Diastolic Stress Research Articles

Myocardial stress and hypertrophy: a complex interface between biophysics and cardiac remodeling

Pressure and volume overload results in concentric and eccentric hypertrophy of cardiac ventricular chambers with, respectively, parallel and series replication of sarcomeres. These divergent patterns of hypertrophy were related 40 years ago to disparate wall stresses in both conditions, with systolic wall stress eliciting parallel replication of sarcomeres and diastolic wall stress, series replication. These observations are relevant to clinical practice, as they relate to the excessive hypertrophy and contractile dysfunction regularly observed in patients with aortic stenosis. Stress-sensing mechanisms in cardiomyocytes and activation of cardiomyocyte death by elevated wall stress continue to intrigue cardiovascular scientists.

Expiratory gass analysis during diastolic exercise stress echocardiography: a clue that can resolve diastolic puzzle?

Expiratory gass analysis during diastolic exercise stress echocardiography: a clue that can resolve diastolic puzzle?

Spironolacton reduces left ventricular diastolic stiffness, remodeling and improves functional status in hypertensive patients with preserved ejection fraction heart failure

Mineralocorticoid receptor antagonists have been shown to be beneficial in treatment and mortality reduction in heart failure with reduced ejection fraction in randomized trials. Data regarding their usefulness in HFPEF remains to be studied. We studied the effects of spironolacton (S) on diastolic stiffness and LV remodeling in diabetic pts with HFPEF. Methods: 137 pts 64±12 yrs (56% female) with HFPEF NYHA III with diabetes mellitus and without renal failure were randomized to two groups in order to receive S on top of their treatment (n=68) 25mg/day to further increase to 50mg/day after 8 weeks if no hyperkalemia (>5.5 mmol/l) has been developed or amilorid (A) 2.5 mg/day to increase to 5mg/day after 8 weeks in pts without hyperkalemia (n=69) for 6 months. Medications as ACEI/ARB, β-blockers, loop diuretics were evenly distributed in groups. NTproBNP levels, and diastolic wall stress (DWS) as (PWs - PWd) /PWs, LV mass index (LVMI), septal E/Em, LA volume index (LAVI) were measured by EchoCG by two independent observers unaware of the aim of the study in 1, 30, 90 and 180 days follow up. Results: In 30 days there were no significant changes in all parameters. In 90 day E/Em were significantly less in S compared with A (10.8±2.3 vs 12.1±3.1, p<0.05) without changes in other parameters. This difference remained unchanged throughout the study. In 180 days DWS, LVMI, LAVI and NTproBNP levels were significantly better in S group. (DWS: S 0.37±0.3 vs A 0.31±0.2, p<0.03; LWMI: male S 114±6 vs A 118±8, p<0.05; female S 96±5 vs A 110±3, p<0.05; LAVI: S 28±5 vs 32±7, p<0.03; NTproBNP S 938±69 vs A 1602±197 pg/ml p<0.02). Conclusion: In our study spironolacton reduces diastolic stiffness and alters LV and LA remodeling as well as NTproBNP levels in diabetic pts with HFPEF.

Abstract 254: Defects in c-kit Receptor Function Affect Myocyte Turnover Resulting in Premature Myocardial Aging in the W/WV Mouse

The objective of this study was to determine whether attenuation of cardiac stem cell (CSC) growth in the adult heart interferes with physiologic cell turnover leading to premature accumulation of senescent myocytes and myocardial aging. For this purpose, W/W V mice, which carry a mutated non-functional c-kit receptor, were studied. The W/W V mouse is a compound heterozygous mutant mouse. The W mutation corresponds to a large amino acid deletion that includes the transmembrane domain of the c-kit receptor while the W V mutation is a point mutation in the kinase domain of this receptor. These genetic modifications reduce c-kit kinase activity by approximately 80-90% affecting hematopoiesis, gametogenesis and melanogenesis. Echocardiographically, at 2-3 months of age, LV diameters and ejection fraction were similar in controls and W/W V mice. However, at 5-6 months and 8-9 months, diastolic and systolic LVDs were larger in W/W V mice than in WT. Ejection fraction decreased with age in W/W V mice. These various aspects of negative ventricular remodeling typically occur with the development of the aging myopathy in mice 24 month-old and older. Moreover, ventricular dilation is commonly associated with wall thinning, both critical parameters of diastolic and systolic wall stress. Importantly, these anatomical and functional changes in W/W V mice were associated with a marked increase in the percentage of CSCs and myocytes expressing the senescence-associated marker p16 INK4a . At two months of age, wild-type mice and W/W V mice had the same number of LV myocytes which were essentially identical in volume. However, in comparison with wild-type mice, W/W V mice at 4 months of age had a decreased number of LV myocytes which were larger in volume. The magnitude of myocyte proliferation at the time of sacrifice was assessed by two markers of the cell cycle, Ki67 and MCM5. On average, cycling myocytes were 3-4-fold higher in wild type mice than in W/W V mice. In contrast, apoptotic myocytes, evaluated by the TdT assay and hairpin 1 in situ ligation, were significantly more frequent in W/W V mice than in WT mice. In conclusion, mutation of the c-kit receptor in CSCs impairs new myocyte formation and promotes accumulation of senescent myocytes.

Sensitivity Analysis of Left Ventricle with Dilated Cardiomyopathy in Fluid Structure Simulation

Dilated cardiomyopathy (DCM) is the most common myocardial disease. It not only leads to systolic dysfunction but also diastolic deficiency. We sought to investigate the effect of idiopathic and ischemic DCM on the intraventricular fluid dynamics and myocardial wall mechanics using a 2D axisymmetrical fluid structure interaction model. In addition, we also studied the individual effect of parameters related to DCM, i.e. peak E-wave velocity, end systolic volume, wall compliance and sphericity index on several important fluid dynamics and myocardial wall mechanics variables during ventricular filling. Intraventricular fluid dynamics and myocardial wall deformation are significantly impaired under DCM conditions, being demonstrated by low vortex intensity, low flow propagation velocity, low intraventricular pressure difference (IVPD) and strain rates, and high-end diastolic pressure and wall stress. Our sensitivity analysis results showed that flow propagation velocity substantially decreases with an increase in wall stiffness, and is relatively independent of preload at low-peak E-wave velocity. Early IVPD is mainly affected by the rate of change of the early filling velocity and end systolic volume which changes the ventriculo:annular ratio. Regional strain rate, on the other hand, is significantly correlated with regional stiffness, and therefore forms a useful indicator for myocardial regional ischemia. The sensitivity analysis results enhance our understanding of the mechanisms leading to clinically observable changes in patients with DCM.

Crucial Role for Ca 2+ /Calmodulin-Dependent Protein Kinase-II in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation

Myocardial diastolic stiffness and cardiomyocyte passive force (F(passive)) depend in part on titin isoform composition and phosphorylation. Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII) phosphorylates ion channels, Ca(2+)-handling proteins, and chromatin-modifying enzymes in the heart, but has not been known to target titin. To elucidate whether CaMKII phosphorylates titin and modulates F(passive) in normal and failing myocardium. Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) mouse, transgenic CaMKIIδC-overexpressing mouse, and human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphoserine-specific titin-antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using stable isotope labeling by amino acids in cell culture mouse heart mixed with wild-type (WT) or DKO heart. F(passive) of single permeabilized cardiomyocytes was recorded before and after CaMKII-administration. All-titin phosphorylation was reduced by >50% in DKO but increased by up to ≈100% in transgenic versus WT hearts. Conserved CaMKII-dependent phosphosites were identified within the PEVK-domain of titin by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence. Phosphorylation at specific PEVK/titin N2B-unique sequence sites was decreased in DKO and amplified in transgenic versus WT hearts. F(passive) was elevated in DKO and reduced in transgenic compared with WT cardiomyocytes. CaMKII-administration lowered F(passive) of WT and DKO cardiomyocytes, an effect blunted by titin antibody pretreatment. Human end-stage failing hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/titin N2B-unique sequence sites than nonfailing donor hearts. CaMKII phosphorylates the titin springs at conserved serines/threonines, thereby lowering F(passive). Deranged CaMKII-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.

Crucial Role for Ca2+/Calmodulin-Dependent Protein Kinase-II Delta in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation

Rationale: Myocardial diastolic stiffness and cardiomyocyte passive force (Fpassive) depend in part on titin isoform composition and phosphorylation. Ca2+/calmodulin-dependent protein kinase-IIδ (CaMKIIδ) phosphorylates ion channels, Ca2+-handling and myofilament proteins in the heart, but has not been known to target titin.Objective: To elucidate whether CaMKIIδ phosphorylates titin and regulates Fpassive in normal and failing myocardium.Methods and Results: Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) and transgenic CaMKIIδC-overexpressing (TG) mouse hearts, as well as human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphospecific titin antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using SILAC mouse heart tissue mixed with wildtype (WT) or DKO heart. Fpassive of single permeabilized cardiomyocytes was recorded before and after CaMKII administration. We detected hypophosphorylation of all-titin in DKO and hyperphosphorylation in TG compared to WT hearts. Conserved CaMKII-dependent phosphosites were identified within titin's PEVK-domain by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence (N2Bus). Phosphorylation at specific PEVK/N2Bus sites was decreased in DKO and amplified in TG versus WT hearts. Fpassive was elevated in DKO and reduced in TG compared to WT cardiomyocytes. CaMKII-administration lowered Fpassive of WT and DKO cardiomyocytes, an effect blunted by titin-phosphoantibody pretreatment. Human failing hypertrophic hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/N2Bus sites than nonfailing donor hearts.Conclusions: CaMKIIδ phosphorylates the titin springs at conserved serines/threonines, thereby lowering Fpassive. Deranged CaMKIIδ-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.

Microfluidic heart on a chip for higher throughput pharmacological studies

We present the design of a higher throughput "heart on a chip" which utilizes a semi-automated fabrication technique to process sub millimeter sized thin film cantilevers of soft elastomers. Anisotropic cardiac microtissues which recapitulate the laminar architecture of the heart ventricle are engineered on these cantilevers. Deflection of these cantilevers, termed Muscular Thin Films (MTFs), during muscle contraction allows calculation of diastolic and systolic stresses generated by the engineered tissues. We also present the design of a reusable one channel fluidic microdevice completely built out of autoclavable materials which incorporates various features required for an optical cardiac contractility assay: metallic base which fits on a heating element for temperature control, transparent top for recording cantilever deformation and embedded electrodes for electrical field stimulation of the tissue. We employ the microdevice to test the positive inotropic effect of isoproterenol on cardiac contractility at dosages ranging from 1 nM to 100 μM. The higher throughput fluidic heart on a chip has applications in testing of cardiac tissues built from rare or expensive cell sources and for integration with other organ mimics. These advances will help alleviate translational barriers for commercial adoption of these technologies by improving the throughput and reproducibility of readout, standardization of the platform and scalability of manufacture.

The influence of thrombolytic therapy on clinical and instrumental parameters of left ventricular remodeling in the late post-infarction period of myocardial infarction with Q-wave

Aim. To evaluate clinical and instrumental parameters of late left ventricular remodeling in patients with myocardial infarction with Q-wave depending on use of thrombolysis. Methods. 87 patients with myocardial infarction with Q-wave on electrocardiography (ECG) were included. First group consisted of 34 patients in whom thrombolytic therapy was performed, second group consisted of 53 patients in whom thrombolysis was not used due to late referral (over 12 hours from initial symptom onset, 88,7%), concomitant hemorrhagic stroke (3,8%), previously reported uncontrolled arterial hypertension (7,6%). All patients were followed up at 3-4 weeks, 60 and 120 months after the onset of myocardial infarction, examination included ECG, echocardiography, clinical examination. Results. In patients of both groups increase of total R-wave amplitude on repetitive ECGs was associated with relative left ventricle wall thickening, increase of left ventricular mass index, decrease of systolic and diastolic wall stresses caused by compensatory hypertrophy of intact cardiomyocytes according to results of correlation analysis. Increase of total amplitude of QS-waves on repetitive ECGs was associated with left ventricular cavity dilatation and spherification with wall thickening, increase of systolic and diastolic wall stresses. Patients in whom thrombolysis was not used had significantly higher rates of angina at post-infarction period. No statistically significant differences of ECG and echocardiography parameters between two groups of patients were found during the whole follow-up period. Non-significant increase of total R-wave amplitude and QS-waves amplitude was registered in patients in whom thrombolysis was started not later than 90 minutes from initial symptom onset compared to patients in whom thrombolysis was started later. Conclusion. Comparison of ECG and echocardiography parameters over time did not reveal any statistically significant differences between the groups with and without thrombolysis.

The effects of asymmetric ventricular filling on left–right ventricular interaction in the normal rat heart

Heart failure is characterised by ventricular dysfunction and with the potential for changes to ventricular volumes constraining the mechanical performance of the heart. The contribution of this interaction from geometric changes rather than fibrosis or metabolic changes is unclear. Using the constant pressure Langendorff-perfused rat heart, the volume interaction between left ventricle (LV) and right ventricle (RV) was investigated. RV diastolic stiffness (P < 0.001) and developed pressure (P < 0.001) were significantly lower than LV. When the RV was fixed at the end-diastolic volume (EDV) or EDV + 50%, both LV systolic and diastolic performance were unaffected with increasing LV balloon volume. However, at fixed LV volume, RV systolic performance was significantly decreased when LV volume increased to EDV + 50% when RV volume was increased incrementally between 50 and 300μl (P < 0.001). Systolic interaction in RV was noted as declining RV peak systolic load with increasing LV systolic pressure (P < 0.05) and diastolic interaction was noted for RV when LV volume was increased from EDV to EDV + 50% (P < 0.05). RV diastolic wall stress was increased with increasing LV balloon volume (P < 0.05), but LV wall stress was unaltered at fixed RV balloon volume. Taken together, increasing LV volume above EDV decreased systolic performance and triggered ventricular constraint in the RV but the RV itself had no effect on the performance of the LV. These results are consistent with overload of the LV impairing pulmonary perfusion by direct ventricular interaction with potential alteration to ventilation-perfusion characteristics within the lung.

Quantitation of the diastolic stress test: filling pressure vs. diastolic reserve

The diastolic stress test (DST) may facilitate the attribution of exertional dyspnoea to cardiac and non-cardiac diseases. However, there is currently no consensus as to the optimal marker of exertional diastolic dysfunction (DD)-the main alternatives being estimated left ventricular (LV) filling pressure (exercise E/e') and diastolic functional reserve (DFRI). We sought to compare the correlates of these parameters. DST was performed by adding the measurement of the transmitral (E) and annular (e') velocities to standard exercise echo in 559 consecutive patients without significant rest or exercise mitral regurgitation. Exertional DD was separately defined by post-stress E/e' >13 or DFRI <13.5. Logistic regression was used to identify the correlates of abnormal responses and linear regression was used to identify the contribution of both to exercise capacity. Abnormal exercise E/e' (n = 112, 20%) and DFRI (n = 317, 57%) were modestly associated (κ 0.35, P < 0.0001). In a linear regression, abnormal exercise E/e' (β = -0.19, P < 0.001) and DFRI (β = -0.15, P = 0.001) were associated with exercise capacity, independent of age, body mass index, wall thickness, haemodynamics or abnormal stress results. Logistic regression revealed abnormal exercise E/e' (R(2)= 0.34) to be independently associated with female gender (β = 0.26, 95% CI: 0.11-0.60, P = 0.002), age (β = 1.04, 95% CI: 1.01-1.07, P = 0.01), hypertension (β = 0.35, 95% CI: 0.15-0.80, P = 0.01) and wall thickness (β = 4.3, 95% CI: 1.3-14.1, P = 0.02). The closest association of abnormal DFRI was exercise capacity (β = 0.89, 95% CI: 0.79-1.02, P = 0.09); no other clinical or stress variable was independently associated. Exercise E/e' and DFRI are both associated with exercise capacity, but E/e' is more closely associated with the expected parameters of DD.

Changes in the content of some cytokines during chronic heart failure

Aim. To determine the changes in the content of cytokines, systolic intraventricular and interventricular dyssynchrony in patients with chronic heart failure. Methods. The study included 223 patients (174 males, 49 females) who suffered a Q wave myocardial infarction of the left ventricle, with clinical manifestations of chronic heart failure with functional class III according to the classification of the New York Heart Association. Pro- and anti-inflammatory cytokines (tumor necrosis factor alpha, interleukin-6, -4, and -10, interferon-gamma) were studied in blood plasma by enzyme immunoassay. Dyssynchrony was studied by pulsed-wave Doppler investigation, M-mode measurements of the left ventricle and pulsed-wave mode of tissue Doppler investigation of the myocardium. Results. Noted was an elevation of levels of tumor necrosis factor alpha, interleukin-6, interferon gamma, in combination with a reduction in the content of interleukin-4 and -10 in all groups. The maximum increase in the content of tumor necrosis factor alpha and interleukin-6 was found in the group of eccentric hypertrophy and dilatation of the left ventricle. Positive correleation links of medium strength have been established between the levels of interleukin-6 and the degree of interventricular mechanical delay, and between systolic and diastolic myocardial stress. In the group with eccentric hypertrophy and dilation of the left ventricle the content of tumor necrosis factor alpha directly correlated with the time interval from the beginning of the Q wave on the electrocardiogram to the beginning of the oflow in the left ventricular outflow tract, as well as with the concentration of N-terminal fragment of the precursor of the human brain natriuretic peptide. During remodeling according to the type of eccentric hypertrophy without dilatation of the left ventricle observed were positive correlation links of medium strength between the content of the tumor necrosis factor alpha and the intraventricular mechanical delay, end-diastolic pressure in the left ventricle. In the group of concentric hypertrophy the content of the tumor necrosis factor alpha and interleukin-6 is positively associated with electrocardiographic interval from the Q wave to the beginning of the systolic Doppler artifact S. Conclusion. One of the factors, which contributes to the preservation of abnormal levels of tumor necrosis factor alpha and interleukin-6 in blood plasma is the intraventricular and interventricular dyssynchrony; the combination of dilatation, myocardial hypertrophy, systolic and diastolic left ventricular dysfunction, dyssynchrony and the toxic effects of proinflammatory cytokines on the myocardium contributes to progression of chronic heart failure.

Diastolic Stress Test for the Evaluation of Exertional Dyspnea

Recent studies have highlighted that dyspneic patients comprise a high-risk subgroup of patients referred for cardiac stress testing. Even after adjusting for the presence and degree of coronary artery disease the risk of cardiac and all-cause mortality is at least three- to fivefold higher in dyspneic patients compared to asymptomatic or those with chest pain. Stress echocardiography is uniquely positioned to characterize all potential cardiovascular etiologies of dyspnea from global and regional systolic dysfunction, myocardial ischemia to valvular heart disease, pulmonary hypertension and diastolic dysfunction. Various data point to diastolic dysfunction and associated heart failure as the major potential etiology for dyspnea as well as the likely cause of the heightened mortality risk. Doppler echocardiography at rest and with stress can now characterize the hemodynamics of diastolic dysfunction and close the loop on the comprehensive assessment of the patient who has exertional shortness of breath. This review discusses the role of the Doppler echocardiographic diastolic stress test in the evaluation of patients with cardiac dyspnea.

Diastolic ventricular support with cardiac support devices: an alternative approach to prevent adverse ventricular remodeling

Heart failure is a global epidemic with limited therapy. Abnormal left ventricular wall stress in the diseased myocardium results in a biochemical positive feedback loop that results in global ventricular remodeling and further deterioration of myocardial function. Mechanical myocardial restraints such as the Acorn CorCap and Paracor HeartNet ventricular restraints have attempted to minimize diastolic ventricular wall stress and limit adverse ventricular remodeling. Unfortunately, these therapies have not yielded viable clinical therapies for heart failure. Cellular and novel biopolymer-based therapies aimed at stabilizing pathologic myocardium hold promise for translation to clinical therapy in the future.

Altered trans-mitral flow velocity pattern after exercise predicts development of new-onset atrial fibrillation in elderly patients with impaired left ventricular relaxation at rest: Prognostic value of diastolic stress echocardiography

This study attempted to determine whether exercise induced left ventricular (LV) diastolic dysfunction estimated by altered trans-mitral flow (TMF) velocity pattern after exercise is associated with increased risk of cardiac events including new-onset atrial fibrillation (AF) in elderly patients with impaired LV relaxation at rest. Diastolic stress echocardiography has been applied to evaluate LV diastolic function during and post-exercise. Prognostic importance of exercise-induced diastolic dysfunction remains uncertain. We studied 126 patients (70±5 years; 70 males) who underwent treadmill stress echocardiography. Doppler measurements were done before exercise and immediately after the post-stress image acquisition, and the ratio between early (E) and atrial (A) TMF velocities was measured. Patients with impaired LV relaxation (E/A<1.0) at rest were studied. Altered TMF velocity pattern was present when patients with E/A<1.0 at rest developed E/A≥1.0 after exercise. Primary endpoints for follow-up were combination of major cardiac events and new-onset AF. There were 42 patients with altered TMF velocity pattern after exercise. During the 5-year follow-up period, there were 30 cardiac events including 13 new-onset AF. Kaplan-Meier survival plot demonstrated that altered TMF velocity pattern after exercise is associated with increased risk of cardiac events (p<0.0001) including development of new-onset AF (p=0.0003). Cox hazard ratio analysis demonstrated that altered TMF velocity pattern after exercise was the best predictor of cardiac events (hazard ratio 3.939; 95%confidence interval 1.662-9.337; p=0.0018). Altered TMF velocity pattern after exercise provides significant prognostic information for predicting cardiac events including new-onset AF in elderly patients with impaired left ventricular relaxation at rest.

Left ventricular remodelling and the athlete's heart: time to revisit the Morganroth hypothesis

A widely held belief in sport cardiology is that the pattern of left ventricular (LV) remodelling associated with athletic training depends on the type of physical conditioning performed. This is based on the 1975 echocardiographic study by Morganroth et al. who found that male collegiate endurance trained (runners and swimmers) athletes had increased LV diastolic cavity size and mass with a normal wall thickness (eccentric hypertrophy) compared to age- and sex-matched non-athletic control subjects (Morganroth et al. 1975). In contrast, resistance trained athletes (wrestlers and shot putters) had increased LV wall thickness and mass with normal diastolic cavity size (concentric hypertrophy) compared to controls (Morganroth et al. 1975). The stimulus for physiological eccentric hypertrophy was attributed to the large LV volume loads (diastolic wall stress) present during endurance exercise while the stimulus for concentric hypertrophy was the result of intermittent increases in arterial pressure loading (systolic wall stress) associated with performing a Valsalva manoeuvre during lifting (Morganroth et al. 1975; Morganroth & Maron, 1977). Although evidence supports the acceptance of the ‘Morganroth hypothesis’ for endurance training, uncertainty remains if LV remodelling is an obligatory adaptation with resistance training (Haykowsky et al. 2002; Naylor et al. 2008). In a recent issue of The Journal of Physiology, Spence et al. (2011) report new data that challenge, at least for resistance training, the Morganroth hypothesis. The authors examined the effects of 6 months of endurance training (3 hours per week of walking/jogging/running, n = 10) or resistance training (3 hours per week of Olympic weightlifting and supplemental strength exercises, n = 13) followed by 6 weeks of detraining on LV morphology and function, aerobic fitness, muscle strength and body composition in younger males (mean age: 27 years). Cardiac magnetic resonance imaging (MRI) and speckle tracing echocardiography were used to assess LV morphology and function. The paper provides novel information because it is the first to directly compare the two forms of exercise using MRI, which is a much more accurate assessment of cardiac morphology than previously utilized methods (Bellenger, et al. 2000) and because it adopted a within subjects longitudinal approach, which is less affected by the limitations of scaling than previous athletic comparisons. Spence et al. reported that total maximal strength and lean mass were significantly higher after resistance training and detraining compared to baseline with no change in LV morphology and function, or aerobic fitness. In contrast, cardiac MRI derived LV mass and aerobic fitness increased significantly after endurance training and returned towards baseline after detraining. Endurance training also significantly increased LV septal wall thickness and end-diastolic volume (P = 0.05) while posterior wall thickness decreased significantly after detraining. Finally, total lean mass and strength were higher after endurance training with the former returning to baseline after detraining. The LV remodelling pattern observed by Spence et al. after 6 months of endurance training is consistent with that expected based on the Morganroth hypothesis. However, their finding that resistance training did not significantly change LV posterior or interventricular septal wall thickness or mass contradicts the expected effect for this type of exercise based on Morganroth's hypothesis. A reason for this finding is that resistance training may not acutely increase in LV systolic wall stress. Indeed, our research group previously reported that (sub)maximal leg-press exercise performed with a 2–3 s Valsalva manoeuvre was not associated with an alteration in LV end-systolic wall stress in younger healthy males (mean age: 27 years) (Haykowsky et al. 2001). This observation combined with the new cardiac MRI findings by Spence et al. suggests that the four-decade old Morganroth hypothesis with respect to resistance training mediated-LV remodelling needs revisiting.

Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways

The heart responds to sustained overload by hypertrophic growth in which the myocytes distinctly thicken or elongate on increases in systolic or diastolic stress. Though potentially adaptive, hypertrophy itself may predispose to cardiac dysfunction in pathological settings. The mechanisms underlying the diverse morphology and outcomes of hypertrophy are uncertain. Here we used a focal adhesion kinase (FAK) cardiac-specific transgenic mice model (FAK-Tg) to explore the function of this non-receptor tyrosine kinase on the regulation of myocyte growth. FAK-Tg mice displayed a phenocopy of concentric cardiac hypertrophy, reflecting the relative thickening of the individual myocytes. Moreover, FAK-Tg mice showed structural, functional and molecular features of a compensated hypertrophic growth, and preserved responses to chronic pressure overload. Mechanistically, FAK overexpression resulted in enhanced myocardial FAK activity, which was proven by treatment with a selective FAK inhibitor to be required for the cardiac hypertrophy in this model. Our results indicate that upregulation of FAK does not affect the activity of Src/ERK1/2 pathway, but stimulated signaling by a cascade that encompasses PI3K, AKT, mTOR, S6K and rpS6. Moreover, inhibition of the mTOR complex by rapamycin extinguished the cardiac hypertrophy of the transgenic FAK mice. These findings uncover a unique role for FAK in regulating the signaling mechanisms that governs the selective myocyte growth in width, likely controlling the activity of PI3K/AKT/mTOR pathway, and suggest that FAK activation could be important for the adaptive response to increases in cardiac afterload. This article is part of a Special Issue entitled “Local Signaling in Myocytes”.

Diastolic Carotid Artery Wall Shear Stress Is Associated With Cerebral Infarcts and Periventricular White Matter Lesions

Low wall shear stress (WSS) is an early marker in the development of vascular lesions. The present study aims to assess the relationship between diastolic and systolic WSS in the internal carotid artery and periventricular (PWML), deep white matter lesions, and cerebral infarcts (CI). Early, mid, and late diastolic and peak systolic WSS were derived from shear rate obtained by gradient echo phase contrast magnetic resonance sequences multiplied by individually modeled viscosity. PWML, deep white matter lesions, and CI were derived from proton density (PD), T2, and fluid attenuated inversion recovery (FLAIR) MRI in 329 participants (70-82 years; PROSPER baseline). Analyses were adjusted, if appropriate, for age, gender, intracranial volume, and multiple cardiovascular risk factors. Mid-diastolic WSS was significantly correlated with the presence of PWML (B=-10.15; P=0.006) and CI (B=-2.06; P=0.044), but not with deep white matter lesions (B=-1.30; P=0.050; adjusted for age, gender, WML, and intracranial volume). After adjustment for cardiovascular risk factors, these correlations weakened but remained significant. Systolic WSS was not correlated with any of the cerebrovascular parameters. This study is the first to our knowledge to present a cross-sectional correlation between carotid artery WSS and cerebrovascular pathology such as PWML and CI in a large population. Furthermore, it shows that diastolic hemodynamics may be more important than systolic or mean hemodynamics. Future studies exploring vascular hemodynamic damage should focus on diastolic WSS.

Clinical outcomes of exercise-induced pulmonary hypertension in subjects with preserved left ventricular ejection fraction: implication of an increase in left ventricular filling pressure during exercise

ObjectiveTo investigate clinical outcomes of exercise-induced pulmonary hypertension (PH) and implications of an increase in left ventricular (LV) filling pressure during exercise in subjects with preserved LV ejection fraction.DesignLongitudinal follow-up...

Impaired flow-mediated dilatation response in uncomplicated Type 1 diabetes mellitus: influence of shear stress and microvascular reactivity

Impaired FMD (flow-mediated dilatation) has traditionally been recognized as an indirect marker of NO bioactivity, occurring in disease states such as DM (diabetes mellitus). Endothelium-dependent FMD is a homoeostatic response to short-term increases in local shear stress. Microvascular dysfunction in DM influences blood flow velocity patterns. We explored the determinants of the FMD response in relation to evoked DSS (diastolic shear stress) and forearm microcirculation haemodynamics by quantifying changes in Doppler flow velocity waveforms between groups. Forty patients with uncomplicated Type1 DM and 32 controls underwent B-mode and Doppler ultrasound scanning to interrogate the brachial artery. Postischaemic Doppler velocity spectral envelopes were recorded and a wavelet-based time-frequency spectral analysis method was employed to track change in distal microcirculatory haemodynamics. No difference in baseline brachial artery diameter was evident between the groups (4.15 compared with 3.94 mm, P=0.23). FMD was significantly impaired in patients with Type1 DM (3.95 compared with 7.75%, P<0.001). Endothelium-independent dilatation in response to GTN (glyceryl trinitrate) was also significantly impaired (12.07 compared with 18.77%, P<0.001). DSS (dyn/cm2) was significantly reduced in the patient group (mean 20.19 compared with 29.5, P=0.001). Wavelet interrogation of postischaemic flow velocity waveforms identified significant differences between groups. In conclusion, DSS, microcirculatory function and endothelium-independent vasodilatation in response to GTN are important determinants that impact on the magnitude of FMD response and are impaired in patients with Type1 DM. Impaired FMD response is multifactorial in origin and cannot be attributed solely to a diminished NO bioavailability.