Heart failure with preserved ejection fraction  ( HFpEF ) is a form of  heart failure  in which the  ejection fraction  – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; [ 1 ]  this may be measured by  echocardiography  or  cardiac catheterization . Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called  heart failure with reduced ejection fraction  (HFrEF). [ 1 ]


Risk factors for HFpEF include  hypertension ,  hyperlipidemia ,  diabetes ,  smoking , and  obstructive sleep apnea .


HFpEF is characterized by abnormal  diastolic  function: there is an increase in the stiffness of the  left ventricle , which causes a decrease in left ventricular relaxation during diastole, with resultant increased pressure and/or impaired filling. [ 2 ]   There is an increased risk for  atrial fibrillation  and  pulmonary hypertension .


There is controversy regarding the relationship between  diastolic heart failure  and HFpEF. [ 3 ] [ 4 ]


Clinical manifestations of HFpEF are similar to those observed in HFrEF and include shortness of breath including exercise induced  dyspnea ,  paroxysmal nocturnal dyspnea  and  orthopnea , exercise intolerance, fatigue, elevated  jugular venous pressure , and  edema . [ 5 ]


Patients with HFpEF poorly tolerate stress, particularly hemodynamic alterations of ventricular loading or increased diastolic pressures. Often there is a more dramatic elevation in systolic blood pressure in HFpEF than is typical of HFrEF. [ 6 ]


Diverse mechanisms contribute to the development of HFpEF, many of which are under-investigated and remain obscure. Despite this, there are clear risk factors that contribute to the development of HFpEF. [ 7 ]


Hypertension ,  obesity ,  metabolic syndrome , and sedentary lifestyle have been identified as important risk factors for diverse types of heart disease including HFpEF. There is mechanistic and epidemiological evidence for a link between  insulin resistance  and HFpEF. [ 8 ]


This pro-inflammatory state may also induce changes in the vascular  endothelium  of the heart. Specifically, by reducing availability of  nitric oxide , an important  vasodilator  and regulator of  protein kinase G  activity. As protein kinase G activity diminishes, cardiomyocytes undergo hypertrophic changes. Endothelial cells also are responsible for the production of  E-selectin , which recruits  lymphocytes  into the tissue beneath the endothelium that subsequently release  transforming growth factor beta , encouraging  fibrosis  and thus ventricular stiffening. Cardiac macrophages are thought to play an important role in the development of fibrosis as they are increased in HFpEF and release pro-fibrotic  cytokines , such as IL-10. [ 9 ] [ 10 ]  Further investigation of the role of inflammation in HFpEF is needed. [ 11 ]


Conditions, such as hypertension, that encourage increased left ventricular  afterload  can lead to structural changes in the heart on a  gross , as well as a microscopic level. It is thought that increased pressure, in concert with a pro-inflammatory state (insulin resistance, obesity), encourage ventricular stiffening and remodeling that lead to poor cardiac output seen in HFpEF. There changes are a result of left ventricular muscle  hypertrophy  caused by the high pressure, leading to the left ventricle becoming stiff. [ citation needed ]


Ischemia , or inadequate oxygenation of the myocardium, is observed in a high proportion of HFpEF patients. This ischemia may be secondary to  coronary artery disease , or a result of the previously described changes in  microvasculature . [ 12 ]
Ischemia can result in impaired relaxation of the heart; when myocytes fail to relax appropriately,  myosin cross bridges  remain intact and generate tension throughout diastole and thus increase stress on the heart. This is termed partial persistent  systole . Ischemia may manifest in distinct ways, either as a result of increasing tissue oxygen demand, or diminished ability of the heart to supply oxygen to the tissue. The former is the result of stress, such as exercise, while the latter is the result of reduced  coronary  flow. [ citation needed ]


Cardiac  senescence , or cellular deterioration that occurs as part of normal aging, closely resembles the manifestations of HFpEF. Specifically, loss of  cardiac reserve , diminished  vascular compliance , and diastolic dysfunction are characteristic of both processes. It has been suggested [ 13 ] [ 14 ]  that HFpEF merely represents an acceleration of a normal aging process.


Senile systemic amyloidosis , resulting from accumulation of aggregated wild-type  transthyretin  as part of the  degenerative aging  process, is emerging as an important and underdiagnosed contributor to HFpEF with age. [ 15 ] [ 16 ]


The decline in  estrogen  levels that occurs with  menopause  has been hypothesized to contribute to the increase in HFpEF observed amongst post-menopausal women. [ 17 ]  Animal studies show that even at a young age, a decline in estrogen leads to changes in expression of  fibrosis  related genes in the heart. [ 18 ]


Any condition or process that leads to stiffening of the left ventricle can lead to diastolic dysfunction. Other causes of left ventricular stiffening include: [ citation needed ]


Causes of isolated right ventricular diastolic failure are uncommon. These causes include: [ citation needed ]


Structural changes that occur with HFpEF are often radically different from those associated with heart failure with reduced  ejection fraction  (HFrEF). [ 19 ]  Many patients experience increased thickening of the ventricular wall in comparison to chamber size, termed  concentric hypertrophy . This leads to increased left ventricular mass and is typically accompanied by a normal, or slightly reduced, end diastolic filling volume. Conversely, HFrEF is typically associated with  eccentric hypertrophy , characterized by an increase in cardiac chamber size without an accompanying increase in wall thickness. This leads to a corresponding increase in left ventricular end diastolic volume. [ 20 ]


Cellular changes generally underlie alterations in cardiac structure. In HFpEF  cardiomyocytes  have been demonstrated to show increased diameter without an increase in length; this is consistent with observed concentric ventricular hypertrophy and increased left ventricular mass. HFrEF cardiomyocytes exhibit the opposite morphology; increased length without increased cellular diameter. This too is consistent with eccentric hypertrophy seen in this condition. [ citation needed ]


Changes in the  extracellular  environment are of significant importance in heart disease. [ 21 ] [ 22 ]  Particularly, regulation of genes that alter  fibrosis  contribute to the development and progression of HFrEF. This regulation is dynamic and involves changes in  fibrillar collagens  through increased deposition as well as inhibition of enzymes that break down extracellular matrix components (matrix  metalloproteinases ,  collagenases ). While early stage HFrEF is associated with a significant disruption of extracellular matrix proteins initially, as it progresses fibrotic replacement of  myocardium  may occur, leading to scarring and increased interstitial collagen. [ 23 ]  Fibrotic changes in HFpEF are more variable. Though there is typically an increased amount of collagen observed in these patients it is usually not dramatically different from healthy individuals. [ 24 ]


Diastolic  alterations in HFpEF are the predominating factor in impaired cardiac function and subsequent clinical presentation. [ 25 ]  Diastolic dysfunction is multifaceted, and a given patient may express diverse combinations of the following: incomplete myocardial relaxation, impaired rate of ventricular filling, increased left atrial pressure in filling, increased passive stiffness and decreased distensibility of the ventricle, limited ability to exploit the  Frank-Starling mechanism  with increased  output  demands, increased diastolic left heart or pulmonary venous pressure. [ 25 ] [ 26 ] [ 27 ]


Diastolic failure appears when the ventricle cannot be filled properly because it cannot relax because its wall is thick or rigid. This situation presents usually a  concentric hypertrophy . In contrast, systolic heart failure has usually an  eccentric hypertrophy . [ 28 ]


Diastolic failure is characterized by an elevated diastolic pressure in the left ventricle, despite an essentially normal/physiologic end diastolic volume (EDV). Histological evidence supporting diastolic dysfunction demonstrates  ventricular hypertrophy , increased interstitial  collagen  deposition and infiltration of the myocardium. These influences collectively lead to a decrease in distensibility and elasticity (ability to stretch) of the myocardium. As a consequence, cardiac output becomes diminished. When the left ventricular diastolic pressure is elevated, venous pressure in lungs must also become elevated too: left ventricular stiffness makes it more difficult for blood to enter it from the left atrium. As a result, pressure rises in the atrium and is transmitted back to the pulmonary venous system, thereby increasing its  hydrostatic pressure  and promoting  pulmonary edema . [ 29 ]


It may be misguided to classify the volume-overloaded heart as having diastolic dysfunction if it is behaving in a stiff and non-compliant manner. The term diastolic dysfunction should not be applied to the dilated heart. Dilated ("remodeled") hearts have increased volume relative to the amount of diastolic pressure, and therefore have increased ( not  decreased) distensibility. The term diastolic dysfunction is sometimes erroneously applied in this circumstance, when increased fluid volume retention causes the heart to be over-filled ( high output cardiac failure ). [ 29 ]


Although the term diastolic heart failure is often used when there are signs and symptoms of heart failure with normal left ventricular systolic function, this is not always appropriate. Diastolic function is determined by the relative end diastolic volume in relation to end diastolic pressure, and is therefore independent of left ventricular systolic function. A leftward shift of the end-diastolic pressure-volume relationship (i.e. decreased left ventricular distensibility) can occur both in those with normal and those with decreased left ventricular systolic function. Likewise, heart failure may occur in those with dilated left ventricular and normal systolic function. This is often seen in valvular heart disease and high-output heart failure. Neither of these situations constitutes a diastolic heart failure. [ 29 ]


Stiffening of the left ventricle contributes to heart failure with preserved ejection fraction, a condition that can be prevented by four exercise sessions/week or more (more than casual exercise) throughout adulthood. [ 30 ]


In diastolic heart failure, the volume of blood contained in the ventricles during diastole is lower than it should be, and the pressure of the blood within the chambers is elevated. [ 31 ]


During diastole, the ventricular pressure falls from the peak reached at the end of  systole . When this pressure falls below the atrial pressure, atrio-ventricular valves open ( mitral valve  at left side and  tricuspid valve  at right side) and the blood passes from the atria into the ventricles. First, ventricles are filled by a pressure gradient but near the end, atria contract (atrial kick) and force more blood to pass into ventricles. Atrial contraction is responsible for around 20% of the total filling blood volume. (In atrial fibrillation, this additional 20% filling volume is lost and the patient may experience systolic heart failure symptoms). [ 32 ]  Complete left ventricular filling is essential to maintain maximum cardiac output. Left ventricular filling is dependent upon  ventricular relaxation  and  compliance , mitral valve area, atrio-ventricular gradient, atrial contraction and end-systolic volume. Diastole has four phases: isovolumetric relaxation, rapid filling, diastasis and atrial contraction. All of these phases can be evaluated by  Doppler echocardiography . [ 29 ]


Though HFpEF is characterized by a normal ejection fraction, this parameter is a rather poor index of the heart's contractile function. [ 33 ]  Some studies have shown that metrics of load independent contractility (such as left ventricular stiffness) reveal diminished systolic function in HFpEF patients compared to healthy controls, [ 20 ]  and are corroborated by tissue Doppler findings that reveal changes in longitudinal contraction and motion abnormalities. [ 34 ]  While these systolic impairments may be minimal at rest, they become more exaggerated with increased demand, as seen in exercise. [ 35 ]


Most HFpEF patients exhibit  pulmonary hypertension  which is significantly associated with increased morbidity and mortality. [ 36 ]  Left atrial and pulmonary venous pressure increases in HFpEF due to diastolic insufficiency thus increasing pulmonary artery pressure. In patients with advanced HFpEF changes in the pulmonary vasculature may develop, leading to pre-capillary pulmonary hypertension. [ 37 ]  Right ventricular dysfunction is also common in HFpEF patients, occurring in 20-35% of patients. This right ventricular dysfunction is more common in patients with more advanced HFpEF as well as those with pulmonary hypertension and lower ejection fractions. [ 38 ]


Cardiac output is dependent on  stroke volume  and  heart rate . A significant portion (55-77%) of HFpEF patients are unable to increase heart rate to compensate for increased output demand (as in the setting of exercise); this is termed  chronotropic  incompetence. [ 39 ]  Combined with the characteristic deficit in stroke volume observed in HFpEF patients, many individuals display poor exercise tolerance. [ 40 ]


Non-simultaneous contraction of the left and right ventricle,  dyssychrony , is present in up to 58% of HFpEF patients. [ 41 ]  However, dyssynchrony is also common in HFrEF and its role in HFpEF in particular remains obscure. While therapies for dyssynchrony, such as  biventricular pacing  provide benefits to HFrEF patients, no benefit is appreciable in HFpEF patients at this time. [ 42 ]


Patients with HFpEF, in addition to cardiac abnormalities, display changes in (endothelial)  microvascular function , skeletal muscle metabolism and in fat distribution and character throughout the body. [ 43 ]  The importance of these changes is demonstrated in that stable, non-decompensated patients seem to benefit from exercise; specifically increased  VO2 max  and exercise tolerance. However, this benefit appears to be derived from changes in muscle and vasculature as opposed to directly on the heart, which displays minimal change in output following exercise training. [ 44 ]


HFpEF is typically diagnosed with  echocardiography . Techniques such as  catheterization  are invasive procedures and thus reserved for patients with  co-morbid  conditions or those who are suspected to have HFpEF but lack clear non-invasive findings. Catheterization does represent are more definitive diagnostic assessment as pressure and volume measurements are taken simultaneously and directly. In either technique, the heart is evaluated for left ventricular diastolic function. Important parameters include, rate of  isovolumic  relaxation, rate of ventricular filling, and stiffness. [ citation needed ]


Frequently patients are subjected to stress echocardiography, which involves the above assessment of  diastolic  function during exercise. [ 45 ]  This is undertaken because perturbations in diastole are exaggerated during the increased demands of exercise. Exercise requires increased left ventricular filling and subsequent output. Typically the heart responds by increasing heart rate and relaxation time. [ 35 ]  However, in patients with HFpEF both responses are diminished due to increased ventricular stiffness. Testing during this demanding state may reveal abnormalities that are not as discernible at rest. [ 46 ]


Diastolic dysfunction must be differentiated from diastolic heart failure. Diastolic dysfunction can be found in elderly and apparently quite healthy patients. If diastolic dysfunction describes an abnormal mechanical property, diastolic heart failure describes a clinical syndrome. Mathematics describing the relationship between the ratio of Systole to Diastole in accepted terms of End Systolic Volume to End Diastolic Volume implies many mathematical solutions to forward and backward heart failure. [ citation needed ]


Criteria for diagnosis of diastolic dysfunction or diastolic heart failure remain imprecise. This has made it difficult to conduct valid clinical trials of treatments for diastolic heart failure. The problem is compounded by systolic and diastolic heart failure commonly coexisting when patients present with many ischemic and nonischemic etiologies of heart failure. Narrowly defined, diastolic failure has often been defined as "heart failure with normal systolic function" (i.e. left ventricular ejection fraction of 60% or more).  Chagasic heart disease  may represent an optimal academic model of diastolic heart failure that spares systolic function. [ citation needed ]


A patient is said to have diastolic dysfunction if they have signs and symptoms of heart failure but the left ventricular ejection fraction is normal. A second approach is to use an elevated  BNP  level in the presence of normal ejection fraction to diagnose diastolic heart failure. Concordance of both volumetric and biochemical measurements and markers lends to even stronger terminology regarding scientific/mathematical expression of diastolic heart failure. These are both probably too broad a definition for diastolic heart failure, and this group of patients is more precisely described as having heart failure with normal systolic function. Echocardiography can be used to diagnose diastolic dysfunction but is a limited modality unless it is supplemented by  stress imaging .  MUGA  imaging is an earlier mathematical attempt to distinguish systolic from diastolic heart failure. [ citation needed ]


No single echocardiographic parameter can confirm a diagnosis of diastolic heart failure. Multiple echocardiographic parameters have been proposed as sufficiently sensitive and specific, including mitral inflow velocity patterns, pulmonary vein flow patterns, E/A reversal, tissue Doppler measurements, and M-mode echo measurements (i.e. of left atrial size). Algorithms have also been developed which combine multiple echocardiographic parameters to diagnose diastolic heart failure. [ citation needed ]


There are four basic echocardiographic patterns of diastolic heart failure, which are graded I to IV. [ citation needed ]  Grade III and IV diastolic dysfunction are called "restrictive filling dynamics"; they are both severe forms of diastolic dysfunction, and patients tend to have advanced heart failure symptoms. [ citation needed ]


The presence of either class [ clarification needed ]  III and IV diastolic dysfunction is associated with a significantly worse prognosis. These patients will have left atrial enlargement, and many will have a reduced left ventricular ejection fraction that indicates a combination of systolic and diastolic dysfunction. [ citation needed ]


Imaged volumetric definition of systolic heart performance is commonly accepted as  ejection fraction . Volumetric definition of the heart in  systole  was first described by  Adolph Fick  as  cardiac output . Fick may be [ clarification needed ]  readily and inexpensively inverted to cardiac output and ejection fraction to mathematically describe  diastole .  Decline of ejection fraction paired with decline of E/A ratio seems a stronger argument in support of a mathematical definition of diastolic heart failure. [ citation needed ]


Another parameter to assess diastolic function is the  E/E' ratio , which is the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E'). Diastolic dysfunction is assumed when the E/E' ratio exceed 15. [ 47 ]


Newer echocardiographic techniques such as speckle tracking for strain measurement, particularly for the left atrium, [ 48 ]  are becoming increasingly utilised for the diagnosis of HFpEF.


Despite increasing incidence of HFpEF effective inroads to therapeutics have been largely unsuccessful. [ 49 ]  Currently [ when? ] , recommendations for treatment are directed at symptom relief and co-morbid conditions. Frequently this involves administration of  diuretics  to relieve complications associated with volume overload, such as  leg swelling  and high blood pressure. [ citation needed ]


Commonly encountered conditions that must be treated for and have independent recommendations for  standard of care  include  atrial fibrillation , coronary artery disease, hypertension, and hyperlipidemia. There are particular factors unique to HFpEF that must be accounted for with therapy. Randomized clinical trials addressing the therapeutic adventure for these conditions in HFpEF have found conflicting or limited evidence. [ 50 ]


Specific aspects of therapeutics should be avoided in HFpEF to prevent the deterioration of the condition. Considerations that are generalizable to heart failure include avoidance of a fast heart rate, elevations in blood pressure, development of ischemia, and atrial fibrillation. Considerations more specific to HFpEF include avoidance of  preload  reduction. As patients display normal ejection fraction but reduced cardiac output they are especially sensitive to changes in preloading and may rapidly display signs of output failure. This means administration of diuretics and vasodilators must be monitored carefully. [ citation needed ]


HFrEF and HFpEF represent distinct entities in terms of development and effective therapeutic management. Specifically, cardiac resynchronization, administration of  beta blockers  and  angiotensin converting enzyme inhibitors  are applied to good effect in HFrEF but are largely ineffective at reducing morbidity and mortality in HFpEF. [ 49 ] [ 51 ]  Many of these therapies are effective in reducing the extent of cardiac dilation and increasing ejection fraction in HFrEF patients. It is unsurprising they fail to effect improvement in HFpEF patients, given their un-dilated phenotype and relative normal ejection fraction. Understanding and targeting mechanisms unique to HFpEF are thus essential to the development of therapeutics. [ 52 ]


Randomized studies on HFpEF patients have shown that exercise improves  left ventricular diastolic function , the heart's  ability to relax , and is associated with improved  aerobic exercise capacity . [ 53 ]  The benefit patients seem to derive from exercise does not seem to be a direct cardiac effect, but rather is due to changes in peripheral vasculature and skeletal muscle, which show abnormalities in HFpEF patients. [ citation needed ]  A two-year exercise trial on otherwise-healthy middle-aged adults having HFpEF showed improved cardiac function, and regular exercise was recommended to prevent future risk of HFpEF. [ 54 ]


Regularly assessment of patients allows determination of progression of the condition, response to interventions, and need for alteration of therapy. Ability to perform daily tasks, hemodynamic status, kidney function,  electrolyte  balance, and serum  natriuretic peptide  levels are important parameters. Behavioral management is important in these patients and it is recommended that individuals with HFpEF avoid alcohol, smoking, and high sodium intake. [ 55 ]


Management of HFpEF is primarily dependent on the treatment of symptoms and exacerbating conditions. The role of specific treatments for diastolic dysfunction  per se  is as yet unclear. [ citation needed ]


Currently treatment with ACE inhibitors, calcium channel blockers, beta blockers, and  angiotensin receptor blockers  is employed, but does not have a proven benefit in HFpEF patients. Caution is required with use of diuretics or other therapies that can alter loading conditions or blood pressure. It is not recommended that patients be treated with  phosphodiesterase-5-inhibitors  or  digoxin . [ 5 ]


MRAs ( spironolactone ,  finerenone ) are recommended for appropriately selected patients with symptomatic HFpEF (LVEF >= 45%, elevated  BNP  level or heart failure admission within 1 year, eGFR > 30 mL/min/1.73 m2, creatinine < 2.5 ml/dL, potassium < 5.0 mEq/L). [ 56 ]  Monitoring of serum potassium levels and kidney function, specifically  glomerular filtration rate , during treatment is necessary.


Beta blockers  play a rather obscure role in HFpEF treatment, though there is suggestion of a beneficial role in patient management. [ 57 ]  Evidence from a meta-analysis demonstrated significant reductions in all-cause mortality with beta-blocker therapy, though overall effects were driven largely by small, older trials of patients post-myocardial infarction. [ 49 ]  Some evidence suggests that vasodilating beta blockers, such as  nebivolol , can provide a benefit for patients with heart failure regardless of ejection fraction. [ 58 ]  Additionally, because of the  chronotropic  perturbation and diminished LV filling seen in HFpEF the  bradycardic  effect of beta blockers may enable improved filling, reduce myocardial oxygen demand, and lower blood pressure. However, this effect also can contribute to diminished response to exercise demands and can result in an excessive reduction in heart rate. [ 59 ] [ 60 ]


Beta-blockers are the first-line therapy: they lower the heart rate and thus give more time for ventricles to fill. They may also improve survival. [ 49 ]


Likewise, treatment with  angiotensin converting enzyme inhibitors , such as  enalapril ,  ramipril , and many others, may be of benefit due to their effect on preventing  ventricular remodeling  but under control to avoid hypotension. [ 61 ]
ACE inhibitors do not appear to improve morbidity or mortality associated with HFpEF alone. [ 60 ]  However, they are important in the management of  hypertension , a significant player in the pathophysiology of HFpEF. [ 62 ]


ARB treatment results in an improvement in diastolic dysfunction and hypertension that is comparable to other anti-hypertensive medication. [ 63 ]


There is some evidence that  calcium channel blockers  may be of benefit in reducing ventricular stiffness. In some cases, ( verapamil  has the benefit lowering the heart rate) [ clarification needed ] .


Diuretics can be useful if significant congestion develops, but patients must be monitored because they frequently develop  low blood pressure . [ 61 ]


In patients with HFpEF, SGLT2 inhibitors carry a class 2a recommendation according to the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure as a potentially beneficial treatment for reducing HF hospitalizations and CV mortality. [ 64 ]


The use of a self-expanding device that attaches to the external surface of the left ventricle has been suggested. When the heart muscle squeezes, energy is loaded into the device, which absorbs the energy and releases it to the left ventricle in the diastolic phase. This helps retain muscle elasticity. This had not been approved by the  FDA  as of 2008 [update] . [ 65 ]  Trials were in progress of the ImCardia (implanted at the level of the pericardium) and the CORolla transapical approach device (CORolla TAA; implanted at the level of the endocardium) as of 2023 [update] [ 66 ]


The progression of HFpEF and its clinical course is poorly understood in comparison to HFrEF.  Despite this, patients with HFrEF and HFpEF appear to have comparable outcomes in terms of hospitalization and mortality. [ 1 ] [ 67 ]  Causes of death in patients vary substantially. However, among patients in more  advanced heart failure  (NYHA classes II-IV), cardiovascular death, including  heart attacks  and  sudden cardiac death , was the predominant cause in population-based studies. [ 68 ]


Until recently, it was generally assumed that the prognosis for individuals with diastolic dysfunction and associated intermittent pulmonary edema was better than those with systolic dysfunction. However, in two studies in the  New England Journal of Medicine  in 2006, evidence was presented to suggest that the prognosis in diastolic dysfunction is the same as that in  systolic dysfunction . [ 1 ]


Heart failure with reduced ejection fraction  ( HFrEF ,  hef- REF ) is a form of  heart failure  in which the  ejection fraction  is reduced. [ 1 ]  This is defined as a  left ventricular   ejection fraction  (LVEF) of 40% or less. About half of heart failure patients have a reduced ejection fraction. [ 2 ]  Other types of heart failure are  heart failure with mildly reduced ejection fraction  (LVEF between 40% and 50%) and  heart failure with preserved ejection fraction  (LVEF 50% or higher). [ 1 ] [ 3 ]


Heart to Heart  is a 1949 American  short   documentary film  about  heart disease  directed by  Gunther von Fritsch . It was nominated for an  Academy Award  for  Best Documentary Short . [ 1 ] [ 2 ]


This article about a scientific  documentary  film is a  stub . You can help Wikipedia by  expanding it .


This article about a short documentary film is a  stub . You can help Wikipedia by  expanding it .


High-output heart failure  is a heart condition that occurs when the  cardiac output  is higher than normal because of increased peripheral demand. There is a circulatory overload which may lead to pulmonary edema secondary to an elevated  diastolic pressure  in the  left ventricle . These individuals usually have a normal systolic function but symptoms are those of  heart failure . With time, this overload causes systolic failure. Ultimately  cardiac output  can be reduced to very low levels. [ 1 ]


It may occur in situations with an increased  blood volume , morbid obesity,  from excess of water and salt (kidney pathology, excess of fluid or blood administration, treatment with retaining water steroids), chronic and severe  anemia , large  arteriovenous fistula  or multiple small arteriovenous shunts as in  HHT  or  Paget's disease of bone , some forms of severe liver or kidney disorders,  hyperthyroidism , and wet  beriberi , [ 2 ]  and acutely in  septic shock , especially caused by  Gram-negative bacteria . [ 3 ] [ 4 ]


(redirect from  hyperactive precordium )


Hyperdynamic precordium  is a condition where the  precordium  (the area of the chest over the heart) moves too much (is  hyper dynamic ) due to some  pathology  of the  heart .  That means a forceful and hyperdynamic impulse ( large amplitude that terminates quickly) can be palpated during physical examination. [ 1 ]  Hyperdynamic precordium is a physical finding which can be normal or pathological. Some possible etiologies are as followings: [ 1 ]


In addition,  hyperactive precordium  indicates this physical finding with a pathologic cause which is noted by a clinician. [ 3 ]


This problem (hyperdynamic precorrdium) can be  hypertrophy  of the ventricles,  tachycardia , or some other heart problem. [ 4 ]


Compared with  forceful and hyperdynamic  impulse finding, another abnormal finding is " forceful and sustained"  impulse, which sustained through the systolic phase. The former means the ventricle is doing " volume " work, and the latter with " pressure"  work (high pressure within left ventricle; some may transmit to the aorta, some may not). The latter can be seen in cases with left ventricle hypertrophy or outflow obstruction. Another possible cause of sustained impulse is heart failure with reduced ejection fraction. [ 1 ]


Hyperdynamic precordium can also be due to  hyperthyroidism , and thus indicates an increased  cardiac contractility , with  systolic hypertension . It may also be due to  aortic coarctation , and most other  congenital  heart malformations. [ citation needed ]


Palpation  of the chest wall can be done to assess volume changes within the heart. A hyperdynamic precordium reflects a large volume change. [ 5 ]


Idiopathic giant-cell myocarditis  ( IGCM ) is a cardiovascular disease of the muscle of the heart ( myocardium ).


The condition is rare; [ 2 ]  however, it is often fatal and there is no proven cure because of the unknown nature of the disorder.


IGCM frequently leads to death with a high rate of about 70% in first year. A patient with IGCM typically presents with symptoms of  heart failure , although some may present initially with  ventricular arrhythmia  or  heart block . Median age from the time the disease is diagnosed to the time of death is approximately 6 months. 90% of patients are either deceased by the end of 1 year or have received a heart transplant. Diagnosis is made by  endomyocardial  biopsy during  heart catheterization . Biopsy shows  multinucleated giant cells  and thus the name. While previously cases universally required heart transplantation, recent studies show that two-thirds of patients can survive past one year with high doses of immunosuppressants such as prednisone and cyclosporine. The transplanted heart has a high chance of disease recurrence. Compared to lymphocytic (presumed  viral ) myocarditis, giant cell myocarditis is much more severe with much more rapid progression.


It is suggested to be caused by  T-lymphocytes .


Isolated atrial amyloidosis  is a form of  amyloidosis  affecting the  atria  of the heart. [ citation needed ]


It is associated with accumulation of the protein  atrial natriuretic factor . [ 1 ]  It may cause  abnormal heart rhythms .


Keshan disease  is a congestive  cardiomyopathy  caused by a combination of  dietary deficiency of selenium  and the presence of a mutated strain of  Coxsackievirus , named after  Keshan County  of  Heilongjiang  province, Northeast China, where symptoms were first noted. These symptoms were later found prevalent in a wide belt extending from northeast to  southwest China , all due to  selenium -deficient soil. The disease peaked in 1960–1970, killing thousands of people. [ 1 ] [ 2 ]


Often fatal, the disease affects children and women of child-bearing age, characterized by  heart failure  and  pulmonary edema . Over decades, supplementation with selenium reduced this condition. [ 3 ]


It had been linked to the  coxsackie B  virus. Current research suggests that the lack of selenium results in a more virulent strain of the coxsackievirus becoming the dominant  viral species  present in the population of virus, but the mechanism of this selection event is unclear. [ 4 ] [ 5 ]


Keshan disease can also lead to higher rates of cancer, cardiovascular disease, hypertension, and strokes. In addition, an individual can experience eczema, psoriasis, arthritis, cataracts, alcoholism, and infections. [ citation needed ]


There are four main types of Keshan disease: acute, subacute, chronic, and latent.


Some signs and symptoms of acute Keshan disease include dizziness,  malaise , nausea, chills, loss of appetite, projectile vomiting, pallor, low arterial blood pressure (less than 80/60 mmHg),  dyspnea , precardiac (anterior to the heart) or substernal (behind or below the sternum) discomfort,  cardiogenic shock , and constricted veins in one's extremities.


Some signs and symptoms of subacute Keshan disease include malaise, restlessness,  gallop rhythm , facial  edema , heart dilation, and cardiac shock.


Some signs and symptoms of chronic Keshan disease include palpitations, dyspnea, cough (with blood), pain in one's right upper quadrant, edema,  oliguria , enlargement of the heart, systolic murmur, gallop rhythm, and  hepatomegaly .


Some signs and symptoms of latent Keshan disease include dizziness, fatigue, palpitations, and mild enlargement of the heart. [ 6 ]


The treatment for Keshan disease is selenium supplementation. The recommended amounts are fifty-five micrograms of selenium per day for adult men and women, sixty micrograms a day for women during pregnancy and seventy micrograms per day for women after pregnancy. A doctor may insist that if a man is sexually active, he may have to take up to seventy micrograms of selenium per day. A doctor may also recommend that the individual take vitamin E; selenium and  vitamin E  are medically linked and seem to work together. An individual will also be advised to have a diet that includes seafood, meats such as kidney, and liver, and some grains and seeds; all of these are high in selenium.  Brewer's yeast  and  wheat germ  both contain high levels of selenium. Garlic, onions, mushroom, broccoli, tomatoes, radishes, and Swiss chard may be good sources of selenium if the soil in which they are grown contains it. An individual will have to be monitored once they begin to take the selenium supplements, due to the fact that too much of it can cause balding, intestinal distress, weakness, and slow mental functioning. Individuals in China with the disease treat it with a herb called  Astragalus , which accumulates selenium from the soil. [ 7 ]


An individual will most likely be prescribed selenium supplements (in the form of  selenomethionine ) or have injections of this mineral.  Other recommendations for managing Keshan disease are to increase consumption of foods rich in selenium in addition to supplements, avoid alcohol, monitor side effects to medications, and increase sleep.  Cardiac surgery (implants, stents or full heart transplant) may be advised. [ 8 ]


Loeffler endocarditis  is a form of heart disease characterized by a  stiffened, poorly-functioning heart  caused by infiltration of the heart by  white blood cells  known as  eosinophils . [ 1 ]  Restrictive cardiomyopathy is a disease of the heart muscle which results in impaired  diastolic  filling of the  heart ventricles , i.e. the large heart chambers which pump blood into the  pulmonary  or  systemic circulation . Diastole is the part of the  cardiac contraction-relaxation cycle  in which the heart fills with venous blood after the emptying done during its previous  systole  (i.e. contraction). [ 2 ]


An eosinophil-based specific type of heart damage was first described by the Swiss doctor,  Wilhelm Loeffler , in 1936. [ 3 ] [ 4 ]  As initially described, the disorder manifests as a restrictive cardiomyopathy, i.e. a poorly expanding and contracting rigid heart that was infiltrated with eosinophils and showed replacement of heart cells by stiff fibrotic  connective tissue . [ 5 ]


Loeffler endocarditis is now regarded as a manifestation of  eosinophilic myocarditis , a disorder that involves the infiltration of the heart's muscular layer by eosinophils that leads to three progressive clinical stages. The first stage involves acute  inflammation  and subsequent  death  of  heart muscle cells . This stage is dominated by signs and symptoms of the  acute coronary syndrome  such as  angina ,  heart attack , and  congestive heart failure . In the second stage, the  endocardium  (i.e. interior wall) of the heart forms  blood clots  which  break off  and then travel through and block various arteries; this clotting stage may dominate the initial presentation in some individuals. The third stage is a fibrotic stage, i.e. Loeffler endocarditis, wherein  scarring  replaces damaged heart muscle tissue to cause a poorly contracting heart and/or  heart valve disease . Recent publications commonly refer to Loeffler endocarditis as a historical term for the third stage of eosinophilic myocarditis. [ 5 ] [ 6 ] [ 7 ]


The signs and symptoms of Loeffler endocarditis tend to reflect the many underlying disorders causing eosinophil dysfunction as well as the widely differing progression rates of cardiac damage. Before cardiac symptoms are detected, individuals may suffer symptoms of a common cold,  asthma ,  rhinitis ,  urticarial , or other allergic disorder. Cardiac manifestations include life-threatening conditions such as  cardiogenic shock  or sudden death due to abnormal  heart rhythms . More commonly, however, the presenting cardiac signs and symptoms of the disorder are the same as those seen in other forms of cardiomyopathy: the  heart arrhythmia  of  ventricular fibrillation  seen as an irregular pulse and heart rate, other  cardiac arrhythmias , symptoms of these arrhythmias such as chest  palpitations , dizziness, light headedness, and fainting; and symptoms of a heart failure such as fatigue,  edema , i.e. swelling, of the lower extremities, and  shortness of breath . [ 8 ] [ 9 ]


Hypereosinophilia  (i.e. blood eosinophil counts at or above 1,500 per microliter) or, less commonly,  eosinophilia  (counts above 500 but below 1,500 per microliter) are found in the vast majority of cases and are valuable clues pointing to this rather than other types of cardiomyopathies. However, elevated blood eosinophil counts may not occur during the early phase of the disorder. Other, less specific laboratory findings implicate a cardiac disorder but not necessarily eosinophilic myocarditis. These include elevations in blood markers for systemic inflammation (e.g.  C reactive protein ,  erythrocyte sedimentation rate ) and cardiac injury (e.g.  creatine kinase ,  troponins ); and abnormal  electrocardiograms  ( mostly  ST segment - T wave  abnormalities). [ 10 ]


Eosinophilic states that may occur in and underlie Loeffler endocarditis (as well as the other stages of eosinophilic myocarditis) include primary and secondary  eosinophilias  or  hypereosinophilias . Primary eosinophilias or hypereosinophilias (i.e. disorders in which the eosinophil appears to be intrinsically diseased) that lead to Loeffler endocarditis are  clonal hypereosinophilia ,  chronic eosinophilic leukemia  and the  hypereosinophilic syndrome . [ 5 ] [ 8 ] [ 10 ] [ 11 ]  Secondary causes (i.e. disorders in which other diseases cause the eosinophil to become dysfunctional) include  allergic  and  autoimmune diseases ; infections due to certain  parasitic worms ,  protozoa , and  viruses ; malignant and premalignant hematologic disorders commonly associated with eosinophilia or hypereosinophilia; and adverse reactions to various drugs. [ 1 ] [ 12 ]


The disorder develops because of  eosinophilic  penetration into the cardiac tissues. This leads to a fibrotic thickening of portions of the heart (similar to that of  endomyocardial fibrosis ) and heart valves. In consequence, the heart becomes rigid and poorly contractile while the heart valves may become  stenotic or insufficient , i.e. reduced in ability to open or close, respectively. The damaged heart may also develop mural  thrombi , i.e. clots which lay against ventricle walls, tend to break off, and flow through and block arteries; this condition often precedes the fibrotic stage of eosinophilic myocarditis and is termed the thrombotic stage. [ 5 ]


The diagnosis of Loeffler endocarditis should be considered in individuals exhibiting signs and symptoms of poor heart contractility and/or valve disease in the presence of significant increases in blood eosinophil counts. Ancillary tests may help in the diagnosis.  Echocardiography  typically gives non-specific and only occasional findings of  endocardium  thickening,  left ventricular hypertrophy , left ventricle dilation, and involvement of the  mitral  and/or  tricuspid valves .  Gadolinium -based  cardiac magnetic resonance  imaging is the most useful  non-invasive procedure  for diagnosing eosinophilic myocarditis. It supports this diagnosis if it shows at least two of the following abnormalities:  a)  an increased signal in  T2-weighted images ;  b)  an increased global myocardial early enhancement ratio between myocardial and  skeletal muscle  in enhanced  T1 images  and  c)  one or more focal enhancements distributed in a non-vascular pattern in late enhanced T1-weighted images. Additionally, and unlike in other forms of myocarditis, eosinophilic myocarditis may also show enhanced gadolinium uptake in the sub-endocardium. [ 8 ] [ 10 ]  However, the only definitive test for Loeffler endocarditis is cardiac muscle biopsy showing the presence of eosinophilic infiltrates. Since the disorder may be patchy, multiple tissue samples taken during the procedure improve the chances of uncovering the pathology but in any case, negative results do not exclude the diagnosis. [ 7 ] [ 10 ]


Small studies and  case reports  have directed efforts towards:  a)  supporting cardiac function by relieving heart failure and suppressing life-threatening  abnormal heart rhythms ;  b)  suppressing eosinophil-based cardiac inflammation; and  c)  treating the underlying disorder. In all cases of Loeffler endocarditis that have no specific treatment regimens for the underlying disorder, available studies recommend treating the inflammatory component of this disorder with non-specific  immunosuppressive drugs , principally high-dosage followed by slowly-tapering to low-dosage maintenance  corticosteroid  regimens. Afflicted individuals who fail this regimen or present with  cardiogenic shock  may benefit from treatment with other non-specific immunosuppressive drugs such as  azathioprine  or  cyclophosphamide , as adjuncts to, or replacements for, corticosteroids. However, individuals with an underlying therapeutically accessible disease should be treated for this disease; in seriously symptomatic cases, such individuals may be treated concurrently with a corticosteroid regimen. Examples of diseases underlying Loefflers myocarditis that are recommended for treatments directed at the underlying disease include: [ 10 ] [ 13 ] [ 14 ] [ 15 ]


Mental stress-induced myocardial ischemia  (MSIMI) is a medical condition in which acute  psychological stress  can trigger a transient  myocardial ischemia , which is a state of reduced blood flow to the  heart muscle , often without the presence of significant  coronary artery disease  (CAD). [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 1 ]  It is distinct from conventional stress ischemia caused by physical exertion or pharmacological agents. [ 3 ]  MSIMI is often silent and detected through specific cardiac function tests during mental stress challenges. [ 6 ]


Mental stress triggers various physiological changes in the body, activating mechanisms such as the  autonomic nervous system  (ANS) and the  hypothalamic–pituitary–adrenal axis  (HPA), resulting in  hemodynamic ,  neuroendocrine , and  immune  responses. Typically, these responses are adaptive and help individuals cope with environmental changes, referred to as the "defense response," which prepares them for  fight or flight . Consequently, the risk of cardiovascular (CV) events resulting from mental stress is influenced by external factors and an individual's stress threshold, which is shaped by  genetic predispositions  and life experiences. This variability explains why people respond differently to stressors. [ 5 ]


Mental stress-induced myocardial ischemia involves abnormal microvascular vasoreactivity and  inflammation , with increased  brain activity  in regions that modulate autonomic nervous system reactivity to  emotional stress ,  fear . [ 2 ] [ 7 ]  Emotional responses and certain psychological traits may influence the occurrence of MSIMI. [ 6 ]  MSIMI can occur at lower cardiac workloads, independent of hemodynamic changes, and is not directly related to the severity of  angiographic  CHD. [ 3 ]  It can occur in patients with normal  cardiac stress testing  and can often be  silent . [ 2 ]


MSIMI is associated with a twofold increased risk of  major adverse cardiovascular events  (MACE) compared to those without MSIMI. It is particularly prevalent among young women with  myocardial infarction  (MI) and those with  psychological comorbidities . [ 2 ]


Studies have found that young women who have had a myocardial infarction are twice as likely to develop mental stress-induced myocardial ischemia (MSIMI) compared to men of similar age. [ 4 ]


Various techniques like  electrocardiogram  (ECG),  echocardiography , and  positron emission tomography  (PET) are used to assess MSIMI. The incidence of MSIMI has varied across studies due to different assessment methods and mental stressors. [ 6 ]


Current research focuses on understanding stress pathways in CAD and integrating  mental health ,  behavioral medicine  with routine cardiology care to improve patient outcomes. [ 2 ]


Approximately 30% of CAD patients experience MSIMI under mental stress, which typically is silent and not related to the severity of CAD. [ 6 ]


Mydicar  is a genetically targeted  enzyme replacement therapy  being studied for use in patients with severe  heart failure . It is designed to increase the level of  SERCA 2a, a  sarcoplasmic   endoplasmic reticulum  calcium (Ca 2+ )  ATPase  found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an  adeno-associated viral  vector. [ 1 ]  Using the α-myosin heavy chain gene promoter in the  cardiac muscle cells , also called cardiomyocytes, Mydicar is able to direct the gene expression only to the  heart muscle . [ 2 ]  Mydicar is being tested [ when? ]  in a phase 2 study, in which has been compared to a  placebo  in 39 advanced heart failure patients. [ 3 ]  Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo. [ 3 ]


Normal function of the heart involves proper coordination between the contraction and relaxation of cardiomyocytes. Proper contraction and relaxation depends on the coordinated rise and fall of Ca 2+  in the  cytosol  of the cardiomyocytes. [ 4 ]  The SERCA2a transporter is found in the membrane of the SR and plays an important role in this cycle by removing cytosolic Ca 2+  from the cardiomyocyte and pumping it back into the SR during relaxation of the heart (diastole). SERCA2a restores SR Ca 2+  for the next contraction of cardiomyocytes. [ 5 ]  SERCA2a activity declines in patients experiencing late-stage heart failure. [ 1 ]  This leads to an above normal amount of cytosolic Ca 2+  in the cardiomyocytes during diastole. It also results in less Ca 2+  remaining in the SR for the next contraction of the heart. The altered cycling of Ca 2+  in cardiomyocytes ultimately leads to improper functioning of the heart, indicating a potentially beneficial effect of  gene therapy  using Mydicar. [ 1 ]


Administration of Mydicar occurs via an intracoronary injection of the drug. Mydicar delivers the SERCA2a gene to cardiomyocytes using an adeno-associated viral-vector (AAV). [ 6 ]  In the cardiomyocytes, the viral vector can insert itself into the genome and increase expression of the SERCA2a protein. Delivering the gene via an AAV is beneficial because it readily infects cardiac tissue and can produce stable, long-term expression of the delivered gene. [ 7 ]  AAVs also produce less of an immune response than alternative viral vehicles, such as  adenoviruses . [ 7 ]  AAVs have been studied in multiple patients and have not been known to cause human disease. [ 5 ]


Proper relaxation of the heart in preparation for the next contraction depends largely on the decline of Ca 2+  in the cytosol of cardiomyocytes during diastole. Along with impaired contractility, an increased level of cytosolic Ca 2+  increases the risk of  arrhythmias  and remodeling of the heart. [ 8 ]  Excess Ca 2+  found in the cytosol leads to asynchronous contractions of cardiomyocytes causing  tachyarrhythmias . The unusual increase in contraction and faster beating of the heart leads to  hypertrophy  by increasing the size of the cardiac myocytes in the heart. Excess hypertrophy of the cardiac myocytes leads to further dysfunction of the heart by affecting their ability to relax and contract properly. [ 5 ]  Administration of Mydicar increasing functioning SERCA2a can assist in lessening these negative effects of an increase in cytosolic Ca 2+  during diastole by increasing reuptake into the SR. [ citation needed ]


A  myocardial bridge  ( MB ) is a common  congenital heart anomaly  in which one of the  coronary arteries  tunnels through the heart muscle ( myocardium ) itself.


In most people, the coronary arteries rest on top of the  heart muscle  and feed  blood  down into smaller  vessels  (e.g. the septal  arteries ) which then carry blood to the heart muscle itself (i.e. populate throughout the myocardium). However, if a band of muscle forms around one of the coronary arteries during the  fetal  stage of development, then a myocardial bridge is formed – a "bridge" of heart muscle over the artery.


Every time the heart squeezes to pump blood, the band of muscle exerts pressure and it is very rarely constricts the artery, reducing blood flow to the heart. Even a very thin ex. <1  mm  and/or short ex. 20 mm MB can cause significant symptoms, although this has not been completely proven. [ citation needed ]  MBs can range in length from a few millimetres to 10  cm  or more. [ citation needed ]


The overall prevalence of myocardial bridge is at 19%, although the prevalence found at autopsies is much higher (42%). Myocardial bridge is usually a harmless condition, and in many cases bridges don't seem to cause any symptoms. However, some people with myocardial bridges may experience  angina , or  chest pain . [ 1 ] [ 2 ] [ 3 ]


While many people have very tiny myocardial bridges that cause no symptoms, others have longer and/or deeper bridges causing significant symptoms, including children. For example, some patients cannot  run  or  exercise  at all, others can exercise despite symptoms such as  shortness of breath  or  feelings of tightness in the chest , and still others find improvement of symptoms during exercise. Many competitive athletes have had severe myocardial bridges and unroofing surgery. [ 4 ] [ 5 ]


The symptoms of myocardial bridges differ slightly from patient to patient depending on the length, depth, and location of the bridge. Common symptoms include: [ 6 ] [ 7 ]


Myocardial bridges can cause numerous complications – which are often as misunderstood in the medical community as the condition itself. These include:


Note that studies have shown that plaque does not form inside myocardial bridges, yet there is virtually always plaque just before the myocardial bridge in adults.


Some common triggers of myocardial bridge symptoms are:


Notably, high heart rate or tachycardia greatly increases  ischemia  (low oxygen to the heart) caused by myocardial bridges. Studies [ 8 ]  have shown that this is because the compressed  artery  reopens only very slowly each heartbeat and thus stays in a state of semi-compression for most or all of the  diastolic period . Thus as the heart rate increases, the time the artery has to reopen (diastolic period) decreases dramatically – to the point that with very high heart rates, the artery never fully reopens and blood flow is constantly reduced.


There are three key tests currently used to diagnose myocardial bridges by  Stanford University : CT scan, cardiac catheterization, and stress ultrasound.


As much of the science of testing for MBs is relatively new, patients frequently go undiagnosed.  Stanford 's center for myocardial bridges has offered second opinion services from a distance for some ten years, including to numerous international patients. [ citation needed ]


Notably,  EKG  is not a reliable or conclusive diagnostic tool for diagnosing MBs. Some symptomatic MB patients show normal EKG results and others abnormal. [ citation needed ]


Many doctors have suggested that there is a need for more awareness of MBs among doctors and better testing, including testing of young people as the disease is congenital. According to a 2007 study: [ 8 ]


Clinical suspicion of a myocardial bridge would be warranted in all cases of typical or atypical  chest pain  in subjects who have a low probability of  atherosclerosis  because they are free from the traditional  cardiovascular  risk factors, particularly in the young.


A 2017 article in  Stanford Medical Center 's official blog  Scope  explains the hardships people with MB face, including the dismissal of their symptoms and obstacles in their lives as a result of the lack of MB education amongst cardiologists: [ 15 ]


Many of these patients have these heartbreaking stories to tell. They can’t hold a job, they can’t travel, they can’t take care of their families. Most  cardiologists  are completely at a loss. They know myocardial bridges exist, but they have been taught they are benign and never cause problems... When these patients go to the  ER , and they go there a lot, all the cardiology tests come back normal. They’re told, 'Here’s a little  Valium . I think you’re  anxious .' They get belittled, not taken seriously, and they get really  depressed .


Myotomy , commonly known as  unroofing surgery , is the first-line surgical treatment for myocardial bridges. [ 6 ] [ 16 ]  It is the only treatment that actually removes the myocardial bridge itself, releasing the artery from compression. Unroofing surgery today is done via open heart ( sternum ),  thoracotomy  (through the ribs), and also using  robot-assisted surgery  (through tiny keyholes in the  chest ). Full  open heart surgery  is usually reserved for very large myocardial bridges and/or specific situations that make  thoracotomy  difficult. By far,  Stanford University  has done more unroofing surgeries than any other  hospital  in the world, with over 200 unroofings completed since starting a decade ago. In 2019,  University of Chicago  surgeon Dr. Husam Balkhy emerged as a provider of robotic-assisted unroofing surgery, with some patients being possible candidates for this route. [ 17 ]


If done properly, unroofing removes the entire band of muscle affecting the  artery , restoring more  blood flow . Stanford University Medical Center's 2016 study by Pargaonkar et al. [ 18 ]  showed that unroofing surgery “significantly improves anginal symptoms” and improves “all five dimensions of the SAQ” i.e. Seattle Angina Questionnaire. Some residual symptoms caused by complications from a lifetime of living with a myocardial bridge may continue after unroofing surgery such as  endothelial dysfunction ,  vasospasm , plaque, narrowed artery. However, these often improve slowly over a year or more once the myocardial bridge is gone. [ citation needed ]


A few cases have occurred in various hospitals in which patients have not been completely unroofed, leaving segments of the MB, resulting in lingering symptoms. [ citation needed ]


A critical point is that the endothelial dysfunction and vasospasms caused by myocardial bridges cannot start to heal until unroofing surgery is done, because the MB continues to squeeze on the artery, damaging the artery lining. [ citation needed ]


Bypass surgery  is not the first line treatment for myocardial bridges for two main reasons: [ 6 ]


Notably, many myocardial bridge patients have had bypass surgery only to later need unroofing surgery after the bypass proved unsuccessful. [ 6 ]


However, papers by Ekeke et al., 2015  [ 19 ]  have shown bypass surgery is helpful as an addition to supplement unroofing surgery, but only when there is significant plaque just before (proximal to) the myocardial bridge or anatomic anomalies increase the risk of recurrence of such plaque. A 2013 Russian study by Bockeria et al. [ 20 ]  concludes that this competitive flow problem is much more likely to occur if the LIMA artery is used for the graft rather than the SVG, so the SVG is recommended.


Stents  are never indicated as a treatment for myocardial bridges because trials have shown they are prone to breaking when the artery is squeezed each heartbeat. [ 6 ]


Unroofing surgery has been performed in the  United States ,  Belgium ,  Spain ,  Italy ,  England ,  China ,  Russia ,  United Arab Emirates , and  Singapore , among other countries. [ citation needed ]  Hospitals that have performed unroofing surgery include:


In many other countries, including a number of highly  developed countries  such as the  UK ,  Australia ,  New Zealand ,  Ireland  and  Sweden , unroofing surgery for myocardial bridges remains unavailable, and in some, the condition remains unrecognized as a medical problem. [ citation needed ]


The true prevalence of MBs is still largely unknown, as studies have made vastly different assessments. As a 2017  Stanford  paper [ 6 ]  points out:


Estimations of the prevalence of MBs vary... at least in part as a result of several key variables, including the means of identification (eg, computed tomography (CT), intravascular ultrasound ( IVUS ), or autopsy), which vessels are examined, and which definition of a bridge is applied (eg, only a “deep” bridge vs both “superficial” and “deep” bridges). Perhaps the most fundamental variable is whether an MB is even considered. Unlike  hypertrophic cardiomyopathy , which will usually be obvious to the  pathologist , MBs can be easily obscured by  epicardial  and  pericardial  fat. As such, autopsy series have estimated the prevalence between 5% and 86%. The largest autopsy report, which included 1056 subjects, found a prevalence of 26%, 88% of which involved the  LAD . One population-based study with CT estimated a prevalence of 22.5%. As a result of these studies and others, an estimated prevalence of approximately 25% is generally accepted.


According to Stanford University Medical Center, MBs are often misunderstood by  doctors , who may have been taught that the condition is always benign. [ 6 ]  As a result, patients are often denied treatment. But a great deal of science has emerged in the past decade to clarify the condition. In particular, Stanford has published over 15 articles on MBs since 2014. One commonly recurring reason for denial of treatment is the myth that myocardial bridges do not significantly affect blood flow. But this myth has been debunked by Stanford and also Daoud and Wafa 2012 who say:


Normally, only 15% of  coronary   blood flow  occurs during  systole  and because myocardial bridging is a systolic event on  angiography , its clinical significance and relevance have been questioned. [However] angiographic and  intravascular   ultrasonographic  studies demonstrated that vessel compression during systole is followed by the delay in the increase in  luminal  diameter during diastole, thus affecting the predominant phase of  coronary   perfusion , especially during episodes of  tachycardia . These data suggest that angina, acute coronary syndromes, and  arrhythmias  in patients with myocardial bridging may be explained by the reduced  ischemic  threshold.” [ 21 ]


In other words, while the myocardial bridge itself only compresses the artery while the heart squeezes ( systolic period ), which is only 15% of the time in the heartbeat cycle, in fact, the artery stays compressed long after the heart relaxes. This is because arteries are sturdy and pliable, so after being compressed they are very slow to reopen, remaining in some level of semi-compression for most if not all of the  diastolic  period i.e. the other 85% of the heartbeat cycle (hence the critical need for dFFR testing in diagnosing myocardial bridges). [ citation needed ]  Thus the coronary artery is fully open to allow normal blood flow for only a small percentage of each heartbeat cycle. [ citation needed ]  This problem is further exacerbated by tachycardia, which can bring the duration of normal blood flow to zero, as explained below. Dr. Ingela Schnittger, head of the Myocardial Bridge Research Center at Stanford, has appeared on  BBC Radio  to explain this. [ citation needed ]


Myocardial disarray , also known as  myocyte disarray , is a term to describe the loss of the normal parallel alignment of  myocytes [ 1 ]  (the  muscle   cells  of the  heart ).  Instead, the myocytes usually form circles around foci of  connective tissue .  Myocardial disarray is associated with  myocardial fibrosis  (the replacement of the myocytes with non-contractile  scar tissue ).


Myocardial disarray can be seen in a number of disease states, including:


The common factor amongst all these diseases is that they all cause varying degrees of remodelling (myocardial fibrosis) of the  ventricles .


Myocardial rupture  is a laceration of the  ventricles  or  atria  of the  heart , of the  interatrial  or  interventricular septum , or of the  papillary muscles .  It is most commonly seen as a serious  sequela  of an acute  myocardial infarction  (heart attack).


It can also be caused by trauma. [ 1 ]


Symptoms of myocardial rupture are recurrent or persistent  chest pain ,  syncope , and  distension of jugular vein . Sudden death caused by a myocardial rupture is sometimes preceded by no symptoms. [ 2 ]


The most common cause of myocardial rupture is a recent  myocardial infarction , with the rupture typically occurring three to five days after infarction. [ 3 ]  Other causes of rupture include cardiac trauma,  endocarditis  (infection of the heart), [ 4 ] [ 5 ]   cardiac tumors , infiltrative diseases of the heart, [ 4 ]  and  aortic dissection . [ citation needed ]


Risk factors for rupture after an acute myocardial infarction include female gender, [ 6 ] [ 7 ]  advanced age of the individual, [ 6 ] [ 7 ]  first ischemic event, and a low  body mass index . [ 6 ]   Other presenting signs associated with myocardial rupture include a pericardial friction rub, sluggish flow in the coronary artery after it is opened i.e. revascularized with an  angioplasty , the  left anterior descending artery  being often the cause of the acute MI, [ 6 ] [ 7 ] [ 8 ]  and delay of revascularization greater than 2 hours. [ 7 ]


Due to the acute hemodynamic deterioration associated with myocardial rupture, the diagnosis is generally made based on physical examination, changes in the vital signs, and clinical suspicion.  The diagnosis can be confirmed with  echocardiography .  The diagnosis is ultimately made at autopsy. [ citation needed ]


Myocardial ruptures can be classified as one of three types. [ citation needed ]


Another method for classifying myocardial ruptures is by the anatomical portion of the heart that has ruptured.  By far the most dramatic is rupture of the free wall of the left or right ventricles, as this is associated with immediate hemodynamic collapse and death secondary to acute  pericardial tamponade .  Rupture of the interventricular septum will cause a  ventricular septal defect .  Rupture of a papillary muscle will cause acute  mitral regurgitation . [ citation needed ]


The rupture will most often occur near the edge of the necrotic myocardium where it abuts healthy (but hyperemic) myocardium where the inflammatory response is at its greatest.  Further, the rupture will occur in an area of greatest  shear stress .  Within the left ventricle, these areas are adjacent to both anterior and posterior papillary muscles (regardless of whether the papillary muscle is involved in the infarction). [ citation needed ]


Left ventricular free wall rupture almost always results in hemopericardium (the exception being in the scenario where the patient has had prior open heart surgery and has obliterative fibrous pericardial adhesions; these would prevent egress of blood) and pericardial tamponade.  An accumulation of as little as 75 ml of blood, acquired acutely in a patient without pre-existing pericardial effusion, is sufficient to produce tamponade (wherein the ventricles are incapable of filling and are thus incapable of producing adequate stroke volume). [ citation needed ]


The treatment for myocardial rupture is supportive in the immediate setting and surgical correction of the rupture, if feasible. [ citation needed ]   A certain small percentage of individuals do not seek medical attention in the acute setting and survive to see the physician days or weeks later.  In this setting, it may be reasonable to treat the rupture medically and delay or avoid surgery completely, depending on the individual's  comorbid  medical issues. [ citation needed ]


The prognosis of myocardial rupture is dependent on a number of factors, including which portion of the myocardium is involved in the rupture.  In one case series, if myocardial rupture involved the free wall of the  left ventricle , the  mortality rate  was 100.0%. [ 6 ]   The chances of survival rise dramatically if the patient: 1. has a witnessed initial event; 2. seeks early medical attention; 3. has an accurate diagnosis by the emergentologist; and 4. happens to be at a facility that has a cardiac surgery service (by whom a quick repair of the rupture can be attempted).  Even if the individual survives the initial hemodynamic sequelae of the rupture, the 30‑day mortality is still significantly higher than if rupture did not occur. [ 6 ]


The incidence of myocardial rupture has decreased in the era of urgent revascularization and aggressive  pharmacological therapy  for the treatment of an acute myocardial infarction.  However, the decrease in the incidence of myocardial rupture is not uniform; there is a slight increase in the incidence of rupture if thrombolytic agents are used to abort a myocardial infarction. [ 10 ]   On the other hand, if  primary percutaneous coronary intervention  is performed to abort the infarction, the incidence of rupture is significantly lowered. [ 7 ]   The incidence of myocardial rupture if PCI is performed in the setting of an acute myocardial infarction is about 1 percent. [ 6 ]


Myocardial scarring  is the accumulation of  fibrous  tissue resulting after some form of trauma to the cardiac tissue. [ 1 ] [ 2 ]  Fibrosis is the formation of excess tissue in replacement of  necrotic  or extensively damaged tissue. Fibrosis in the heart is often hard to detect because  fibromas , scar tissue or small tumors formed in one cell line, are often formed. [ 3 ]  Because they are so small, they can be hard to detect by methods such as  magnetic resonance imaging . [ 1 ]  A cell line is a path of fibrosis that follow only a line of cells.


A  myocardial infarction , also known as a heart attack, often result in the formation of fibrosis. [ 2 ]  A myocardial infarction is an  ischemic  event, or a restriction of blood flow to body tissue, such as by  atherothrombosis . [ 4 ]  Without blood flow to the myocardium, it is deprived of oxygen, causing tissue death and irreversible damage. [ 5 ]  The tissue destroyed by the infarction is replaced with non-functioning fibrosis, restoring some of the structural integrity of the organ but resulting in impaired myocardial function. [ 6 ]


Coronary heart disease , also known as coronary artery disease, is one of the most common causes of myocardial damage, affecting over three million people in the United States. [ 7 ]  In coronary heart disease, the  coronary arteries  narrow due to the buildup of  atheroma  or fatty deposits on the vessel walls. The atheroma causes the blood flow of the arteries to be restricted. [ 6 ]  By restricting the blood flow, the tissue is still receiving some oxygen, but not enough to sustain the tissue over time. [ 5 ]  The accumulation of the fibrotic tissue is much slower in coronary heart disease compared to an infarction because the tissue is still receiving some oxygen. [ 6 ]


Another form of myocardial scarring results from surgical repairs. [ 2 ]  Surgical repairs are often necessary for a person born with a  congenital defect of the heart . [ 8 ]  While surgical  laparoscopy  still leaves myocardial scarring, the trauma seems to be less damaging then naturally occurring scarring. [ 2 ]


Immediately after damage to the myocardium occurs, the damaged tissue becomes inflamed. Inflammation is the accumulations of  neutrophils ,  macrophages , and  lymphocytes  at the site of the trauma. [ 9 ] [ 10 ]  In addition, "inflammatory cells upregulate the release of a myriad of signaling cytokines, growth factors, and hormones including transforming growth factor β, interleukins 1, 2, 6, and 10, tumor necrosis factor α, interferon γ, chemokines of the CC and CXC families, angiotensin II, norepinephrine, endothelin, natriuretic peptides, and platelet-derived growth factors". [ 10 ]   Both the necrotic cells and the inflamed myocardium secrete and activate matrix  metalloproteinase . Metalloproteinase aids in the destruction and reabsorption of necrotic tissue. After several days,  collagen  accumulation at the site of injury begins to occur. [ 10 ]  As part of the  extracellular matrix , granulated tissue consisting of  fibrin ,  fibronectin ,  laminin , and  glycosaminoglycan  is suspended in a collagen base. [ 10 ]   The extracellular matrix acts as scaffolding for the fibrillar collagen to form. The fibrillar collagen is the main constitute of what will become the scar tissue. [ 10 ]


Myocardial stunning  or   transient post-ischemic myocardial dysfunction  is a state of mechanical cardiac dysfunction that can occur in a portion of  myocardium  without  necrosis  after a brief interruption in  perfusion , despite the timely restoration of normal  coronary blood flow . [ 2 ] [ 3 ]  In this situation, even after  ischemia  has been relieved (by for instance  angioplasty  or  coronary artery bypass surgery ) and myocardial blood flow (MBF) returns to normal, myocardial function is still depressed for a variable period of time, usually days to weeks. [ 2 ] [ 1 ]  This reversible reduction of function of  heart contraction [ 4 ]  after  reperfusion  is not accounted for by tissue damage or reduced blood flow, but rather, its thought to represent a perfusion-contraction "mismatch". [ 5 ] [ 2 ]  Myocardial stunning was first described in laboratory canine experiments in the 1970s where LV wall abnormalities were observed following coronary artery occlusion and subsequent reperfusion. [ 6 ]


Clinical situations associated with myocardial stunning include: [ 2 ]


Myocardial stunning has been implicated in the development of  Takotsubo (Stress) cardiomyopathy . [ 1 ]


The underlying mechanisms of myocardial stunning have remained the subject of debate for several decades. [ 7 ]  Two leading hypotheses implicate reperfusion-induced oxygen free-radical damage and altered calcium flux resulting in intracellular hypercalcemia and desensitization of myofilaments. [ 1 ]  After total ischemia occurs, the myocardium switches immediately from  aerobic glycolysis  to  anaerobic glycolysis  resulting in the reduced ability to produce high energy phosphates such as  ATP  and  Creatinine Phosphate . At this point, the lack of the energy and  lactate  accumulation results in cessation of contraction within 60 seconds of  ischemia  (i.e. Vessel Occlusion).  Subsequent to this is a period of "myocardial stunning," in which reversible ischemic damage is taking place.  At approximately 30 minutes after the onset of total ischemia the damage becomes irreversible, [ 6 ]  thereby ending the phase of myocardial stunning. The generation of oxygen-derived [free radicals] during the initial period of reperfusion after ischemia is believed to contribute to the pathogenesis of myocardial stunning. [ 7 ]


Some evidence suggests that brief, repetitive episodes of myocardial ischemia may result in chronic myocardial stunning and ventricular contractile impairment. [ 1 ]


Imaging techniques such as  echocardiography ,  ventriculography , and  nuclear imaging  can be used to detect a contractile dysfunction following reperfusion after an episode of ischemia. [ 1 ]  The area of dysfunction should also maintain normal perfusion, detected via  Positron Emission Tomography , echocardiography with contrast, and/or  thallium scintigraphy  in order for a diagnosis of myocardial stunning to be considered. [ 1 ]  However, there are many practical challenges to diagnosing myocardial stunning using these methods. Accurate detection of regional myocardial blood flow and contraction function abnormalities must be detected at levels of high sensitivity. [ 2 ]   The diagnosis of myocardial stunning must also be differentiated from other conditions such as  hibernating myocardium  and persistent (silent) subendocardial ischemia, which can also co-exist with superimposed stunning. [ 2 ]


Treatment considerations for myocardial stunning should be determined based on the clinical judgment of the cardiologist or physician, the degree of LV impairment and symptoms, and the wishes of the person. [ 6 ]


Some evidence supports the use of  inotropic drugs  in the case of severe myocardial dysfunction. [ 8 ]


Results from canine experimental trials investigating the oxygen free-radical hypothesis for myocardial stunning have shown a reduction in free radical generation and improvement in myocardial function following anti-oxidant infusion. [ 6 ] [ 9 ]


Myocarditis  is defined as  inflammation  of the  myocardium . Myocarditis can progress to  inflammatory cardiomyopathy  when there are associated ventricular remodeling and cardiac dysfunction due to chronic inflammation. [ 6 ] [ 7 ]  Symptoms can include  shortness of breath ,  chest pain ,  decreased ability to exercise , and an  irregular heartbeat . [ 1 ]  The duration of problems can vary from hours to months. Complications may include  heart failure  due to  dilated cardiomyopathy  or  cardiac arrest . [ 1 ]


Myocarditis is most often due to a  viral infection . [ 1 ]  Other causes include  bacterial infections , certain medications, toxins and  autoimmune disorders . [ 1 ] [ 2 ]  A diagnosis may be supported by an  electrocardiogram  (ECG), increased  troponin ,  heart MRI , and occasionally a heart  biopsy . [ 1 ] [ 2 ]  An  ultrasound of the heart  is important to rule out other potential causes such as  heart valve problems . [ 2 ]


Treatment depends on both the severity and the cause. [ 1 ] [ 2 ]  Medications such as  ACE inhibitors ,  beta blockers , and  diuretics  are often used. [ 1 ] [ 2 ]  A period of no exercise is typically recommended during recovery. [ 1 ] [ 2 ]   Corticosteroids  or  intravenous immunoglobulin  (IVIG) may be useful in certain cases. [ 1 ] [ 2 ]  In severe cases an  implantable cardiac defibrillator  or  heart transplant  may be recommended. [ 1 ] [ 2 ]


In 2013, about 1.5 million cases of acute myocarditis occurred. [ 8 ]  While people of all ages are affected, the young are most often affected. [ 9 ]  It is slightly more common in males than females. [ 1 ]  Most cases are mild. [ 2 ]  In 2015  cardiomyopathy , including myocarditis, resulted in 354,000 deaths up from 294,000 in 1990. [ 10 ] [ 5 ]  The initial descriptions of the condition are from the mid-1800s. [ 11 ]


The signs and symptoms associated with myocarditis are varied, and relate either to the actual inflammation of the  myocardium  or to the weakness and dysfunction of the heart muscle that is secondary to the inflammation. While myocarditis may develop over periods ranging from hours to months, patients typically present with signs and symptoms that resemble heart failure, including the following: [ 1 ] [ 12 ]


Since myocarditis is often due to a viral illness, many patients experience symptoms consistent with a recent viral infection including a fever, rash, loss of appetite, abdominal pain, vomiting,  diarrhea ,  joint pains , and easily becoming tired. [ 13 ]  Additionally, myocarditis is often associated with  pericarditis , and many people with myocarditis present with signs and symptoms that suggest myocarditis and pericarditis at the same time. [ 14 ] [ 13 ]


Children primarily present with the aforementioned symptoms associated with a viral infection. [ 12 ]  Later stages of the illness can involve the respiratory system and lead to increased work of breathing. These are often mistaken for  asthma . [ 12 ]


Myocarditis can be distinguished as either fulminant or acute based on the severity of symptoms on presentation, as well as the time course over which symptoms develop and persist. This categorization can help predict the treatment, outcomes, and complications of myocarditis. [ citation needed ]


Fulminant myocarditis is defined as sudden and severe myocarditis that is associated with signs and symptoms of heart failure while at rest. [ 15 ]  More specifically, fulminant myocarditis is characterized by a distinct, rapid onset of severe heart failure symptoms, such as shortness of breath and chest pain, that develop over the course of hours to days. Additionally, treatment requires the use of medications or mechanical devices to improve heart function. [ 15 ] [ 16 ]


Acute non-fulminant myocarditis has a less distinct onset in contrast to fulminant myocarditis, and evolves over days to months. [ 16 ] [ 17 ]  While the symptoms of acute myocarditis overlap with those of fulminant myocarditis, they do not typically occur at rest, and treatment does not require the use of mechanical circulatory support. [ 17 ]


While many causes of myocarditis are known, there are many cases in which a causative agent cannot be identified. In Europe and North America, viruses are common culprits. [ 18 ]  Worldwide, however, the most common cause is  Chagas disease , an illness endemic to Central and South America that results from infection with the protozoan  Trypanosoma cruzi . [ 12 ]  Overall, myocarditis can be caused by infections, immune conditions, toxins, drug reactions, and physical injuries to the heart. [ 2 ]


The most common causes of myocarditis are infectious organisms. Viral infections are the most common cause in developed countries, with a majority of cases being caused by those with single-stranded RNA genomes, such as Coxsackie viruses (especially Coxsackie B3 and B5). [ 19 ] [ 20 ]  Globally,  Chagas disease  is the leading cause of myocarditis, which results from infection with the  protozoan   Trypanosoma cruzi . [ 12 ]  Bacteria can also result in myocarditis, although it is rare in patients with normal heart function and without a preexisting  immunodeficiency . [ 18 ] [ 21 ]  A list of the most relevant infectious organisms is below.


Most forms of myocarditis involve the infiltration of heart tissues by one or two types of pro-inflammatory blood cells,  lymphocytes  and  macrophages  plus two respective descendants of these cells,  NK cells  and  macrophages .  Eosinophilic myocarditis  is a subtype of myocarditis in which cardiac tissue is infiltrated by another type of pro-inflammatory blood cell, the  eosinophil . Eosinophilic myocarditis is further distinguished from non-eosinophilic myocarditis by having a different set of causes and recommended treatments. [ 36 ] [ 20 ]


The pathophysiology of viral myocarditis is not well understood, but it is believed to involve cardiotropic viruses (viruses with a high affinity for the heart muscle) gaining entry to cardiac muscle cells, usually via binding to a transmembrane receptor. [ 31 ]  Over approximately the next 1–7 days the virus replicates and causes inflammation leadings to  necrosis  and  apoptosis  of cardiac muscle cells (myocytes) and activation of the innate immune system. [ 31 ]  Over the next 1–4 weeks, viral replication continues with subsequent activation of the  acquired immune system  leading to  T cell  infiltration and the formation of antibodies, including possibly auto-antibodies. [ 31 ]  Over the next few months to years, this process either resolves and concludes with viral clearance or it may progress to cause permanent heart damage such as dilated cardiomyopathy, ventricular dysfunction or other cardiomyopathies. [ 31 ]  Coxsackie B, specifically B3 and B5, has been found to interact with coxsackievirus-adenovirus receptor (CAR) and  decay-accelerating factor  (DAF). However, other proteins have also been identified that allow Coxsackieviruses to bind to cardiac cells. The natural function of CAR and mechanism that the Coxsackievirus uses to infect the cardiac muscle is still unknown. [ 19 ]  The mechanism by which coxsackie B viruses (CBVs) trigger inflammation is believed to be through the recognition of CBV virions by  Toll-like receptors . [ 19 ]


The binding of many types of  coronaviruses , including the  SARS-CoV-2 virus , through  ACE2 receptors  present in heart muscle may be responsible for direct viral injury leading to myocarditis. [ 25 ]  In a study done during the  2002-2004 SARS outbreak ,  SARS viral RNA  was detected in the autopsy of heart specimens in 35% of the patients in the  Toronto ,  Canada  area who had died due to SARS. [ 37 ]  It was also observed that an already diseased heart has increased expression of ACE2 receptor contrasted to healthy individuals which may lead to greater viral infiltration in the heart muscle. Hyperactive immune responses in COVID-19 patients may lead to the initiation of the  cytokine storm . This excess release of cytokines may lead to myocardial injury. [ 25 ]  In addition to direct cardiac myocyte (heart muscle cell) damage due to SARS-CoV-2 viral infiltration and inflammation, there are other suspected mechanisms that Covid-19 may indirectly cause myocarditis. During COVID-19, the other indirect mechanisms thought to contribute to myocarditis include: oxygen supply-demand mismatch to the heart muscle leading to myocardial (heart muscle) injury; microvascular thrombi, or blood clots in the small blood vessels of the heart causing injury; the systemic hyperinflammatory state in Covid-19 leading to heart muscle injury; or the virus causing indirect damage to the heart by inducing auto-immune mediated damage to the heart muscle (and frequently other organs). [ 31 ]


Myocarditis refers to an underlying process that causes inflammation and injury of the heart.  It does not refer to inflammation of the heart as a consequence of some other insult.  Many secondary causes, such as a heart attack, can lead to inflammation of the myocardium and therefore the diagnosis of myocarditis cannot be made by evidence of inflammation of the myocardium alone. [ 38 ] [ 39 ]


Myocardial inflammation can be suspected on the basis of elevated inflammatory markers including  C-reactive protein  (CRP),  erythrocyte sedimentation rate  (ESR), or an increased  IgM  ( serology ) against viruses known to affect the  myocardium . Markers of myocardial damage ( troponin  or  creatine kinase  cardiac isoenzymes) are elevated. [ 12 ]  The CRP and ESR are sometimes elevated in myocarditis but they are not specific as they may be elevated due to many other causes. [ 31 ]  Similarly, CK may be elevated in myocarditis but is also non-specific, as it may be elevated in myositis (skeletal muscle injury). [ 31 ]  High sensitivity troponin is usually elevated in myocarditis and this marker is very specific to myocardial (heart muscle) injury. [ 31 ]


Myocardial inflammation may also be suspected based on ECG findings, but these findings are not specific to myocarditis. [ 40 ]  The ECG finding most commonly seen in myocarditis is sinus tachycardia with non-specific ST or T wave changes. [ 40 ]  But other findings that may be seen in perimyocarditis (a combination of  pericarditis  and myocarditis) include PR segment depression, PR segment depression with associated ST segment elevation, diffuse ST segment elevation (in a pericarditis pattern). [ 40 ]  ST segment elevation was seen in 62% of people with myocarditis. [ 31 ]  The presence of Q waves, a widened  QRS complex , prolongation of the  QT interval , high degree AV nodal blockade, and ventricular tachyarrhythmias are associated with a poor prognosis when seen on ECG in people with myocarditis. [ 40 ]


The  gold standard  is the  biopsy  of the myocardium, in general done in the setting of  angiography . A small tissue sample of the  endocardium  and  myocardium  is taken and investigated. The cause of the myocarditis can be only identified by a biopsy. Endomyocardial biopsy samples are assessed for histopathology (how the tissue looks like under the microscope):  myocardial interstitium  may show abundant  edema  and inflammatory infiltrate, rich in  lymphocytes  and  macrophages . Focal destruction of myocytes explains the myocardial pump failure. [ 12 ]  In addition samples may be assessed with   immunohistochemistry  to determine which types of immune cells are involved in the reaction and how they are distributed. Furthermore,  PCR  and/or  RT-PCR  may be performed to identify particular viruses. Finally, further diagnostic methods like microRNA assays and gene-expression profile may be performed. [ citation needed ]


Cardiac  magnetic resonance imaging  (cMRI or CMR) has been shown to be very useful in diagnosing myocarditis by visualizing markers for  inflammation  of the  myocardium . [ 41 ]  Cardiac MRI is most sensitive when performed 2–3 weeks after the initial clinical presentation of myocarditis and may be repeated 6–12 months after onset to monitor the evolution of disease or response to treatment. [ 31 ]  The Lake Louise Criteria (established in 2009) are a commonly used MRI criteria to establish the diagnosis of myocarditis in suspected cases. [ 42 ]  The Lake Louise Criteria include increased signal intensity after gadolinium contrast enhancement (a sign of hyperemia, or increased blood flow to damaged tissue), increased myocardial T2 relaxation time or an increased T2 signal intensity (which are signs of tissue edema or swelling), and late gadolinium contrast enhancement (which is a sign of tissue necrosis (tissue damage) or fibrosis (scarring)). [ 31 ]  In 2018, additional radiographic MRI criteria were added, including increased T1 signal intensity and increased extracellular volume (both of which being signs of myocardial injury). [ 31 ]  The original 2009 Lake Louise Criteria had a 74% sensitivity and 86% specificity in the diagnosis of myocarditis, but when adding the 2018 update to the criteria (in which T1 signal intensity was found to have high diagnostic sensitivity), the sensitivity and specificity in the diagnosis of myocarditis increased to 88% and 96% respectively. [ 31 ] [ 43 ]  Cardiac MRI, if available, is recommended in all cases of suspected myocarditis. [ 31 ]


While myocarditis has many etiologies and a variable constellation of signs and symptoms, many causes do not have a specific treatment thus the primary focus is on supportive care and symptom management. [ 17 ]  In some cases of biopsy-proven myocarditis, the causative cell type may indicate condition specific treatments that are beneficial. These treatments typically consist of corticosteroids, or immunosuppressants. [ 45 ]   Eosinophilic myocarditis ,  giant cell myocarditis  and  cardiac sarcoidosis  are usually responsive to immunosuppressive treatments; in the form of glucocorticoids with or without  azathioprine  and  cyclosporine . [ 31 ]  Some of these immune mediated forms of myocarditis require an extended course (maintenance course) of immunosuppressive therapy. [ 31 ]  It is recommended to rule out drugs and parasites as potential causes of eosinophilic myocarditis as these common causes of the variant can be effectively treated with discontinuation of the offending drug or specific anti-parasitic treatment respectively. [ 31 ]  Empiric IV glucocorticoids are indicated in acute myocarditis with cardiogenic shock, heart failure, ventricular arrhythmias or high degree AV block that is suspected due to auto-immune disease; but the  European Society of Cardiology  also recommends subsequent viral genome testing of endomyocardial biopsy specimens due to risk of viral activation, which may necessitate discontinuation of immunosuppression therapy. [ 46 ]


In a majority of cases, the main therapies are used to support patients and are dependent on the severity of symptoms and the time course across which myocarditis develops. [ 17 ]  Supportive therapies can be divided into two broad categories, medications and mechanical support. [ 47 ]


The specific medications that are used to support patients are directly related to the cause of the symptom or sign. Just as the symptoms of myocarditis mirror those of congestive heart failure, so too do the therapies. [ 45 ]  Additionally, the order in which  therapies are used depends on the degree of heart dysfunction, with stabilization of patient blood pressure and breathing taking highest priority when present. [ 17 ]  This can involve the use of  inotropes , or medications that make the heart contract with greater force, as well as  antiarrhythmic  drugs such as adenosine or carvedilol. [ 15 ]  In patients that have stable and adequate heart function, further treatments are based on heart failure guidelines. [ 45 ]   ACE inhibitors  or  Angiotensin Receptor Blockers  (ARBs) can have a protective benefit to the heart, so either are typically used in any patient with symptomatic myocarditis. [ 31 ]  Simultaneously, beta blockers are used in patients that can tolerate their heart beating at a slower rate. Shortness of breath at rest and swelling can be relieved with diuretics such as furosemide, and the addition of aldosterone receptor blockers can augment the diuresis while preventing the excess loss of potassium. In patients with symptoms while resting, additional medications can be added such as digoxin. [ 45 ] [ 48 ]


Mechanical support is used in cases of myocarditis in which medications alone do not lead to adequate heart function and the body requires additional support to achieve organ perfusion. [ 15 ] [ 16 ]  Myocarditis cases that require mechanical circulatory support are categorized as fulminant by definition. [ 15 ]  People that require additional support with their heart function can benefit from the use of  ventricular assist devices  like  intra-aortic balloon pumps . [ 15 ] [ 16 ]  In people with myocarditis severe enough to cause cardiac arrest, extracorporeal membrane oxygenation (ECMO) is used to adequately pump blood and provide oxygen if needed. [ 15 ]  Both ventricular assist devices and ECMO can be used as bridge therapy until heart transplantation in patients that are candidates.  Heart transplantation  is reserved for those that do not respond to the aforementioned conventional medical therapies. [ 49 ]  An  implantable cardioverter-defibrillator  (ICD) is sometimes required in those with cardiomyopathy or heart failure caused by myocarditis due to the risk of fatal ventricular arrhythmias. [ 31 ]  The need for ICD is usually assessed 3–6 months after the onset of myocarditis, after the acute phase of myocarditis has passed, with a temporary,  wearable cardioverter-defibrillator  acting as a temporary treatment in the interim. [ 31 ]


The prognosis associated with myocarditis is stratified by the severity and time course along which symptoms develop. In addition to symptom severity, there are also several indicators of heart function that can be used to predict patient outcomes, many of which are part of the standard evaluation of patients presenting with cardiovascular dysfunction. Most people with myocarditis have an uncomplicated, self-limited and mild course while making a full recovery. [ 31 ]  However, those with myocarditis that present with a decreased  ejection fraction , or those who present with  heart failure , advanced  atrioventricular block , with sustained  ventricular arrhythmias  or with  hemodynamic instability  have a worse prognosis with an increased risk of death or need for heart transplantation. [ 31 ]


An electrocardiogram is one of the most common screening tools used in cases of suspected cardiac pathology, such as myocarditis. The findings that correlate with poorer outcomes are non-specific and include widened QRS complexes and QT intervals, partial or complete atrial-ventricular heart block, and malignant ventricular arrhythmias like sustained ventricular tachycardia or ventricular fibrillation. [ 50 ]  Electrocardiogram findings of ST elevations with upward concavity and an early repolarization pattern, however, were associated with a better cardiovascular prognosis in general. [ 50 ]


In cases of acute myocarditis, cardiac magnetic resonance imaging can reveal several prognostic indicators that, similar to ECGs, are non-specific and reflect poorer cardiac physiology. Late gadolinium enhancement on cardiac MRI demonstrates perturbations in extracellular volume as a result of cell necrosis or edema, and is significantly associated with increases in all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events. The association was strongest with any late gadolinium enhancement, but remained true for findings of anterolateral-specific enhancement. [ 51 ] [ 52 ]  A similar relationship was found between a left ventricular ejection fraction < 50%, increased mortality, and increased major adverse cardiovascular events. [ 53 ]


Myocarditis has been reported to be a major cause of  sudden cardiac death  (SCD) in infants, adolescents, and young adults, but the reported rates show wide variation (1 to 14 percent) among young people depending on differences in SCD definition and classification/ definition of myocarditis post-mortem as well as heterogeneity of study populations. [ 54 ]


In  fulminant  myocarditis, in which an inflammatory cytokine storm occurs, cardiac functions decline rapidly and the death rate is high. [ 16 ]


The prevalence of myocarditis is estimated to be about 1-10 cases per 100,000 persons per year, with higher estimates at 22 cases per 100,000 persons annually. [ 31 ] [ 55 ]  The highest incidence of myocarditis is seen in men between the ages of 20 and 40. [ 31 ]  Fulminant myocarditis, the most severe subtype, has been shown to occur in up to 2.5% of known myocarditis presentations. When looking at different causes of myocarditis, viral infection is the most prevalent, especially in children; however, the prevalence rate of myocarditis is often underestimated as the condition is easily overlooked and is sometimes asymptomatic. [ 55 ]  Viral myocarditis being an outcome of viral infection depends heavily on genetic host factors and the pathogenicity unique to the virus. [ 56 ]  If one tests positive for an acute viral infection, clinical developments have discovered that 1-5% of said population may show some form of myocarditis. [ 55 ]


In regard to the population affected, myocarditis is more common in pregnant women, children, and those who are immunocompromised. [ 57 ]  Myocarditis, however, has shown to be more common in the male population than in the female. [ 55 ]  Multiple studies report a 1:1.3-1.7 female-male ratio of prevalence of myocarditis. [ 58 ]  In young adults, up to 20% of all cases of  sudden death  are due to myocarditis. [ 12 ]  Young males specifically have a higher incidence rate than any other population due to their testosterone levels creating a greater inflammatory response that increases the chance of cardiac pathologies. [ 55 ]  While males tend to have a higher risk of developing myocarditis, females tend to display more severe signs and symptoms, such as ventricular tachycardia and ventricular fibrillation, but do so at an older age. [ 55 ]  Among patients with HIV, myocarditis is the most common cardiac pathological finding at  autopsy , with a prevalence of 50% or more. [ 59 ]