contractile efficiency deteriorated in both patient groups at baseline, yet the Responder group had an even more energy-consuming contractile pattern. However, as we mentioned when introducing the definitions of efficiency indexes, a poorer ECTR indicates a higher possibility to be improved Fig. .Fig. 2Co.Compared to baseline (Pre-implant), ECT and ECTR improved significantly and TCT remained unchanged in the Responder group. The Responder group had a more efficient contractile pattern after CRT. Although the Non-responder group failed to achieve a higher ECTR or a longer ECT, it did start a similar compensation contractile pattern with a longer TCT as the Responder group did at baseline. TCT of the Non-responder extended after CRT. Fig. .EC of both Non-responder and Responder group decreased significantly than that of the Control group. This may result from the weakened myocardium contractility and the previously stated finding that ECT shortened in both patient groups. Moreover, the Control Group showed the best ECR, followed by those of the Non-responder group, while the Responder group exhibited the worst ECR. This suggested that the low EFs of both patient groups were related not only to the contractility disorder but also to the contractile efficiency. Besides, the Responder group again showed the worst efficiency in contractility, consistent with the performance of its efficiency in contraction timing, enhancing its possibility to be improved. It was interesting for us to find that when most the parameters of mechanical contraction ability and efficiency turned out to be the worst in the Responder group, and it had better MLS than Non-responder group. A better MLS means a better contractility or myocardial vitality, so although the Responder group showed a worse contractile efficiency than the Non-responder group, it had a better baseline contractility or viability. Together with the previous mentioned finding that the Responder group may extend its TCT as compensation to maintain its ECT and ECTR, it is very likely that the Responder group may actually be at an earlier stage of the disease than the Non-responder group Fig. .Fig. 3Cop > 0.05) . CRT can improve the electrical activation sequence of myocardium segments and increase EC through changing the time of the events. An improved MLS may be achieved by the virtuous cycle of the energy-saving contractile in the remaining viable myocardium.All parameters of contractility and contractile efficiency including EC, MLS and ECR were improved significantly in Responder Group while remain unchanged in the Non-responder Group  Figs. , Table 2(Table ). However, only ECTR and MLS were proved to be the predictors for CRT response by multinomial logistic regression (Table ). ECTR and ECR are the indexes for contraction efficiency. A high ECTR or ECR represents a better contractile efficiency and indicates less potential to be improved. However, ECTR provided nothing but the information of contractile timing and neglected the contractility or the viability. Therefore it turned to be useless in predicting CRT outcome. Although MLS is not an index measured within LVEj, it represents the myocardial maximum reformation ability, or viability.Among all parameters, ECTR and ECR exhibited the best AUC in predicting non-response for CRT, while MLS had the best AUC in predicting response Table . Howeveron Table . ECTR anThe Average time consumed for calculating EC, ECT, MLS, TTO and TTP were 165 ± 25 s(about 2~ 3 min) while the time spent for ECR and ECTR were about 240 ± 45 s(about 4~ 5 min).p < 0.0001), and the result indicated a favorable reproducibility [The value of inter-observer ICC and intra-observer ICC for EC and ECT, ECR ECTR, MLS, TTO, TTP were analyzed respectively  was developed to analyze myocardium deformation and with adapting strain curve, it’s possible to learn the contraction synchrony of different segments and have the advantage of high spatial and temporal resolution and angle independence. Efforts have been made to find the optimal parameters for the detection of CRT responders using STE from different points of view and to better understanding the pathophysiologic mechanism of CRT. Risum et al  show thaEj), using speckle tracking echocardiography. The current study found that at baseline, the responder group has a more energy-consuming contractile pattern than that of the Non-responder group. At 6-month follow-up, ECR improved significantly in the responder group and contractile efficiency became better than the Non-responder group. Contraction that does not fall into LVEj, either earlier than AVO or later than AVC makes no contribution to cardiac output or LVEF. Myocardial contraction efficiency is closely associated with the CRT response. Compared with the maximum contractility throughout the cardiac cycle (MLS), the contraction during LVEj (EC) provided us the information of contractile efficiency (ECR = EC/MLS*100%). As Galli E [Our study used AVO instead of the beginning of QRS as the reference point of time for predicting response to CRT and focused on the mechanical contraction performance in left ventricular ejection period  and post-systolic shortening (PSS) are often reported in pathologic status such as ischemia and dyssynchrony , 36, botIn contrast to the previous reports , TTP dysHowever, there are some limitations of this study. MLS represents the viability to recover or contract better, ECR has a close relationship with both deformation velocity and time consumption within LVEj, representing the contractile efficiency and the potential to be improved. The current study investigated both important parameters above and regardless of LV lead position, which inevitably influenced CRT response. It may accounts for a suboptimal ROC AUC since it is unknown whether the LV lead is implanted at the most delayed segments and further animal and clinical experiments are needed to verify this. We compared the global strain of each STE parameter while Risum N  reports Myocardial contraction pattern within left ventricle ejection indicates the contraction efficiency and has a close relationship with patients’ CRT response. The onset of mechanical activation, rather than the onset of the QRS complex, should be used as the reference point to determine original myocardium length when measuring myocardial contractility. The influence of TTO, TTP, and their dyssynchrony indexes should be carefully interpreted considering their association with LV ejection period.


Neonatal heart failure (HF) is a progressive disease caused by cardiovascular and non-cardiovascular abnormalities. The most common cause of neonatal HF is structural congenital heart disease, while neonatal cardiomyopathy represents the most common cause of HF in infants with a structurally normal heart. Neonatal cardiomyopathy is a group of diseases manifesting with various morphological and functional phenotypes that affect the heart muscle and alter cardiac performance at, or soon after birth. The clinical presentation of neonates with cardiomyopathy is varied, as are the possible causes of the condition and the severity of disease presentation. Echocardiography is the selected method of choice for diagnostic evaluation, follow-up and analysis of treatment results for cardiomyopathies in neonates. Advances in neonatal echocardiography now permit a more comprehensive assessment of cardiac performance that could not be previously achieved with conventional imaging. In this review, we discuss the current and emerging echocardiographic techniques that aid in the correct diagnostic and pathophysiological assessment of some of the most common etiologies of HF that occur in neonates with a structurally normal heart and acquired cardiomyopathy and we provide recommendations for using these techniques to optimize the management of neonate with HF. In these neonates at risk for acquired cardiomyopathy, the integration of clinical and echocardiographic features allows for a better assessment of both immediate risk and long-term prognosis. The echocardiographic assessment of intrinsic abnormality of myocardial systolic function (contractility), diastolic function (relaxation and compliance), and structural growth (hypertrophy and dilatation) can help identify cardiovascular compromise earlier, guide therapeutic intervention, monitor treatment response, and hopefully improve overall outcome.8The clinical presentation of neonatal cardiomyopathy is varied, and the diagnostic evaluation of HF is complicated by a wide spectrum of rare genetic causes, numerous acquired causes, and varied clinical presentations that range from asymptomatic to congestive heart failure, multi-organ shock, arrhythmia, or encephalopathy.Neonatologist Performed Echocardiography (NPE) plays a pivotal role in detecting the disease and understanding its’ pathophysiology in neonates. In this review, we discuss the classifications and etiologies of neonatal cardiomyopathies, the most common acquired diseases that manifest with neonatal cardiomyopathies in the immediate postnatal period and the emerging echocardiographic methodology that can help in the correct diagnosis and pathophysiological assessment of neonates with cardiomyopathies.4 The causes of HF can be divided into several diverse overlapping categories:The appropriate classification of HF in neonates has been hampered by the diversity of its’ etiologies and uncertain pathogenesis.1. Cardiovascular vs. non-cardiovascular .3. Congenital cardiac malformation vs. structurally normal heart  based on feeding history, growth parameters, and physical findings.9Infants with cardiomyopathy can be further classified as genetic cause, acquired, or mixed.10 However, the infant with a structurally normal heart, who is at risk for an acquired cardiomyopathy, may present in the immediate postnatal period with overt signs of HF and shock that were not expected. For these infants, there must be an even higher index of suspicion to be able to properly assess, manage, and mitigate the HF. In this way, the clinician can screen for the cardiomyopathy with clinical examination and echocardiography at birth based on the known risk factors. The acquired causes of cardiomyopathy that lead to ventricular pump dysfunction may be due to hypoxic ischemic injuries , maternal endocrine disorders (IDM), infectious- or immune-related, fetal/neonatal arrhythmias, fetal preload and afterload alterations (twin-twin transfusion), or iatrogenic drug induced causes .The ability to anticipate or screen for HF in infants with congenital cardiac malformation or known genetic causes of cardiomyopathy has significantly improved based on antenatal diagnostic testing capabilities.An objective echocardiographic assessment of structure and function is important in classifying the acquired cardiomyopathies into the two most common phenotypic forms in neonates:1. Congestive/dilated cardiomyopathy (DCM); and2. Hypertrophic cardiomyopathy (HCM), , myocardial failure occurring due to ventricular dysfunction, impaired myocardial contractility, decreased cardiac output, and/or abnormal postnatal circulatory transition may also contribute to the neurological injury and exacerbate organ damage.17 Myocardial dysfunction has a reported incidence of 30–82% in neonates with severe neonatal encephalopathy,21 with hemodynamic instability ranging from 33 to 77% in patients receiving therapeutic hypothermia . The incidence of myocardial injury may actually be higher in the preterm infant with neonatal encephalopathy who is already at risk for myocardial dysfunction due to immaturity.22 The reduced heart function is often transient, with the most severe cardiovascular abnormalities typically occurring 2 to 3 days after the initial insult, followed by gradual recovery.24Perinatal hypoxic ischemic insults may result in multi-organ system dysfunction, and are a common cause of acute, often reversible cardiovascular dysfunction in neonates.25 The cardiac side effects of TH have been documented,33 but these are outweighed by the benefits on survival and neurodevelopmental outcome.29 TH alters systemic and pulmonary hemodynamics through increasing vascular resistance and lowering resting heart rate, which reduces cardiac output.32 Severe arrhythmia is rare, while transient sinus bradycardia is frequent during the cooling phase of TH, but does not usually require medical treatment.29 Cooled neonates have reduced heart function during treatment,28 probably at a similar level as non-cooled neonates.28 Although the heart function is reduced during cooling, the lactate levels that are often high at the start of treatment30 usually improve during cooling,28 due to reduced metabolic demands at low body temperature. The long-term cardiovascular consequences of rewarming and the impact of reperfusion on vital organs are not well delineated.In cases where the hypoxic ischemic insult causes encephalopathy, term and near-term neonates now receive TH as standard of care.34 While there is an association between outcome and heart function during TH,36 the long-term cardiac consequences from the perinatal hypoxic ischemic insult are not known. There is also a lack of clarity regarding thresholds for cardiovascular intervention; non-judicious use of inotropic agents may increase the risk of brain injury by promoting excessive cerebral reperfusion.15 There is evidence that neonates with higher flow in the superior vena cava are at greatest risk of brain injury.37Although TH has become the standard therapy, the ongoing hemodynamic instability, related either to the primary insult, the effects of TH (cooling and/or rewarming), or even the hemodynamic approach to intervention, may actually decrease the effectiveness of neuroprotective strategies by compromising vital organ perfusion and metabolism.38 Myocardial injury will ultimately develop when this “compensation mechanism” fails.39 Myocardial dysfunction will worsen further following the reperfusion injury due to reactive oxygen species and the injury eventually reduces the contractile responsiveness of the myocardium, causing a significant reduction in cardiac output,35 hypotension, and further impairment of cerebral blood flow and perfusion of other organs.40 The heart may be affected on all levels, but with a predilection for the papillary muscles and sub-endocardial regions.43 Though there has been no consistent link between the degree of hemodynamic instability and neurodevelopmental outcome,15 there are two major patterns of myocardial dysfunction that have been observed in neonates with a perinatal hypoxic insult. The first event results from depression of LV function with subsequent reduced cardiac output. The moderate to severe LV systolic dysfunction may lead to pulmonary venous hypertension because of diastolic impairment.15After the initial perinatal hypoxic insult, myocardial contractility increases and the myocardium works to enhance blood flow and protect against systemic hypoxia.44 This persistent pulmonary hypertension (PPHN) picture leads to right ventricular (RV) dysfunction and reduced RV output. As the PPHN worsens , the impairment in oxygenation and pulmonary venous return further compounds the already reduced systemic blood flow from LV dysfunction.14 TH and rewarming can affect systemic and pulmonary blood pressure.38 If the PPHN worsens it may necessitate an early termination of cooling31 with a gradual rewarming may have theoretical benefit in achieving a more controlled change in hemodynamics.15 “Rewarming hemodynamics” and how to actively adjust the cardiovascular specific medications throughout the warming period requires further study.15 Global ventricular dysfunction, which starts on the left and progresses to the right, may also lead to biventricular enlargement and dilated cardiomyopathy.7The second event results from the hypoxia preventing the normal relaxation of the pulmonary vascular bed, and the elevated pulmonary vascular resistance (PVR) causing deoxygenated blood to be shunted to the systemic vasculature.45 Cardiac troponins are biochemical markers of myocardial damage, and their levels increase in newborns with neonatal encephalopathy.53 Measurement of troponins has replaced the creatine kinase-MB (CK-MB) isoform as the biochemical test for cardiac involvement in neonates with neonatal encephalopathy.54 Troponin levels have prognostic significance with regards to mortality and outcome in perinatal hypoxic ischemia, and elevation of cardiac troponin T and I levels appears to correlate with neurodevelopment at 18 months.55 Elevation of cord troponin is a good early predictor of severity of encephalopathy from a perinatal hypoxic insult and mortality in term infants.56 There may also be a role for serum N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) as recent evidence has demonstrated that its levels can reflect myocardial injury in neonates with asphyxia and may also guide diagnosis.57Early and accurate detection of myocardial injury in neonates with neonatal encephalopathy presents an ongoing challenge for the neonatologist. A high index of suspicion for cardiopulmonary dysfunction is important in the neonate with clinical and biochemical evidence of a hypoxic ischemic insult. The clinical signs of myocardial injury and associated PPHN, coupled with the electrocardiographic and radiographic findings are all non-specific and inconclusive.7 In the most severe form, all of these etiologies can result in DCM with depressed global function and performance. If functional abnormalities are detected , NPE may then be utilized to perform longitudinal assessments and serially follow hemodynamic effects of treatment response in the sick neonates with neonatal encephalopathy.15 In the absence of clinical compromise or elevated troponin levels, NPE should be considered on an individual basis.14 NPE can still be used to provide clinically relevant information, i.e. assess fluid responsiveness and identify an underlying structural contribution to end-organ perfusion. Furthermore, irrespective of blood pressure, cardiac output may not be low, but sometimes quite high with very good myocardial contractility, even during cooling (suggestive of a low SVR). In general, NPE can be used to assess myocardial function, detect PPHN at an early stage, distinguish right-to-left atrial shunting caused by myocardial dysfunction or PPHN, and follow circulatory changes during cooling and rewarming phases of TH.14 During the cooling and rewarming phases, the assessment of hemodynamics may be challenging, and there may be a place for the use of NPE in optimizing hemodynamic management.38In the presence of clinical cardiovascular compromise and/or elevation of biomarkers, NPE should be used to first characterize the structural and then functional components of the heart disease. The etiology of an acquired hypoxic-ischemic myocardial insult is either from a perinatal hypoxic event or a coronary insult .14Conventional and emerging quantitative echocardiographic techniques are used to provide clinically useful measures of cardiac performance in the neonate with encephalopathy from a hypoxic ischemic event. Qualitative assessment with NPE in the parasternal long axis and short-axis views can provide useful information about myocardial function but should be considered in conjunction with the clinical examination and other established quantitative measures. For example, visualizing the LV cavity size in end-diastole, may aid in the assessment of fluid responsiveness . Although there is a paucity of data on the qualitative assessment of fluid status in neonates using echocardiography, neonates with encephalopathy from a hypoxic ischemic event often receive volume expansion therapy because of a failure to respond to stabilization, rather than clinically suspected hypovolemia. Excessive fluid administration may actually cause further impairment of gas exchange in the setting of myocardial dysfunction.58 Furthermore, they are both limited in the neonate for assessment of LV systolic function because of the presence of higher RV pressure and reduced septal motion.58 Functional assessment by FS often fails to detect impaired heart function in neonates treated at normothermia,60 especially in milder cases of perinatal hypoxic ischemic insults,23 while in more severe cases FS is reduced.62M-mode function allows for quantification of the initial visual assessment with fractional shortening (FS) and ejection fraction (EF). These conventional measures of LV function assess the changes in cavity dimensions, but may be insufficient to detect overt dysfunction in a timely manner because their measurements are influenced by image quality, inadequate reproducibility and standardization in neonates.47 Although SVC flow is not a true representation of cardiac output, it may potentially act as proxy measure for cerebral blood flow.14 The assessment for PPHN should include the various methods of estimation of pulmonary pressure , the assessment of patency and direction of shunt in the patent ductus arteriosus, degree of RV enlargement or hypertrophy, right atrial dilation, or any degree of ventricular septal wall flattening. We caution users on the subjective qualitative assessment of RV function, as this method has been shown to be inaccurate.64Cardiac output can be assessed by measuring the outflow tract diameter and the velocity time integral, and it has been shown that decreased LV outflow and stroke volume is evident in neonates with neonatal encephalopathy.45 in addition to deformation imaging26 are more sensitive than FS to detect reduced heart function.45 Measurements of RV dimensions, RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and deformation imaging are feasible for evaluation RV performance (structure and function) in both term and preterm infants67 and appear to be suitable techniques for measuring changes in myocardial function in neonatal encephalopathy.68 Nestaas et al. demonstrated a decrease in global and regional myocardial function with TD derived strain imaging in infants with neonatal encephalopathy who received TH and normothermic infants. Similarly, Seghal et al.27 observed that STE derived strain was impaired and Czernick et al.26 showed that strain rate by 2D STE was lower during TH and improved after re-warming, reflective of improvement in myocardial contractility after re-warming. .Advances in neonatal cardiac imaging permit a more comprehensive assessment of myocardial performance in neonatal encephalopathy that could not be previously obtained with conventional imaging. Tissue Doppler (TD) velocities and timing events of the AV-plane,ng. Fig. ; 68.Fig.11 Functional myocardial abnormalities are present in up to 30% of IDMs and include intraventricular septal hypertrophy and cardiomyopathy (HCM). While symptomatic HCM occurs in 10–15% of IDMs, it is found in up to 30% of IDMs when routinely searched for with an echocardiogram.70 The incidence of HCM is higher in infants born to mothers with pre-gestational DM.71 During the gestational periods, the high levels of glucose in the maternal blood will cause fetal hyperglycemia through the placenta and affect the heart in multiple ways, including cardiac malformations, hypertrophic cardiomyopathy, and functional impairment.72 IDMs may also suffer from delayed transitional pulmonary circulation that can progress to more severe PPHN.73 While most of the alterations in systemic and pulmonary haemodynamics appear to resolve during the first year of age, there is limited information regarding the long-term cardiac performance in the IDM population.The reversible cardiomyopathy seen in IDM’s is the most common form of HCM during the early neonatal period.72 The majority of the IDMs are actually asymptomatic despite this dysfunction, and the septal wall hypertrophy is typically transient, resolving in 2 weeks to 4 months.77 The myocardial hypertrophy predominantly affects the interventricular septum but may also involve the free walls symmetrically. As the hypertrophy extends to the rest of the myocardium and the right and left posterior walls become thickened and enlarged, the non-obstructive moderate form of HCM leads to mild diastolic dysfunction in the setting of normal systolic function.78 In extreme cases of hypertrophy, LVOT obstruction occurs with severe diastolic and systolic dysfunction. The obstructive HCM in the IDM can generate an elevated pressure gradient in the cavity during systole, with maximum peak at the end of the systole, leading to systolic obstruction to LV ejection. The LV mass and contractility are increased and there is LVOT obstruction with apposition of the anterior leaflet of the mitral valve to the interventricular septum during systole, all of which can be seen on echocardiography. The cardiac output is significantly reduced, secondary to reduced stroke volume, and is directly related to the degree of septal hypertrophy.The diagnosis and management of HCM in IDM is based on a thorough understanding of the underlying anatomy and pathophysiology, but the clinical outcome relates directly to the degree of dynamic obstruction to the LV outflow tract (LVOT) and/or to the degree of diastolic dysfunction. IDMs can have abnormal cardiac performance ranging from asymmetrical septal hypertrophy in the mildest cases, non-obstructive HCM in moderate cases, or massive obstructive HCM and major HF in extreme cases. As the most common cardiac pathology in IDMs, asymmetric septal hypertrophy is an anabolic result of fetal hyperinsulinemia triggered by maternal hyperglycemia during the third trimester.The approach to cardiovascular care in the IDM should consider actual pathophysiology, phase of intervention, and impact of concomitant treatments. IDMs should be evaluated for clinical signs of:1. HF  and2. PPHN . Dehydration and hyperviscosity (caused by polycythemia) exacerbate these symptoms and should be accounted for in the cardiovascular assessment.Echocardiography is used for screening and preclinical diagnosis to detect the different presentations of HCM in IDMs. When clinical signs of HF or PPHN are present, postnatal echocardiography screening and identification of which IDMs to serially follow with NPEs is warranted to modulate infant cardiac dysfunction. In the extreme cases of HCM and PPHN, serial echocardiographic imaging can facilitate the identification of potential candidates for such treatment and help guide therapy. For example, neonatal symptoms of low cardiac output can present with variable severity and could be a result of the diastolic dysfunction (poor ventricular filling) with or without LVOT obstruction or from LV systolic dysfunction. Echocardiograms can follow the response to the decrease in the LVOT gradient and improvement in diastolic function following medical treatment. IDMs with documented septal hypertrophy on echocardiogram and signs of HF or PPHN should be followed.79 The interventricular septum is best visualized from the parasternal long axis view and short axis view  flow is not affected by the PDA or FO shunts, which makes it a proxy measure of systemic blood flow during early transition. It should be noted that LVO and RVO calculations may be inaccurate in the presence of non-laminar flow due to mid-cavity or outflow tract obstruction with flow acceleration. Screening for mid-cavity flow acceleration may be warranted. RV performance (structure and function) is measured from the apical view and the parasternal long axis view to properly assess inflow and outflow linear dimensions. RV areas are assessed during end-diastole and end-systole from the apical four-chamber view.In the IDM with suspected HCM, NPE is utilized to evaluate ventricular dimensions  and function, the severity of dynamic LVOT obstruction, the presence of mitral valve abnormalities; special attention is paid towards the septum and its relationship to the LVOT. Both M-mode and 2D echocardiography are utilized. Linear internal measurements of the LV are acquired in the parasternal long-axis view. Volume measurements are based on tracings of the blood-tissue interface in the apical four- and two- chamber views. In the normally shaped LV, both M-mode and 2D echocardiographic formulas are used to calculate LV mass, of which normal reference ranges exist for term and preterm infants.iew Fig. . The deg83 Al-Bitalgi showed that torsion and LV longitudinal systolic strain by STE were significantly impaired in IDMs during the transitional period.81 Liao et al. demonstrated a similar decrease in torsion, but with preserved EF, suggesting that rotational mechanics may offer a more sensitive measure of ventricular function.82 Systolic function is thought to be preserved in IDM, yet the use of more sensitive echocardiographic techniques have revealed that systolic dysfunction may be evident at birth and persist through 1 month of age.83 Cade et al. showed that septal wall thickness was not different at 1 month, but global and segmental systolic and diastolic strain values were significantly lower in IDM.83 Therapeutic approaches are beyond the scope of this review but should ensure adequate LV filling (maintenance of preload) and avoidance of diuretics which can considerable worsen condition (by compromising LV filling). Maintaining adequate afterload (to minimize the pressure gradient across the LVOT) and avoiding tachycardia are the other two mainstays of treatment.Normal strain  and shear strain  have recently been studied in IDMs.84 Myocarditis has been classified as both an inflammatory and infectious cause of cardiomyopathies, which is reflective of its myriad presentations range from minimal symptoms to severe HF and sudden death.4 Myocarditis accounts for approximately 15% of patients with DCM in children, but is less common in neonates . Although the incidence in neonates is decreasing, it remains a significant complication of infection.85 Neonatal infectious myocarditis can be caused by several viruses  or bacteria , but is predominantly caused by Coxsackie B. Neonatal Coxsackie B myocarditis can affect both full-term and preterm infants and usually presents within the first week of age.85 The signs of neonatal myocarditis are nonspecific and range from mild respiratory or gastrointestinal illness to significant meningoencephalitis.86 Manifestations include congestive HF, tachycardia, and electrocardiographic changes.85Myocarditis is an inflammatory process that affects the heart muscle and can cause rare, yet devastating HF in neonates.87 In the second stage, the inflammatory phase, activation of the host immune system by the primary viral infection causes myocellular damage that results in myocardial dysfunction (often LV) leading to impaired contractility and HF.88 The acute myocarditis is commonly followed by complete recovery of LV function, but can progress to a secondary DCM with chronic HF.84 During this third phase, some neonates will develop significant arrhythmias , conduction disturbances, or circulatory collapse.85 This cardiovascular collapse may occur several days after the onset of the sepsis-like illness during this second wave of a biphasic pattern of infection.88 The prognosis for neonates that develop myocarditis varies. Neonatal myocarditis can be fatal in early infection. However, for patients that survive the acute illness, recovery with few long-term sequelae may be seen. Full recovery can be prolonged and associated arrhythmias may persist for months afterwards.In neonates, cardiac muscle involvement is more prominent and the myocardial damage primarily occurs due to direct lysis of infected myocytes during the initial viral infection phase.84 The methodical approach to neonates with suspected myocarditis will account for the varied differentials that range from bacterial/viral sepsis, critical congenital heart diseases with ductal dependent systemic circulation to acute metabolic crises.88 Routine laboratory investigations should also include cardiac enzyme levels (e.g. cardiac troponins). Electrocardiogram (ECG) findings are usually nonspecific and include sinus tachycardia, PR prolongation and nonspecific ST changes. ST segment and T-wave abnormalities are the typical ECG patterns, but they are usually transient.89 Cardiorespiratory focused therapies  may be indicated based on the level of support appropriate for the clinical symptoms, but the specifics are beyond the scope of this review. The prognosis is poor and further aggravated by prematurity.90The diversity of signs, symptoms, and clinical presentations accompanying acute myocarditis makes its diagnosis challenging. The clinical symptoms encountered in neonates may include tachycardia, tachypnea with abnormal respiratory patterns, cyanosis, and poor perfusion. Neonates may not tolerate feedings and present with emesis. Fever (or hypothermia) may be present. Other cardiac specific signs such as pallor, hypotension, edema, and hepatomegaly occur in only a minority of cases.NPE should be performed when myocarditis is suspected in a neonate with new onset clinical findings of cardiac dysfunction , a rise in cardiac biomarkers, or ECG changes suggestive of acute myocardial injury or arrhythmia.91 and others have shown RV dysfunction to be an independent predictor of outcome.92 In addition, the presence of myocardial interstitial edema and pericardial effusions (myopericarditis) in acute myocarditis leads to thickening of the ventricular wall, which can also be detected by echocardiography. Although the most common echocardiographic finding associated with myocarditis is a DCM phenotype, hypertrophic and restrictive phenotypes have been described in histologically proven myocarditis in adults.91 Fulminant myocarditis is less common in neonates, but has a distinct symptom complex from acute myocarditis with characteristic echocardiographic phenotype of reduced LV ejection, normal cavity size, and increased septal thickening.93The gold standard for diagnosing myocarditis is endomyocardial biopsy, however the invasive nature and potential serious complications, make this impractical in neonates. Non-invasive techniques, such as echocardiography, to detect myocarditis are necessary. Traditional echocardiography findings are LV regional or global dysfunction, LV wall motion abnormalities, and LV dilatation. However, some studies in adults with histologically proven myocarditis have also found evidence of RV dysfunction,94 In children and neonates with myocarditis there are a paucity of reports on the utility of these novel echocardiographic modalities.95 Although the literature is expanding, most of the adult studies lack a correlation to muscle biopsy or even cardiovascular magnetic resonance imaging, limiting the reliability of the measures in this clinical scenario. Nonetheless, the findings suggest there may be a role for using deformation imaging in the diagnosis and management of acute myocarditis.Although conventional echocardiography is considered as a reliable tool for ventricular wall motion evaluation, the visual estimation is subjective and has high inter-observer and intra-observer variability in neonates. There is growing evidence from studies in adult patients that has evolved from case reports to prospective studies that utilizes deformation imaging techniques to asses ventricular function in patients with acute myocarditis at risk to develop DCM.96 but atrial ectopic tachycardia (AET) is the most common of AINC.97 In older infants and children, the etiologies of cardiomyopathy also include re-entry tachycardia (i.e. WPW) and permanent junctional reciprocating tachycardia . Tachycardia-induced cardiomyopathy  is a rare entity of AINC caused by prolonged periods of sustained tachycardia. Neonatal complete heart block seen in association with a maternal autoimmune disease or a congenital cardiac malformation can rarely lead to AINC. The cardiomyopathy and accompanied LV systolic dysfunction is transient, often normalizing following treatment to restore normal sinus rhythm, and carries a favorable prognosis in younger infants.98 The tachycardia could either be the primary cause of the cardiomyopathy, or secondary to a cardiomyopathy of different etiology.Fetal and early persistent neonatal arrhythmias can cause a transient DCM phenomenon, referred to as arrhythmia-induced neonatal cardiomyopathy (AINC). In neonates, all tachyarrhythmia (even supraventricular and ventricular ectopy) could potentially cause AINC,96 The sustained tachycardia in AINC may lead to abnormal cellular remodeling, diminishing the number of microtubules in the cardiac myocyte and contributing to contractile dysfunction.99 Chronic tachycardia may lead to a depletion of high-energy phosphates and cellular reduction in sarcolemmal sodium/potassium ATPase activity and enzyme distribution that may affect calcium handling.100 Neonates will therefore have more rapid deterioration in function due to lower intracellular calcium reserves.96The incidence of AINC is difficult to estimate due to a paucity of published case reports in neonates and case series in children. This is probably an under-appreciated etiology of dilated cardiomyopathy and myocardial dysfunction in children.99 The first presenting sign may either be the arrhythmia or the clinical symptoms that manifest as systolic HF develops. Even a single, sustained episode of typical supraventricular tachycardia may be unrecognized until HF symptoms emerge; thus, neonates may present with clinical signs of shock.99 If the arrhythmia is first recognized after birth, the infant may still be asymptomatic, but left untreated or unrecognized after a few days to weeks of accelerated ventricular rates, signs of congestive heart failure and a state of cardiac contractile dysfunction can evolve because of the DCM.96 AINC can also present with tachycardia interspersed with periods of sinus rhythm, and therefore the responsible tachycardia may also not be evident at presentation.97 The neonate cannot verbalize the common symptoms of palpitations, further complicating the early identification of heart failure. Neonates with initial symptomatic AINC might have also had fetal tachycardia.The clinical presentation of AINC is variable in neonates and although a high index of clinical suspicion may point to subtle diagnostic clues, the condition may still go unrecognized initially.99 Therapy options are beyond the scope of this review, but should be tailored to the suspected arrhythmia that is inducing the cardiomyopathy.99 In contrast to adult cases of AIC, where LV systolic functional recovery may take weeks to months and reverse remodeling may take years to bring the heart rate and rhythm under control, in neonate the median time to recovery is reported at less than 2 months.99The diagnostic evaluation of AINC initially relies on electrocardiogram (ECG) to document the cardiac rhythm and ventricular heart rate. Comparisons to prior ECGs should be routinely performed, when available. Usually the diagnosis of AINC can only be made following a successful trial of therapy to slow the ventricular rate or to restore sinus rhythm along with the exclusion of other potential causes of cardiomyopathy.A high index of clinical suspicion of AINC should be suspected in neonates with a history of fetal tachycardia and evidence of new onset LV systolic dysfunction soon after birth. These infants should undergo NPE to assess cardiac structure and function.101). Neonates with AINC will have a smaller LV end-diastolic diameter and smaller LV Mass index than those with pre-existing dilated cardiomyopathy and concomitant tachyarrhythmia. In addition, LV end-systolic dimensions, EF, and the degree of mitral regurgitation should be assessed.98Systolic ventricular dysfunction is often the first manifestation of AINC, followed by LV dilatation after prolonged dysfunction Fig. ; 101. NeThere are no reported studies in the literature that utilize emerging measures to characterize cardiac performance in neonates with AINC.Neonatal HF is a clinical condition that results from impairment of the ventricle to fill with or eject blood. The causes of HF can be divided into pathophysiologic categories that aid in the understanding of the underlying physiology and clinical manifestations (see Table


Right-sided heart failure is the major cause of death among patients who suffer from various forms of pulmonary hypertension and congenital heart disease. The right ventricle (RV) and left ventricle (LV) originate from different progenitor cells and function against very different blood pressures. However, differences between the RV and LV formed after birth have not been well defined. Work from our laboratory and others has accumulated evidence that redox signaling, oxidative stress and antioxidant regulation are important components that define the RV/LV differences. The present article summarizes the progress in understanding the roles of redox biology in the RV chamber-specificity. Understanding the mechanisms of RV/LV differences should help develop selective therapeutic strategies to help patients who are susceptible to and suffering from right-sided heart failure. Modulations of redox biology may provide effective therapeutic avenues for these conditions. Patients with pulmonary hypertension and repaired congenital heart disease are at risk for developing right-sided heart failure ,2,3. HowDevelopmentally, LV and RV myocytes are derived from different precursor cells. Cells in the first heart field (primary heart field) contribute to the formation of the LV myocardium, whereas cells in the second heart field (anterior heart field) construct the RV myocardium ,8,9. FunS-glutathionylation, nitrotyrosine formation, and S-nitrosocysteine formation were found to be higher in the failing RV compared to control RV [S-nitrotyrosinylated proteins include heat shock protein-90 and sarcoplasmic reticulum Ca2+-ATPase, and S-glutathionylated proteins include heat shock protein-90 and NADH-ubiquinone oxidoreductase [In rats, the injection of an inhibitor of the vascular endothelial growth factor receptor SU5416) plus stimuli such as hypoxia and ovalbumin immunization trigger pulmonary arterial hypertension ,15 and r plus stintrol RV . Mass speductase .Total protein carbonylation was not altered in the RVs of rats with pulmonary hypertension compared with the controls . HoweverGata4 promoter [GATA4 gene expression [GATA4 gene transcription is through releasing the negative regulation by annexin A1 [GATA4 gene expression -3-hydroxy-8′-apocarotenol (R)-3-hydroxy-8′-apocarotenol has potential to confer a similar activity as β-carotene. In addition, it possesses a hydroxyl group that may be redox active. Coprocholic acid and 1alpha,25-dihydroxy-25,25-diphenyl-26,27-dinorvitamin D3 also contain four and three hydroxyl groups, respectively.To investigate the possible differences between the adult RV and LV, metabolomics analysis was performed using RV and LV free wall tissues obtained from adult rats by examining molecules with mass less than 1000. While a majority of metabolites seem to be expressed at similar levels between the RV and LV, some molecules exhibited statistically significant difference between their levels in the two ventricles. From these data, four biologically relevant molecules that occur at different levels between the RV and LV were identified. Among them, the levels of (3arotenol A and coparotenol B were foarotenol C and neuarotenol D were foNeuromedin N and another larger peptide, neuromedin N, both elicit cell signaling by activating neurotensin receptors. Neuromedin N is a small peptide with six amino acids, Lys-Ile-Pro-Tyr-Ile-Leu, while neurotensin contains 13 amino acids, Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu. Interestingly, both peptides are relatively rich in carbonylation-susceptible amino acids described above. 33% of amino acids in neuromedin N and 38% in neurotensin are composed of carbonylation-susceptible amino acids.To investigate the possible role of neurotensin/neuromedin N in right heart failure, immunohistochemistry experiments using the neurotensin/neuromedin N antibody were performed to compare the RVs of control rats to those of rats with right heart failure promoted by the injection of SU5416 plus chronic hypoxia that promotes severe pulmonary hypertension . The exaStudies of experimental animals and human patients revealed that the RV is more susceptible to the occurrence of oxidative stress than the LV in the setting of heart failure because the RV has weaker antioxidant-adaptive defense mechanisms ,29,30.In female Wistar rats, Schreckenberg et al.  found thIn human heart failure patients, Borchi et al.  reported2 saturations.In children with tetralogy of Fallot, Chaturvedi et al.  observedThe RV health is crucial to patients with pulmonary hypertension as well as with congenital heart disease including tetralogy of Fallot, pulmonary atresia, transposition of the great arteries and hypoplastic left heart syndrome. While the global RV and LV gene expression patterns and cell signaling mechanisms are similar, there are some subtle but crucial differences between RV and LV that may potentially define chamber-specific therapeutic strategies. Redox signaling, oxidative stress status and antioxidant regulation define important RV/LV differences. Further work focusing on these biological mechanisms may improve preventative and/or treatment strategies to help patients who are susceptible to developing right-sided heart failure. We hope that this article will promote further basic research concerning redox mechanisms of RV failure and possibly future clinical trials for the use of redox agents for the treatment of right-sided heart failure.