Review Question Answers

Cardiac relaxation is regulated by NO. ROS can affect NO-related signaling at multiple sites. NO is generated by NO synthase (NOS), which requires tetrahydrobiopterin as a cofactor for the reaction. Hypertension and activation of the renin-angiotensin system lead to a depletion of tetrahydrobiopterin.

Transcriptional control of mRNA encoding procollagen I is one mechanism by which levels of secreted procollagen can increase. Procollagen maturation in the extracellular space requires cleavage of both the N and C terminal propeptides from the procollagen monomer. Other proteins secreted into the extracellular space influence the assembly of collagen into insoluble fibrils and include matricellular proteins such as SPARC and periostin as well as other collagen family members and proteoglycans.

Early infiltration of neutrophils is associated with detection of neutrophil extracellular traps (NETs) in the heart. The release of chromatin by neutrophils in the form of NETs is thought to be an antimicrobial defense mechanism.

The patient has age-induced diastolic dysfunction without any evidence of HFpEF. Comorbidity management is the only needed management.

The patient has postoperative myocardial edema from the cardioplegia and pump run and has edema-induced increased LV diastolic stiffness in addition to AS-induced increased LV stiffness. To increase cardiac output and reduce inotrope dependency, she needs to recruit Starling forces by increasing LV diastolic wall stress (increased PCWP) as long as she can successfully oxygenate.

The PADP at insertion was significantly elevated, and the subsequent PADP rose further. Both the elevated baseline and change from baseline pressures predict increased morbidity (HF hosp) and mortality. Therapeutic interventions must be taken based on PADP independent of symptom status.

The impairment of diastolic filling is continuous through the entire diastole in cardiac tamponade. The size of the effusion as well as its distribution may be variable in cardiac tamponade. Since the pericardium is relatively stiff, if a pericardial fluid collects quickly, such as in hemopericardium, the limit of pericardial stretch is reached soon with volumes of 200 to 300 mL. On the other hand, a slowly accumulating pericardial effusion allows the pericardium to stretch and become more distensible, allowing effusions to reach 1 to 2 L before the development of cardiac tamponade.

Constrictive pericarditis is a syndrome where the pericardium becomes relatively rigid and inelastic, may be thickened and calcified or not, and impairs mid- to late diastolic filling.

Ventricular interdependence leads to impairment of LV and RV filling in cardiac tamponade, constrictive pericarditis, and effusive constrictive syndromes. In tamponade, the rate of fluid accumulation determines pericardial distensibility, allowing larger volumes of fluid to accumulate before a significant increase in pericardial pressure if the rate is slow. Pericardial constriction is caused by increased pericardial rigidity, which is not necessarily related to increased thickness.

Net mechanical work is the difference between the A and V loop areas. Options b and c are incorrect, as they require additional ventricular measurements. Option d is incorrect, as strain measures tissue deformation, not volume.

Option a is incorrect, as it is the definition of atrial compliance, not contractility. Option c is incorrect as several investigators have derived atrial P-V loops in human subjects. Option d is incorrect, as it is a measure of booster pump, not reservoir function.

This is the correct answer because it is one of the determinants of atrial reservoir function. Option a is incorrect, as it is the LV end-systolic, not diastolic volume that influences atrial reservoir function. Options b and c are incorrect, as they primarily modulate atrial booster pump function.

This is the correct answer, as it is the characteristic hemodynamic finding in the stiff LA syndrome. Option b is incorrect because, by definition, atrial compliance (the inverse of stiffness) is decreased. Option c is incorrect since the highest prevalence estimates of the stiff LA syndrome are in the range of 1% to 2%. Option d is incorrect because the diastolic transmitral velocity is increased, not decreased.

This is the correct answer since hemodynamic overload in animal and human atria results in a switch from the fast (a) to slow (b) myosin heavy chain isoform. This is associated with decreased myosin ATPase activity, increased LA stiffness, and increased mechanical work. Therefore options a, c, and d are incorrect.

This is the correct answer since the inotropic response to calcium infusion is markedly attenuated. Option a is incorrect because the relative reservoir/conduit function is decreased. Option b is incorrect since there is no hypertrophy in this model. Option d is incorrect because this model is associated with a marked increase in LA stiffness.

Deceleration time is inversely proportional to chamber stiffness. Patch material has a much higher stiffness than a muscle—in other words, it lacks any stretchability. Because of that, deceleration time will decrease. The time constant of relaxation (τ) reflects active properties (i.e., only alive tissues that are capable of modulating the relaxation process affect it). Since patch material is not alive, it will not affect τ.

Time constant of relaxation (τ) will increase early LV diastolic pressure with almost no impact on LVEDP. Relaxation is an asymptotic process that almost completely dissipates after the time interval of ∼3 τ. In other words, if τ is 60 msec, the relaxation process will have no effect on LV pressure after ∼180 ms (i.e., 3 × τ) after closure of the aortic valve, or 120 msec after the opening of the mitral valve. Since filling time at rest is much longer that 120 msec, τ will not affect LV end-diastolic pressure.

E wave velocity is decreased if relaxation is impaired (slow), but is increased if the filling pressure and ventricular chamber stiffness are increased. Flow propagation velocity is decreased if relaxation is impaired, or if the left ventricle is dilated. Constrictive pericarditis patients have high E wave velocities, as relaxation is normal while filling pressures are normal or increased, and high flow propagation velocity as the left ventricle is small (tubular deformity of the left ventricle). Hypertrophic cardiomyopathy patients have low or normal E wave velocities, as relaxation is impaired while filling pressures are normal or elevated. Finally, in dilated cardiomyopathy, the left ventricle operates in the region of the diastolic pressure-volume relationship characterized by high chamber stiffness, and therefore has high E wave velocity. In contrast, when rapid initial inflow across the mitral valve meets a wide ventricle of dilated cardiomyopathy, flow propagation velocity slows down even if relaxation is normal. Think about what happens when a narrow Alpine creek meets a meandering river in the meadows.

The first event of relaxation is peak LV untwisting. The untwisting of the left ventricle in turn leads to the unmasking of restoring forces—namely, elastic forces within the left ventricle that aim to restore the left ventricle to its initial, unstressed size that is larger than the one observed in end systole (think about the force that returns your stress ball to spherical shape after you squeezed it). Restoring forces create an intraventricular pressure gradient (i.e., suction). Finally, suction opens the mitral valve and E wave occurs.

End-systolic elastance represents the stiffness generated by the myocardium at end systole, the slope of which provides a load-independent measure of contractility but is in addition influenced by chamber geometry and remodeling. Therefore it represents a ventricular property. Effective arterial elastance provides a lumped measure of steady-state and pulsatile vascular load, total arterial compliance reflects pulsatile load, and systemic vascular resistance is a measure of steady-state load. The augmentation index quantitates the impact of reflected waves on increasing aortic systolic pressure and is an additional measure of vascular load.

Patients with HFpEF have a steep end-systolic elastance (Ees), and as a result, any change in effective arterial elastance with afterload reduction will lead to a large drop in systolic blood pressure, with a minimal improvement in stroke volume. This contrasts to patients with HFrEF, where for any degree of afterload reduction, there will be a minimal drop in blood pressure but a large improvement in stroke volume, reflecting the shallower Ees in these patients.

There is no randomized trial that has demonstrated a symptomatic benefit to afterload reduction in HFpEF patients, so blood pressure should be controlled primarily for cardiovascular risk reduction as advocated for by current guidelines. This in part likely reflects the greater drop in blood pressure with minimal improvement in forward flow that occurs with vasodilation in HFpEF due to their steep end-systolic elastance relationship. Patients with HFpEF frequently also demonstrate normal hemodynamics at rest (including afterload measures) that can markedly worsen during the stress of exercise, leading to exertional dyspnea in part from abnormal ventricular-vascular coupling during exercise.

The risk of HFpEF increases sharply with age. Patients with HFrEF tend to be younger, with CAD, and predominantly men. While there are many attributable risk factors for the development of HFpEF, few have emerged as more likely to greatly augment the risk. Among these are hypertension, older age, and female sex. The 5-year mortality rate in patients with newly diagnosed heart failure is actually in the 50% range. Roughly 60% of these deaths are attributable to cardiovascular causes. While the mechanism of death is often times difficult to pinpoint in large registry data available, it remains clear that HFpEF is a highly morbid condition with a mortality similar to HFrEF. Natriuretic peptides have emerged as important biomarkers in both HFrEF and HFpEF. Levels are higher in women and in patients with renal failure.

In response to exercise, there will be an exaggerated elevation in systemic blood pressure and intracardiac filling pressure, making choices a and c incorrect. While a right heart catheterization may demonstrate normal hemodynamics, a right heart catheterization with exercise can often confirm a suspected diagnosis of HFpEF. For patients with normal hemodynamics at rest, a pulmonary artery systolic pressure with exercise of greater than 45 mmHg suggests a diagnosis of HFpEF with high sensitivity. HFpEF is associated with a lack of chronotropic response, making choice e incorrect.

There have been several randomized controlled trials examining the effect of RAAS blockade in HFpEF. To the disappointment of the scientific community, all trials have been largely neutral. There has been much debate about the specifics of these trials, mostly about the lack of uniform diagnostic criteria for HFpEF. To date, however, there has been no trial definitively showing improved survival with neurohormonal therapy. Similarly, despite nearly 30% to 40% of all HFpEF deaths attributable to sudden cardiac death, there has been no trial showing ICD therapy is indicated in this cohort of patients. By far the most effective treatment strategy has been to target risk factors for the disease: hypertension, coronary disease, diabetes, and obesity. A promising target for HFpEF has been to condition the periphery and potentially reverse the maladaptive vascular remodeling through exercise. There have been several small, short-duration exercise trials conducted in HFpEF to date. Although results are difficult to interpret given the small numbers, the prevailing underpinning is that exercise is safe and does improve functional capacity and quality of life.

Many patients with HFpEF display normal natriuretic peptide and echocardiogram, without apparent clinical congestion at rest. However, they develop abnormal increases in filling pressure during exercise. Noninvasive estimates of filling pressure, such as natriuretic peptides or echocardiography used in the current guidelines (average E/e′ >14 and LA volume index >34 mL/m ² ), do not exclude the diagnosis of HFpEF due to poor sensitivity. Since this case has multiple typical comorbidities of HFpEF (obesity, hypertension, and atrial fibrillation), further testing should be considered. Invasive right heart catheterization during exercise has emerged as the gold standard to establish or exclude HFpEF and thus should be considered to bring out hemodynamic abnormalities that develop during exercise. Noninvasive diastolic stress echocardiography could be performed to rule out HFpEF. However, a positive exercise echocardiography does not establish HFpEF because of a high rate of false positive.

Incorrect wedge values can occur if the position of the catheter tip is incorrectly placed or if the balloon occlude is underinflated or overinflated. Intrathoracic pressure is transmitted to the pulmonary venous system. Values can oscillate dramatically and differ from atmospheric pressure in patients with severe dyspnea, air trapping, or receiving positive airway pressure ventilation. High-fidelity micromanometer-tipped catheters respond faster than fluid-filled catheters to rapid changes in pressure. These are not routinely used due to their much higher cost. Simultaneous recording of LV and capillary wedge pressure is required in some instances to establish the diagnosis of mitral stenosis or severe mitral regurgitation as the etiology of HF.

Even though by definition HFpEF patients have normal or near-normal EF, contractility is commonly impaired as demonstrated when using advanced quantitative imaging methods such as strain imaging. Pulmonary hypertension can occur not only secondary to increase LA pressure but as a result of chronic pulmonary vascular remodeling. This often leads to impaired RV function. Ventricular interdependence imposed by the pericardium can lead to elevation of LV filling pressures secondary to acute RV failure in conditions such as RV infarction, hypoventilation, and pulmonary embolism.

The patient is young and has abnormal loading conditions with a very high cardiac output. The LVEDP is elevated as pulmonary venous A wave duration exceeds mitral A wave duration by 30 msec.

The evidence that LV filling is a normal pattern is the concordance of the E/A wave velocity ratio with the TDI MAM e′/a′ velocity ratio. Although the left atrium is enlarged because of the high cardiac output, there is no evidence of increased LA pressure by either LV IVRT or reduced pulmonary venous systolic flow.

A Valsalva maneuver that showed a decrease in both mitral E and A wave velocities with LA pressure reduction would have been confirmatory evidence of the normal LV relaxation present.

The patient is middle aged and has normal loading conditions at the time of his echo. There is no evidence of increased filling pressures.

Mitral filling pattern is abnormal with a long IVRT, reduced mitral E wave, and increased A wave, indicating impaired relaxation. His TDI MAM e′ and a′ also have a ratio consistent with decreased longitudinal function, which suggests LV hypertrophy from either HT or obesity.

As in the previous answer, this patient represents the large group of patients with early diastolic dysfunction due to impaired LV relaxation who have no increase in filling pressures. However, in long-term studies, they are at increased risk for progression of disease and future adverse CV events.

This elderly male has multiple risk factors for cardiac disease and systolic and diastolic dysfunction. He has moderate LV hypertrophy with stage III–IV chronic kidney disease and is significantly volume overloaded, as seen by his dilated IVC.

His increased LA volume, short LV IVRT, increased mitral E/A wave ratio, and short DT and A wave duration are all consistent with pseudonormal filling. His TDI e′ and a′ MAM also has a pattern (ratio <1) consistent with decreased longitudinal function, which suggests LV hypertrophy. The e′/a′ ratio less than 1 is discordant from the mitral filling pattern, which is also consistent with pseudonormal filling.

The elevated LA pressure masks the impaired LV relaxation, but is revealed by a Valsalva maneuver, which lowers the LA pressure. This shows that LV chamber compliance is likely reduced because of the volume overload more than myocardial stiffness. Therefore the patient’s main diastolic abnormality is most likely impaired relaxation if loading conditions were normalized.

This elderly female fits the classic profile for HFpEF. She has long-standing HT with marked LV hypertrophy. Although her CVP is normal, she has HT with a very wide pulse pressure. As expected, her BNP is mildly elevated and left atrium enlarged.

This elderly female fits the classic profile for HFpEF. She has long-standing HT with marked LV hypertrophy. Although her CVP is normal she has HT with a very wide pulse pressure. As expected, her BNP is mildly elevated and left atrium enlarged.

As in the previous case, the elevated LA pressure masks the impaired LV relaxation. However, the rather modest changes in mitral inflow velocity with a Valsalva maneuver suggests the main problem here is increased myocardial stiffness, an advanced form of diastolic dysfunction. This is reflected in the blunted pulmonary venous systolic flow, which also indicates an elevated LA pressure even though preload is normal.

The reduced pulmonary venous systolic flow in a patient with pseudonormal filling is associated with a marked increase in CV mortality that is nearly similar to restrictive filling, as it indicates LA systolic function is failing. Therefore the patient’s main diastolic abnormality is impaired relaxation if loading conditions could be normalized.

Global longitudinal strain can be calculated from apical views (AP3, AP4, and AP2), while radial and circumferential strains are calculated from short axis views.

TDI-derived strain is less affected by segmental tethering and translational motion but is still limited by angle dependency, while 2-D speckle tracking–derived strain is angle-independent.

Global longitudinal strain represents the percentage change from end diastole to end systole in the length of the LV wall perimetry measured from one basal segment, around the apex, to the opposite basal segment averaged from the three apical views.

Vp is a complex phenomenon that is determined by rate of LV relaxation, geometry, and intraventricular pressures and gradients. Abnormalities in those parameters will impair diastolic suction and slow down early ventricular flow propagation.

In normal conditions, it represents the motion of columnar flow from base to apex. Presence of vortices and convective forces influence Vp on a variety of clinical conditions.

In normal conditions Vp is relatively fast, above 45 cm/sec.

Severe LV hypertrophy typically has a small cavity with intracavitary flow acceleration depending more on the geometry of the cavity than the early diastolic properties. In cases of constrictive pericarditis, Vp can be particularly fast, as in the case shown at the beginning of this chapter. In restrictive cardiomyopathy and LV systolic dysfunction, velocity flow propagation is slow, particularly when there is also significant ventricular dilatation.