New Molecular Mechanism in Diastolic Heart Failure

See related articles, pages 631–638 Diastolic performance is regulated by net myocardial stiffness, which is determined by the mechanosensitive protein network comprised of extracellular proteins such as collagen, intracellular sarcomeric proteins, and cell surface integrins. Mechanical force and its regulation are sensed and propagated by each of these components in a concerted fashion.1 During diastole, titin filaments serve as tensiometers and passive force generators. This is accomplished by modulation via directional signaling of multiple linkages between different regions within the titin molecule and the cellular contractile apparatus. An intricate network of signaling molecules coordinates the extracellular and intracellular components in the contraction of a sarcomere. In this issue of Circulation Research , Hidalgo et al present an elegant set of experiments that reveal a novel mechanism whereby altering the phosphorylation state of titin modulates myocardial passive stiffness.2 Specifically, they demonstrated that titin, in addition to being a protein kinase (PK)A and PKG substrate, is also a PKCα substrate. They further identified the PEVK region of titin as the prominent site of PKCα phosphorylation, and showed that phosphorylation at this site increased passive tension. Titin is an approximately 3000-kDa molecular-mass sarcomeric protein that spans the Z disk to the M line of the sarcomere.3 Originally thought to only provide structural scaffolding to link the many regulatory, contractile, and structural proteins within the sarcomere, titin is now recognized to be a major regulator of intracellular myocyte stiffness. Titin determines the passive tension of the intracellular component of cardiomyocytes, which, together with collagen, determines the total myocardial passive stiffness. Although the immunoglobulin-like domain and fibronectin type III repeats make up 90% of the titin molecule, titin also includes a unique I-band region that is flexible and specifically serves as a molecular spring to determine passive stiffness. …

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

The beauty of the new titin hypothesis is that the heart is able to change its resting length-tension relationship under chronic stress conditions by isoform switching, thereby rehabilitating the old clinical paradigm of “diastolic tone.” The path from hypothesis to reality is rocky, however, as the articles by Wu and Neagoe in this issue of Circulation show.1,2⇓ See pp 1333 and 1384 Wu et al1 found that the titin isoforms N2BA/N2B ratio was decreased from a normal ratio of 1.0 to 0.8 in the paced dog heart. Because N2B represents the isoform with stiffer elastic properties, this resulted in an increased passive stiffness in isolated muscle strips. The authors suggest that this “titin-based” stiffness is acting in concert with “collagen-based” stiffness and that it may counteract ventricular dilatation in canine hearts failing because of chronic pacing. The results are somewhat in contrast with an earlier study by the same group in which a switch to the more extensible isoform N2BA was shown to occur in the subendocardium of canine hearts after 2 weeks of pacing. This seemingly contradictory result might reflect a different time course of titin isoform expression.3 Neagoe et al2 report a titin isoform shift from 30:70 (ratio 0.42) of N2BA/N2B in normal human myocardium to 47:53 (ratio 0.89) in nonischemic regions from human hearts transplanted because of coronary artery disease (CAD). Total passive tension was reduced in CAD compared with control, indicating a more compliant behavior of the myocardium. The authors, referring to the well-known increase in cardiac stiffness due to collagen in chronic heart failure, hypothesize that this isoform shift occurs to counteract the global stiffening caused by chronic preload elevation in CAD patients. The giant molecule titin, the “third sarcomeric filament system,” is the third most abundant (10%) of the …

Heart failure

The SENIORS trial demonstrated that nebivolol has beneficial effects in patients with heart failure. However, the role of beta-blocker therapy in patients with heart failure and preserved left ventricular ejection fraction (HFPEF) is still unsettled. To assess the long-term effects of administration of nebivolol, compared to placebo, on the clinical symptoms, exercise capacity and parameters of left ventricular (LV) function in patients with HFPEF. The Effect of Long-term Administration of Nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with Diastolic Dysfunction (ELANDD) study is a prospective multicenter European trial in 120 patients with HFPEF randomised to nebivolol or placebo. HFPEF is defined as symptoms or signs of heart failure, a LV ejection fraction >45% and evidence of diastolic LV dysfunction by Doppler echocardiography. Procedures include a baseline clinical examination, 6-min walk test (6MWT), electrocardiography, Doppler echocardiography and Minnesota QoL questionnaire. Nebivolol or placebo is started at 2.5 mg/day and gradually uptitrated to 10 mg/day. After initiation of the study, patients are assessed at 1, 2, 5 and 6 weeks (titration phase) and at weeks 12 and 26. The primary endpoint is the change from baseline in the 6MWT distance with nebivolol versus placebo. Sample size calculations are based on an anticipated 15% difference (70 m) in the 6MWT distance between nebivolol and placebo-treated patients. This study will allow the collection of data regarding the possible clinical benefits and the effects on LV function of nebivolol administration in patients with HFPEF.

Hypertensive heart disease is a major contributor to cardiovascular morbidity and mortality, especially in African Americans, in whom LV hypertrophy is 2 to 3-fold more common in the general population as compared with whites.1 In the classic paradigm of hypertensive heart disease, concentric hypertrophy (a nondilated, thick-walled left ventricle typically with a normal left ventricular ejection fraction [LVEF]) is a common precursor to LV failure (an increased LV volume with reduced LVEF).2 Although molecular triggers of this transition from concentric hypertrophy to failure have been the subject of intense investigation, there are no previous large, longitudinal cohort studies in humans demonstrating that this progression occurs frequently. The transition from concentric LV hypertrophy to failure has been well demonstrated in animal models including the spontaneously hypertensive rat,3 or after aortic banding4 or transgenic manipulation,5 and also in humans with aortic stenosis6 or familial hypertrophic cardiomyopathy.7 Whether this paradigm faithfully represents the natural history of hypertensive heart disease is not yet known (Figure). An alternative paradigm is that the LV response to elevated blood pressure is either hypertrophy or failure, with transition between the 2 uncommon in the absence of an interval cardiac injury. Potential pathways in progression of hypertensive heart disease. Hypertension can lead to concentric left ventricular hypertrophy (LVH), characterized by nondilated, thick-walled left ventricle (arrow, top left). After “transition to failure,” the LV is dilated with reduced LVEF. Coronary artery disease often via MI is a common contributor to this transition (first horizontal arrow). Whether concentric LVH commonly leads to low EF in absence of an interval MI or significant coronary artery disease is uncertain (second horizontal arrow). If LVH is not common precursor to LV …

Cardiac remodelling patterns and proteomics: the keys to move beyond ejection fraction in heart failure?

Titin is a giant sarcomeric protein that functions as a complex, molecular spring. Its presence in the sarcomere of striated muscle was recognized in the 1980s,1 but its functions have been appreciated only over the past decade, in considerable measure because of the efforts of Granzier, Labeit, Linke, and coworkers.2–4 Earlier work by these investigators and others4 delineated the spring properties of titin and its role as the prime source of passive tension in the cardiomyocyte and, along with collagen, in myocardium. Titin also interacts and/or binds with a host of other proteins,4 including actin, a number of Z-disc proteins,5 obscurin,6 muscle LIM protein,4 and the group of muscle ankyrin repeat proteins.4,7 These interactions suggest additional functions, and recent evidence indicates that titin directly modifies sarcomere shortening and has intriguing and potentially diverse roles in mechanical sensing and signaling pathways.4 See p 155 Titin is encoded by a single gene containing 363 exons.8 Differential splicing results in two major isoforms, the shorter and stiffer N2B and the longer, more compliant N2BA.4,8 N2BA titin has numerous fetal-neonatal variants, but most variation is lost in adult life. Titin is positioned within the sarcomere such that its N-terminal segments are anchored in the Z disc and its C-terminal segments are bound to the thick filament in the M-line region (see Figure 1 in Granzier and Labeit4). The N-terminal segment penetrating the Z-disc is capped by telethonin (T-cap), a protein that may have a role in mechanical signaling and maintenance of important structural relationships4,8—for example, with the T-tubule system and sarcoplasmic reticulum. Adjacent to the Z disc is a nonextensible segment followed by titin’s complex, extensible I-band sequences consisting of tandem immunoglobulin (Ig)- and PEVK-rich segments, and the N2B sequence …

Funding Acknowledgements Type of funding sources: None. Background Left atrial (LA) maximal volume and index (LAVI) had a prognostic value in patients with heart failure and incidence of atrial fibrilation(AF) . Recently, LA mechanical function and LA strain have been introduced as alternative methods to assess LA performance more accuratly. Aim To evaluate the relation between early changes in LA function and strain ( PALS) and correlate the association with global left ventricular (LV) function and longitudinal strain (GLS) in patients with HFpEF. Methods We evaluated 132 subjects in sinus rhythm: 22 normals (31y ± 5), and 70 pts with HFpEF (65y ± 12), 60 pts HFrEF ( 64 y ± 10). Echocardiography was performed in all patients and follow up after 12 monts and analyzed offline in order to extract the global and segmental strain values of the LV and LA and LA volume and LAVI. Results The two groups of patients were comparable for most of clinical variables. LV volumes, ejection fraction, stroke volume, and mitral valve effective regurgitant orifice were similar between the two groups. The LA diameter and maximal volume were higher in HFrEF group. The GLS is significantly reduced in HFrEF group. LV GLS is the main parameter for myocardial dysfunction, which changed significantly in the HFrEF (p < 0,001) at 12mFU. Reduced PALS in HFrEF was associated with impairment of all measures of LV systolic and diastolic function and events of atrial fibrilation / 33 % in HFrEF and 12 % in HFpEF/ and the correlation between global longitudinal strain and PALS was highly significant (p < 0.001; r=-0.71). At 12mFU, PALS was significantly associated with lower global longitudinal strain in group with HFrEF (p < 0.001, r = 0.61 ), LAVI > 28 ml/m2 (p < 0.01,r = 0.57) and slightly decreased in HFpEF /p <0.5, r =0.34/. ROC analysis shows the cut –of value of 29 % for PALS which correlated with AF events. Conclusions: PALS and GLS are significantly reduced in HFpEF patients and decreased in HFpEF. PALS provides additional ,prognostic value beyond LA volume and LAVI. Severe LV myocardial dysfunction and reduced GLS and decreased PALS, even still normal LAVI is a prognostic index for AF.

Introduction: Heart failure (HF) is a clinical syndrome characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Electrocardiogram (ECG) is a widely available tool; it is relatively inexpensive and simple to perform; and it yields an instant result. A normal ECG makes systolic dysfunction unlikely and is rare in patients with suspected heart failure. Low ECG voltage has been reported as a marker of the severity of HF and is a risk factor for adverse outcomes in patients with systolic HF at 1 year. However, the relationship between ECG QRS voltage and left ventricular function in patients with heart failure has not been evaluated. Therefore, the objective of this study is to determine the relationship between electrocardiographic QRS voltage and left ventricular function. Methodology: This was a prospective cross-sectional study conducted among inpatients with HF in the medical ward of the hospital. Results: Three hundred and sixty patients were recruited for the study, of which 19 had incomplete data and were excluded in the analysis. The remaining 341 subjects were analyzed comprising 215 female and 126 male with a mean age of 47.54 ± 18.85 years. Majority of patients with normal or high QRS voltage had HF with preserved ejection fraction (HFpEF), while those with low QRS voltage had HF with reduced ejection fraction (HFrEF). On the other hand, patients with high QRS voltage had impaired relaxation pattern of diastolic dysfunction, while those with low QRS voltage had a restrictive pattern of diastolic dysfunction. There was a positive and significant correlation between the QRS voltage and ejection fraction, fractional shortening, isovolumic left ventricular relaxation time, and left ventricular deceleration time, while a negative but not significant correlation was observed between electrocardiographic QRS voltage and transmitral E/A ratio. Majority of patients with normal QRS voltage had normal left ventricular geometry, while those with high QRS voltage predominantly had concentric left ventricular hypertrophy and those with low QRS voltage had eccentric left ventricular hypertrophy. Patients with concentric left ventricular hypertrophy had predominantly HFpEF and impaired relaxation pattern of diastolic dysfunction, while those with eccentric left ventricular hypertrophy had HFrEF and restrictive pattern of diastolic dysfunction. Conclusion: HF patients with high QRS voltage had preserved left ventricular systolic function, impaired relaxation pattern of left ventricular diastolic dysfunction, and concentric left ventricular hypertrophy. While those with low QRS voltage predominantly had reduced left ventricular systolic function, restrictive pattern of left ventricular diastolic dysfunction, and eccentric left ventricular hypertrophy.

Trastuzumab-Induced Cardiotoxicity: Heart Failure at the Crossroads

AimsHeart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline‐recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy.Methods and resultsWe performed a retrospective post‐hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT‐CHF study. LV geometry was classified using two‐dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N‐terminal pro‐B‐type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P‐selectin were central hubs. Up‐titration of beta‐blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P‐value for interaction ≤0.001). For angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant.ConclusionPatients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.‐titration of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and beta‐blockers compared to patients with eccentric hypertrophy.

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD) patients. Tissue Doppler velocity imaging (TVI) is a new objective method that accurately quantifies myocardial tissue velocities, deformation, time intervals and left ventricular (LV) filling pressure. In this study, TVI was compared with conventional echocardiography for the assessment of left ventricular (LV) function in pre-dialysis patients with different stages of CKD. The results obtained by TVI were used to analyse possible relationships between LV function and clinical factors such as hyperparathyroidism and hypertension that could influence LV function. Conventional echocardiography and TVI images were recorded in 40 patients (36 men and 4 women, mean age 60+/-14 years, range 28-80 years) and in 27 healthy controls (21 men and 6 women, mean age 58+/-17 years, range 28-82 years). Twenty-two patients had mild/moderate CKD (CCr>29 ml/min; Group 1) and 18 patients had severe CKD (CCr<or=29 ml/min; Group 2). Using TVI, the myocardial tissue velocities (v; cm/s) for isovolumetric contraction (IVCv), peak systole (PSv), early (E') and late (A') diastolic filling velocities as well as strain rate (SR), mitral annulus displacement, isovolumetric relaxation time (IVRT) and LV filling pressure were estimated using TVI. The average of six LV wall measurements was used to evaluate LV global function. Using TVI, we were able to identify significantly more patients with diastolic dysfunction than using conventional echocardiography (33 vs 26, P<0.05). There was no difference in the prevalence of diastolic dysfunction between Group 1 and 2. However, using TVI, Group 2 CKD patients had lower E' velocities (6.2+/-1.9 vs 8.0+/-2.9 cm/s, P<0.05) and higher IVRT (137.4+/-13 vs 88.2+/-26 ms, P<0.001) in comparison with controls, indicating more accentuated diastolic dysfunction. Systolic blood pressure (SBP) was associated with E' velocities (rho=-0.68, P<0.005) and E'/A' was strongly associated with SBP (rho=-0.60; P<0.01) and PTH (rho=-0.64, P<0.005) in Group 2. Using conventional echocardiography, there was no difference in the prevalence of systolic and diastolic dysfunction between patients with and without LVH. However, using TVI, patients with LVH had significantly lower IVCv (2.8+/-1.3 vs 3.8+/-1.5 and 3.8+/-1.5 cm/s, P<0.05) and PSv (5.5+/-1.0 vs 6.3+/-1.2 and 6.4+/-1.3 cm/s, P<0.05) compared with patients without LVH and controls, and they also had lower E' velocities (7.1+/-2.7 vs 8.0+/-2.9 cm/s, P<0.05) compared with controls, indicating disturbances in systolic and diastolic left ventricular function. TVI provided additional information on left ventricular function in CKD patients. In patients with advanced renal failure, TVI revealed more accentuated diastolic dysfunction associated with increased systolic blood pressure (SBP) and increased levels of PTH. TVI also demonstrated disturbances in contractility and contraction in patients with LVH, which could not be detected by conventional echocardiography.

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It has recently become firmly established that patients can experience chronic and acute heart failure with a normal ejection fraction (HFNEF).1–5 We now know this disorder is the dominant form of HF in the community, and that compared with HF with reduced ejection fraction (HFREF), it is increasing in prevalence and incidence,6 causes at least as many hospitalizations and healthcare expenditures,1,6,7 causes at least as severe chronic symptoms and reduced objectively measured exercise tolerance,4 and, once patients are hospitalized, has death rates that are similarly grim.1,6 Until recently, however, we have invested nearly all our resources into understanding the pathophysiology and treatment of HFREF. As a result, a physician managing a patient with HFREF can rely on practice guidelines that are solidly supported by dozens of large trials demonstrating substantial improvements in each of the meaningful HF outcomes: mortality, hospitalizations, exercise intolerance, and reduced quality of life. When the patient instead has HFNEF, there is relatively little information about pathophysiology or treatment to guide the physician. This fact is reflected in outcomes, which a recent study indicates are improving in patients with HFREF but worsening in those with HFNEF.6 This disconcerting imbalance is magnified by sex and age, as the large burden of HFNEF falls primarily on older women.1,2,6 Article p 2051 In the present issue of Circulation , Westermann and colleagues8 report a welcomed and important study aimed at addressing the dearth of information about the pathophysiology of HFNEF. They studied 70 very well-characterized patients with documented symptoms of HF, normal left ventricular (LV) EF, and no other detectable cause for their symptoms, including pulmonary and ischemic heart disease. The investigators used a conductance catheter to measure pressure–volume loops during supine rest, handgrip exercise, and atrial pacing to 120 bpm. They …