Key words
diastole, endothelial dysfunction, Heart failure, inflammation
Outline
Physiology of Diastolic Filling and Compliance, 151
Diastolic Dysfunction, 152
Invasive Measurement of Diastolic Function: Relaxation and Chamber Stiffness, 152
Noninvasive Measurement of Diastolic Function: Echocardiography, 152
Estimation of Left Ventricle Filling Pressures, 153
Left Ventricle Hypertrophy, 153
Left Atrial Dysfunction, 153
Natriuretic Peptides, 154
Diagnosis of Heart Failure With Preserved Ejection Fraction, 154
Heart Failure With Preserved Ejection Fraction: High Diastolic Left Ventricle Stiffness, 155
Regulation of Diastolic Stiffness by the Extracellular Matrix, 155
Regulation of Myocardial Stiffness by the Cardiomyocyte, 157
Comorbidities in Heart Failure With Preserved Ejection Fraction, 159
Increased Age, 159
Female Gender, 159
Chronic Obstructive Pulmonary Disease, 159
Anemia, 160
Renal Dysfunction, 160
Hypertension, 161
Metabolic Risk Factors, 162
Inflammation and Endothelial Dysfunction, 162
The New Paradigm for Heart Failure With Preserved Ejection Fraction, 162
Heart Failure With Preserved Ejection Fraction: A Systemic Disorder, 163
Heterogeneity in Heart Failure With Preserved Ejection Fraction, 164
Pathophysiologic Stratification in Heart Failure With Preserved Ejection Fraction, 164
Summary and Future Directions, 164
Acknowledgment
Supported by grants from CVON (Cardioavasculair Onderzoek Nederland), Dutch Heart Foundation, The Hague (RECONNECT, EARLY HFPEF).
Heart failure (HF) with preserved ejection fraction (EF; HFpEF) currently accounts for greater than 50% of all HF cases, and its prevalence relative to HF with reduced EF (HFrEF) continues to rise at a rate of 1% per year ( see also Chapter 39 ). By 2020, the prevalence of HFpEF is projected to exceed 8% of people older than 65 years of age, and the relative prevalences of HFpEF and HFrEF are predicted to be 69% and 31%, respectively, turning HFpEF into the most prevalent HF phenotype. Outcomes in patients with HFpEF and HFrEF are equally poor, with 5-year mortality rates up to 75% in both HF phenotypes. In contrast to HFrEF, modern HF pharmacotherapy did not improve outcome in HFpEF, which is related to incomplete understanding of HFpEF pathophysiology, patient heterogeneity, suboptimal trial designs, and lack of insight into primary pathophysiologic processes. Patients with HFpEF are frequently elderly females, and patients have a high prevalence of noncardiac comorbidities, which independently adversely affect myocardial structural and functional remodeling. Furthermore, although diastolic left ventricular (LV) dysfunction represents the dominant abnormality in HFpEF, numerous ancillary mechanisms are frequently present, which also negatively affects cardiovascular reserve. Over the past decade, clinical and translational research has led to improved insight into HFpEF pathophysiology and the importance of comorbidities and patient heterogeneity. Recently, a new paradigm for HFpEF has been proposed, which suggests that comorbidities drive myocardial dysfunction and remodeling in HFpEF through coronary microvascular inflammation. In the conceptual framework of HFpEF treatment, emphasis may need to shift from a “one-size-fits-all” strategy to an individualized approach based on phenotypic patient characterization and diagnostic and pathophysiologic stratification of myocardial disease processes. This chapter describes these novel insights from a pathophysiologic standpoint.
Physiology of Diastolic Filling and Compliance
Normal diastolic function allows adequate filling of the heart without an excessive increase in diastolic filling pressure both at rest and with exercise. LV relaxation starts at end-systole, and LV pressure falls rapidly when the LV expands, creating a left atrial (LA)-to-LV pressure gradient when LV diastolic pressure drops below LA pressure ( Fig. 11.1 A ). This accelerates blood out of the LA and produces rapid early diastolic LV filling, with the LA-to-LV pressure gradient being considered a measure of LV suction. Following filling of the LV, the pressure gradient from the LA to the LV apex decreases and then transiently reverses. The reversed mitral valve pressure gradient decelerates and then stops the rapid flow of blood into the LV in diastole. During the midportion of diastole (diastasis), the LA and LV pressures equilibrate and mitral flow nearly ceases. Late in diastole, atrial contraction produces a second LA-to-LV pressure gradient that again propels blood into the LV (see Fig. 11.1A ). After atrial systole, as the LA relaxes, its pressure decreases below LV pressure, causing the mitral valve to begin closing.
Diastolic Dysfunction
Normally, early diastole is responsible for the majority of ventricular filling, but with disturbed myocardial relaxation the rate of early diastolic LV pressure decline is reduced, which increases the time to reach minimal LV diastolic pressure and augments the importance of the contribution of atrial contraction for diastolic filling. As LA pressure increases, early diastolic filling becomes more dominant despite impaired myocardial relaxation. Early filling is initiated by increased LA pressure, which pushes the blood into the LV, instead of the negative LV diastolic pressure, which pulls the blood from the LA by suction (see Fig. 11.1A ). As diastolic function worsens, LA pressure is elevated and myocardial relaxation is impaired at rest, as evident from prolongation of the time constant of isovolumic relaxation (see Fig. 11.1B ). Most of diastolic LV filling now occurs during early diastole, and LA contraction may not be sufficient. In this situation, LA contraction pushes blood back into the pulmonary veins, especially if pulmonary venous diastolic forward flow is already completed at the time of atrial contraction. The term diastolic dysfunction indicates an abnormality of diastolic distensibility, filling, or relaxation of the LV, regardless of whether the EF is normal or abnormal and regardless of whether the patient is symptomatic or asymptomatic. After adjustment for established HF risk factors, asymptomatic antecedent LV diastolic dysfunction was associated with incident HF in individuals recruited in the Framingham Heart Study. Thus diastolic dysfunction refers to abnormal mechanical (diastolic) properties of the ventricle and is present in virtually all patients with HF. The term HFpEF refers to a clinical syndrome characterized by symptoms or signs of HF, preserved LVEF, and diastolic LV dysfunction.
Invasive Measurement of Diastolic Function: Relaxation and Chamber Stiffness
Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness can be acquired invasively during cardiac catheterization. Ventricular pressure fall is the hemodynamic manifestation of myocardial relaxation, and the rate of global LV myocardial relaxation is reflected by the exponential course of isovolumic LV pressure fall (see Fig. 11.1B ). Isovolumic relaxation can be quantitated by calculating the peak instantaneous rate of LV pressure decline, peak (−)dP/dt, and the time constant of isovolumic LV pressure decline, tau (τ) (see Fig. 11.1B ). Tau is inversely related to the rate of LV pressure fall, becoming shorter when LV pressure fall accelerates and longer when LV pressure fall slows, such that τ greater than 48 milliseconds represents evidence for delayed relaxation. Another invasive approach that can be used to determine LV chamber stiffness and compliance is through measurement of LV pressure volume loops with the use of high-fidelity LV conductance catheters, which simultaneously measure LV pressure and LV volume ( Fig. 11.2A ). By changing preload (e.g., transient inferior vena caval occlusion) or afterload (e.g., administration of phenylephrine), a family of loops is obtained (see Fig. 11.2B ). The end-diastolic pressure-volume relationship (EDPVR), constructed by connecting the end-diastolic pressure-volume points of each loop, is nonlinear and defines the passive physical properties of the chamber with the myocardium in its most relaxed state. The end-systolic pressure-volume relationship (ESPVR), constructed by connecting the end-systolic pressure-volume points of each loop, defines a reasonably linear relationship that characterizes properties of the chamber with the myocardium in a state of maximal activation at a given contractile state (see Fig. 11.2B ). An important difference between HFrEF and HFpEF patients resides in these pressure-volume loops, with HFrEF being characterized by decreased contractility and downward and rightward displacement of the LV ESPVR (see Fig. 11.2C ), whereas HFpEF is characterized by preserved global contractility but impaired LV relaxation, elevated filling pressures, and increased stiffness with an upward and leftward shift of the LV EDPVR, representing raised LV end-diastolic pressure at any given LV end-diastolic volume (see Fig. 11.2C ). This steep LV EDPVR in patients with HFpEF seems the most important determinant for impaired exercise tolerance, with deficient early diastolic LV recoil, blunted LV lusitropic or chronotropic response, vasodilator incompetence, and deranged ventriculovascular coupling serving contributory roles. Elevated LV filling pressures constitute the hallmark of diastolic LV dysfunction, and filling pressures are considered elevated when the mean pulmonary capillary wedge pressure (PCWP) is greater than 12 mm Hg or when the LVEDP is greater than 16 mm Hg.
Noninvasive Measurement of Diastolic Function: Echocardiography
Echocardiography provides assessment of cardiac structural and functional remodeling and is most commonly used to assess LV diastolic (dys)function. Tissue Doppler (TD) echocardiography of early diastolic mitral annular movement, designated as e′ or E′ velocity, provides a noninvasive estimate of myocardial relaxation. The ratio of peak early Doppler mitral valve flow velocity (E) divided by e′ (E/e′ ratio) provides a noninvasive assessment of diastolic LV filling pressure. Because E depends on LA driving pressure, LV relaxation kinetics, and age and because e′ depends mostly on LV relaxation kinetics and age, in the E/e′ ratio, effects of LV relaxation kinetics and age are eliminated, and the ratio becomes a measure of LA driving pressure or LV filling pressure. With a value of E/e′ greater than 15, LV filling pressures are elevated, and this is considered diagnostic evidence for diastolic LV dysfunction. In contrast, when E /e′ ratio is less than 8, LV filling pressures are low, and this is considered diagnostic evidence of absence of HFpEF. An E /e′ ratio ranging from 8 to 15 is considered suggestive but nondiagnostic evidence of diastolic LV dysfunction and needs to be implemented with additional echocardiographic measurements or evidence of elevated biomarkers to confirm the diagnosis of HFpEF.
Estimation of Left Ventricle Filling Pressures
In contrast to earlier studies, which demonstrated close correlation of the E/e′ ratio with LV filling pressures, recent studies combining right heart catheterization and echocardiography demonstrated that E/e′ did not reliably track changes in left-sided filling pressures at rest and during alterations in loading conditions, whereas in some patients, elevated filling pressure is observed only during exercise. Therefore normal filling pressure at rest does not exclude clinically significant diastolic dysfunction or HFpEF. In addition, presence of structural LV and/or LA remodeling is suggestive for diastolic LV dysfunction.
Left Ventricle Hypertrophy
LV geometry can be described based on the LV mass (hypertrophy) and the relative wall thickness (RWT), which describes the relationship between wall thickness and cavity size (concentricity). LV hypertrophy can occur in the context of increased RWT (concentric hypertrophy) or normal to reduced RWT (eccentric hypertrophy). Increased concentricity can also occur in the absence of frank hypertrophy (concentric remodeling). LV concentric remodeling and/or hypertrophy was present in 59% to 77% of HFpEF patients included in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and Irbesartan in HFpEF (I-PRESERVE) trials with concentric LV remodeling and/or hypertrophy being related to increased mortality and HF hospitalization.
Left Atrial Dysfunction
LA volume is strongly associated with severity of diastolic LV dysfunction, independent of LVEF, age, gender, and cardiovascular risk score, and patients with HFpEF frequently demonstrate both increased LA volume and impaired LA function, which are independently associated with worse outcome. The principal role of the LA is to modulate LV filling and cardiovascular performance by functioning as a reservoir for pulmonary venous return during ventricular systole, a conduit for pulmonary venous return during early ventricular diastole, and a booster pump that augments ventricular filling during late ventricular diastole. In the I-PRESERVE and TOPCAT echocardiographic substudies, 65% of HFpEF patients had LA dilatation. In HFpEF patients enrolled in TOPCAT, lower peak LA strain was associated with older age, higher prevalence of atrial fibrillation and LV hypertrophy, worse LV systolic and diastolic function, and higher risk of HF hospitalization.
Natriuretic Peptides (See Also Chapters 9 and 33 )
Natriuretic peptides (NPs) represent the third modality that can be used in the diagnosis of HFpEF. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are produced by atrial and ventricular myocardium in response to an increase of atrial or ventricular diastolic stretch due to volume or pressure overload, and their secretion results in natriuresis, vasodilation, and improved LV relaxation. Cardiac myocytes produce proBNP, which is subsequently cleaved in the blood into N-terminal (NT)-proBNP and BNP. NP levels are lower in HFpEF than in HFrEF, which is usually attributed to lower LV diastolic wall stress in HFpEF because of concentric LV remodeling. Recently, a cushioning effect of epicardial fat was also suggested to contribute to the low NP levels in HFpEF as it dampens LV distension in diastole. The latter finding explains why low NT-proBNP plasma levels are frequently observed in HFpEF patients suffering from obesity, a highly prevalent comorbidity and important contributor to HFpEF. Indeed, patients with invasively proven HFpEF frequently even have low or even normal NP levels. A recent study, which used combined rest and exercise PCWP measurements to diagnose HFpEF, reported a median value of 406 pg/ml with 18% of patients having a normal plasma NT-proBNP level (<125 pg/mL). In early-stage HFpEF, increase of LV filling pressures, which triggers NP release, can be limited to conditions of physical exercise with normal or near-normal filling pressures at rest. Low NP expression was confirmed in LV myocardial biopsies of HFpEF patients, who had four times lower myocardial proBNP 108 content than HFrEF patients. Therefore, when used for diagnostic purposes, NPs do not provide diagnostic standalone evidence of HFpEF and always need to be implemented with other noninvasive investigations. Despite low levels of NPs in HFpEF, NPs remain an indicator of disease severity in HFpEF as they predicted prognosis in several HFpEF outcome trials. In the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) trial, BNP levels were lower in HFpEF than in HFrEF, but, for a similar elevation in BNP, prognosis was equally poor in both conditions. In the I-PRESERVE trial, baseline log transformed NT-proBNP was the strongest predictor of all three outcomes.
Diagnosis of Heart Failure with Preserved Ejection Fraction
According to current recommendations, three obligatory conditions need to be satisfied for the diagnosis of HFpEF: (1) presence of signs or symptoms of congestive HF; (2) presence of preserved LV systolic function, defined as LVEF greater than 50% and LV end-diastolic volume index (LVEDVI) less than 97 mL/m 2 ; and (3) evidence of diastolic LV dysfunction determined either by invasive measurements or by echocardiography alone or by echocardiography in conjunction with biomarkers ( Fig. 11.3 ). Decompensated patients with HFpEF typically display overt congestion on physical examination and chest radiography, and in this setting the diagnosis is straightforward. However, compensated, euvolemic patients presenting with exertional dyspnea in the absence of overt clinical, radiographic, or biomarker evidence of congestion present a greater diagnostic challenge. The reference standard to diagnose HFpEF in these patients is by right heart catheterization followed by invasive exercise testing if resting intracardiac pressures are normal. Because of its invasive nature, technical complexity, and cost, this test is impractical for routine evaluation but is more logically reserved for situations in which diagnosis remains uncertain after less invasive test results are equivocal. To make this determination, the probability of disease must first be estimated, allowing clinicians to decide whether disease is likely present or absent, or intermediate, when more definitive testing is required. A recent study evaluated clinical data from consecutive patients for whom the diagnosis of HFpEF or a noncardiac etiology of dyspnea was ascertained conclusively by invasive exercise testing to develop a scoring system that can be used in the diagnostic evaluation of HFpEF. HFpEF patients were identified by elevated PCWP at rest (≥15 mm Hg) or during exercise (≥25 mm Hg). Logistic regression was performed to evaluate the ability of clinical findings to discriminate cases from controls, and a scoring system was developed and validated in a separate test cohort. Obesity, atrial fibrillation, age greater than 60 years, treatment with two or more antihypertensives, echocardiographic E/e′ ratio greater than 9, and echocardiographic pulmonary artery systolic pressure greater than 35 mm Hg were selected as the final set of predictive variables. A weighted score based on these six variables was used to create a composite score (H 2 FPEF score) ranging from 0 to 9 ( Fig. 11.4 ). The odds of HFpEF doubled for each 1-unit score increase (odds ratio [OR] 1.98 1.74–2.30], P < .0001) with an area under the curve (AUC) of 0.841 ( P < .0001) (see Fig. 11.4 ). By establishing the probability of disease, the H 2 FPEF score may be used to effectively rule out disease among patients with low scores (e.g., 0 or 1), establish the diagnosis with reasonably high confidence at higher scores (e.g., 6–9), and identify patients for whom additional testing is needed with intermediate scores (e.g., 2–5) (see Fig. 11.4 ).
Heart Failure With Preserved Ejection Fraction: High Diastolic Left Ventricle Stiffness
In the absence of endocardial or pericardial disease, high diastolic LV stiffness results from increased myocardial stiffness, which is regulated by the extracellular matrix (ECM) and the cardiomyocytes ( Fig. 11.5 ).
Regulation of Diastolic Stiffness by the Extracellular Matrix
The ECM contributes to passive stiffness in diastole and prevents overstretch, myocyte slippage, and tissue deformation during ventricular filling, and components of the ECM also serve as modulators of growth and tissue differentiation ( see also Chapter 4 ). The ECM is composed of fibrillary proteins (such as collagen and elastin), nonfibrillary proteins (such as aminoglycans, fibronectin, laminin), and bioactive proteins (such as transforming growth factor-β [TGF-β], matrix metalloproteinases [MMPs], tissue inhibitors of matrix metalloproteinases [TIMPs], and matricellular proteins). Collagen importantly determines ECM-based stiffness, through regulation of its total amount, expression of collagen type I, and degree of collagen cross-linking, which are increased and linked to diastolic LV dysfunction and outcome in patients with HFpEF. Diffuse interstitial myocardial fibrosis, assessed by magnetic resonance imaging–derived T1 mapping, was recently shown to predict invasively measured LV stiffness in patients with HFpEF. Collagen metabolism requires sequential, highly orchestrated and regulated steps: (1) procollagen synthesis and secretion, (2) procollagen postsynthetic processing, (3) collagen posttranslational modification, and (4) collagen degradation ( Fig. 11.6 ). Each of these steps is altered in HFpEF, contributes either individually or in aggregate to LV diastolic dysfunction, is mirrored in plasma biomarkers, and serves as a unique treatment target. In HFpEF, fibroblasts are presumed to convert to myofibroblasts because of exposure to TGF-β as a result of monocyte/macrophage myocardial infiltration, whereas matrix degradation is decreased because of altered expression of MMPs and upregulation of TIMPs. Distinct expression profiles of MMPs and TIMPs also correspond to differences in ECM geometry, composition, and homeostatic mechanisms in HFpEF versus HFrEF. HFpEF is more often associated with interstitial, reactive fibrosis and HFrEF with focal, replacement fibrosis ( Table 11.1 ). As recently shown in LV biopsies, increased diastolic LV stiffness in hypertensive HFpEF patients was caused by both the ECM and elevated intrinsic cardiomyocyte stiffness.
| HFpEF | HFrEF | |
|---|---|---|
| LV structure/function | ||
| End-diastolic volume | ↔ | ↑ |
| End-systolic volume | ↔ | ↑ |
| Wall thickness | ↑ | ↔ |
| Mass | ↑ | ↑ |
| Mass/volume ratio | ↑ | ↓ |
| Remodeling | Concentric | Eccentric |
| Ejection fraction | ↔ | ↓ |
| Stroke work | ↔ | ↓ |
| End-systolic elastance | ↔ | ↓ |
| End-diastolic stiffness | ↑ | ↓ |
| LV ultrastructure | ||
| Myocyte diameter | ↑ | ↔ |
| Myocyte length | ↔ | ↑ |
| Myocyte remodeling | Concentric | Eccentric |
| Fibrosis | Interstitial/reactive | Focal/replacement |
Regulation of Myocardial Stiffness by the Cardiomyocyte (see also Chapters 1 , 2 and 9 )
High intrinsic cardiomyocyte stiffness importantly contributes to high diastolic LV stiffness in HFpEF. Cardiomyocyte stiffness is mainly determined by the elastic sarcomeric protein titin, which functions as a bidirectional spring, responsible for early diastolic recoil and late diastolic distensibility (see Fig. 11.5 ). Titin spans a half sarcomere running from the Z disc to the M band with an elastic spring element in the I band of the sarcomere. Titin-based cardiomyocyte stiffness results from dynamic changes in expression of stiff (N2B) and compliant (N2BA) isoforms and from posttranslational modifications including titin isoform phosphorylation and oxidative changes of the N2B segment. Phosphorylation of the N2B segment decreases titin-based myofilament stiffness. Kinases known to phosphorylate the N2B segment include extracellular signal regulated kinase-1/2 (ERK1/2), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase (PKG), and calcium/calmodulin-dependent kinase II (CaMKII). In contrast, phosphorylation of the PEVK-region increases titin-based myofilament stiffness, mediated by phosphorylation by Ca 2+ -dependent protein kinase C (PKCα) (see Fig. 11.5 ). Hypophosphorylation of the N2B segment and hyperphosphorylation of PEVK can act complementary to elevate passive tension (e.g., in end-stage HF) and are important to fine-tune passive myocardial stiffness and diastolic function in the heart.
Cardiomyocyte stiffness was higher in patients with HFpEF than in patients with HFrEF or aortic stenosis (AS) and correlated with reduced myocardial concentration of the pivotal second messenger cGMP and lower activity of its effector kinase PKG in HFpEF than in HFrEF or AS ( Fig. 11.7 ). The generation of the second messenger molecule cGMP results from activation of soluble guanylate cyclase (sGC) by nitric oxide (NO) and from activation of particulate GC (pGC) by NPs ( Fig. 11.8 ). Once generated, cGMP activates PKG, allowing PKG-mediated phosphorylation of a vast number of target proteins, exerting a wide range of downstream effects such as enhanced reuptake of calcium (Ca 2+ ) into the sarcoplasmic reticulum (SR), inhibition of Ca 2+ influx, suppression of hypertrophic signaling through inhibition of G protein–coupled receptors and the transient receptor potential canonical channel; inhibition of ischemia-reperfusion injury through phosphorylation of the ATP-sensitive potassium channel; and stimulation of LV relaxation and LV distensibility by phosphorylation of troponin I and the stiff titin N2B segment (see Fig. 11.8 ). In addition to posttranslational modifications of titin consisting of lack or excess phosphorylation at specific sites along the titin molecule, altered diastolic stiffness was recently suggested to also originate from titin being damaged by oxidative or physical stress. Using single-molecule atomic force microscopy force-extension measurements on recombinant immunoglobulin (Ig) domain polyprotein constructs, it was shown that the human titin N2-B-unique sequence (N2-B[us]) contains up to three disulfide bridges under oxidizing conditions, leading to increased titin-based cardiomyocyte stiffness. In addition, mechanical unfolding of titin Ig domains exposes buried cysteine residues, which then can be S-glutathionylated. S-glutathionylation of cryptic cysteines greatly decreases the mechanical stability of the parent Ig domain, as well as its ability to fold. Both effects favor a more extensible state of titin. Recently, it was demonstrated that the family of small heat shock proteins (sHSPs), including HSP27 and αB-crystallin, provide myofilamentary protection upon cardiomyocyte harmful insults. Typically, sHSPs are upregulated under diverse stress situations, and their overexpression protects cells from oxidative stress, energy depletion, and other unfavorable conditions. In the heart, αB-crystallin and HSP27 are induced during ischemic injury, heat stress, or end-stage failure. In response to potentially harmful insults, the myocyte sHSPs, including αB-crystallin and HSP27, preferentially translocate from the cytosol to the myofibrils, where they bind to the sarcomeric Z disc and/or I band ( Fig. 11.9 ). Previous exposure of cardiomyocytes to stretch and low pH caused a rise of cardiomyocyte stiffness and was indeed suppressed by HSP27 and αB-crystalline. Sarcomere stretch unfolds titin domains, exposing concealed hydrophobic sites, leading to aggregation of titin Ig domains, which results in loss of function and increased cardiomyocyte stiffness. Interestingly, HSP27 and αB-crystallin provided protection against titin aggregation, with lowering of cardiomyocyte stiffness. Administration of αB-crystallin also reversed the combined effects of prestretch and acidic pH on the diastolic passive tension (F passive )—sarcomere length (SL) relation in cardiomyocytes isolated from LV tissue samples of patients with dilated cardiomyopathy (DCM) or AS ( Fig. 11.10 ). In AS and DCM cardiomyocytes, αB-crystallin lowered diastolic stiffness well below baseline values, as previously reported after administration of PKA or PKG. This supports overlapping effects of titin phosphorylation and stretch-induced titin aggregation possibly because of preexisting stretch-induced titin aggregation obstructing phosphorylation at sites that specifically increase titin elasticity. This finding has important therapeutic implications because it implies limited efficacy of drugs that increase PKA or PKG activity for treatment of diastolic LV dysfunction related to high cardiomyocyte stiffness and could relate to the failure of dobutamine to improve diastolic LV dysfunction and of phosphodiesterase (PDE) 5 inhibitors to improve exercise tolerance or hemodynamics in HFPEF. In addition, upregulation and subsarcolemmal localization of αB-crystallin was observed in AS and DCM cardiomyocytes. Because of the close vicinity of capillaries ( white arrows in Fig. 11.11 ), the localization of αB-crystallin in subsarcolemmal aggresomes was consistent with signals from the microvascular endothelium being involved in their formation. The subsarcolemmal localization also suggested that endogenous αB-crystallin was diverted from the sarcomeres and therefore failed to exert its protective action on titin distensibility, which was, however, restored after administration of exogenous αB-crystallin. The latter finding supports future therapeutic efforts to raise concentration of αB-crystallin in failing myocardium through direct administration of αB-crystallin, through administration of αB-crystallin analogues or through administration of HSP-inducing drugs such as geranylgeranylacetone or NYK9354.
