Heart failure with preserved ejection fraction
Diastolic dysfunction | |
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In those with HFpEF, the left ventricle of the heart (large chamber on right side of the picture) is stiffened and has impaired relaxation after pumping blood out of the heart. | |
Specialty | Cardiology |
Heart failure with preserved ejection fraction (HFpEF) is a form of
Risk factors for HFpEF include hypertension, hyperlipidemia, diabetes, smoking, and obstructive sleep apnea.
HFpEF is characterized by abnormal
There is controversy regarding the relationship between diastolic heart failure and HFpEF.[3][4]
Signs and symptoms
Clinical manifestations of HFpEF are similar to those observed in HFrEF and include shortness of breath including exercise induced
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]
Risk factors
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
Hypertension
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
Aging
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.
Other
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]
- Aortic stenosis of any cause where the ventricular muscle becomes hypertrophied, and thence stiff, as a result of the increased pressure load placed on it by the stenosis.
- Diabetes
- Age – elderly patients mainly if they have hypertension.
Causes of isolated right ventricular diastolic failure are uncommon. These causes include:[citation needed]
- Constrictive pericarditis
- Restrictive cardiomyopathy, which includes Amyloidosis (most common restrictive), Sarcoidosis and fibrosis.
Pathophysiology
Gross structural abnormalities
Structural changes that occur with HFpEF are often radically different from those associated with heart failure with reduced
Cellular abnormalities
Cellular changes generally underlie alterations in cardiac structure. In HFpEF
Changes in the extracellular environment are of significant importance in heart disease.[19][20] 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.[21] 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.[22]
Diastolic dysfunction
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
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
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 (
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.[27]
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.[28]
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.[29]
Diastole
During diastole, the ventricular pressure falls from the peak reached at the end of
Non-diastolic dysfunction
Though HFpEF is characterized by a normal ejection fraction, this parameter is a rather poor index of the heart's contractile function.[31] 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,[18] and are corroborated by tissue Doppler findings that reveal changes in longitudinal contraction and motion abnormalities.[32] While these systolic impairments may be minimal at rest, they become more exaggerated with increased demand, as seen in exercise.[33]
Pulmonary hypertension and right ventricular dysfunction
Most HFpEF patients exhibit pulmonary hypertension which is significantly associated with increased morbidity and mortality.[34] 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.[35] 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.[36]
Heart rate
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.[37] Combined with the characteristic deficit in stroke volume observed in HFpEF patients, many individuals display poor exercise tolerance.[38]
Dyssynchrony
Non-simultaneous contraction of the left and right ventricle, dyssychrony, is present in up to 58% of HFpEF patients.[39] 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.[40]
Systemic abnormalities
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.[41] 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.[42]
Diagnosis
HFpEF is typically diagnosed with
Frequently patients are subjected to stress echocardiography, which involves the above assessment of diastolic function during exercise.[43] 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.[33] 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.[44]
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
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]
- Grade I diastolic dysfunction, the mildest form, is called an "abnormal relaxation pattern". On the mitral inflow Doppler echocardiogram, there is reversal of the normal E/A ratio. This pattern may develop normally with age in some patients, and many grade I patients will not have any clinical signs or symptoms of heart failure.
- Grade II diastolic dysfunction is called "pseudonormal filling dynamics". This is considered moderate diastolic dysfunction and is associated with elevated left atrial filling pressures. These patients more commonly have symptoms of heart failure, and many have left atrial enlargement due to the elevated pressures in the left heart.
- Class III diastolic dysfunction patients will demonstrate reversal of their diastolic abnormalities on echocardiogram when they perform the Valsalva maneuver. This is referred to as "reversible restrictive diastolic dysfunction".
- Class IV diastolic dysfunction patients will not demonstrate reversibility of their echocardiogram abnormalities, and are therefore said to have "fixed restrictive diastolic dysfunction".
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
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.[45]
Newer echocardiographic techniques such as speckle tracking for strain measurement, particularly for the left atrium,[46] are becoming increasingly utilised for the diagnosis of HFpEF.
Treatment
Despite increasing incidence of HFpEF effective inroads to therapeutics have been largely unsuccessful.[47] 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.[48]
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.[47][49] 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.[50]
Randomized studies on HFpEF patients have shown that exercise improves
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,
Pharmacologic therapy
Indications
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]
Benefit
Currently treatment with ACE inhibitors, calcium channel blockers, beta blockers, and
Agents
Mineralocorticoid receptor antagonists
An
Beta blockers
Beta blockers play a rather obscure role in HFpEF treatment, though there is suggestion of a beneficial role in patient management.[54] 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.[47] Some evidence suggests that vasodilating beta blockers, such as nebivolol, can provide a benefit for patients with heart failure regardless of ejection fraction.[55] 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.[56][57]
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.[47]
Angiotensin converting enzyme (ACE) inhibitors
Likewise, treatment with
Angiotensin II receptor blockers (ARBs)
ARB treatment results in an improvement in diastolic dysfunction and hypertension that is comparable to other anti-hypertensive medication.[60]
Calcium channel blockers
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
Diuretics can be useful if significant congestion develops, but patients must be monitored because they frequently develop low blood pressure.[58]
SGLT2 Inhibitors
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.[61]
Experimental
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
Prognosis
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][64] 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.[65]
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
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