MRI Assessment of Diastolic and Systolic Intraventricular Pressure Gradients in Heart Failure.

A deep phenotypic characterization of heart failure (HF) is important for a better understanding of its pathophysiology. In particular, novel noninvasive techniques for the characterization of functional abnormalities in HF with preserved ejection fraction are currently needed. While echocardiography is widely used to assess ventricular function, standard echocardiographic techniques provide a limited understanding of ventricular filling. The application of fluid dynamics theory, along with assessments of flow velocity fields in multiple dimensions in the ventricle, can be used to assess intraventricular pressure gradients (IVPGs), which in turn may provide valuable insights into ventricular diastolic and systolic function. Advances in imaging techniques now allow for accurate estimations of systolic and diastolic IVPGs, using noninvasive methods that are easily applicable in clinical research. In this review, we describe the basic concepts regarding intraventricular flow measurements and the derivation of IVPGs. We also review existing literature exploring the role of IVPGs in HF.

Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction.

Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant ß, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF.

No shorter telomeres in subjects with a family history of cardiovascular disease in the Asklepios study.

OBJECTIVE: Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population-representative Asklepios Study. METHODS AND RESULTS: Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (≈ 35-55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without. CONCLUSIONS: These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD.

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease.

In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP(iso)) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP(iso) (r = -0.96), and directly related to changes in the time constant of relaxation τ (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP(iso) (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterload-induced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P < 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.

Time-varying myocardial stress and systolic pressure-stress relationship: role in myocardial-arterial coupling in hypertension.

BACKGROUND: Myocardial afterload depends on left ventricular (LV) cavity size, pressure, and wall thickness, all of which change markedly throughout ejection. We assessed the relationship between instantaneous ejection-phase pressure and myocardial stress and the effect of arterial wave reflections on myocardial stress in hypertensive and normotensive adults. METHODS AND RESULTS: We studied 42 untreated hypertensive, 42 treated hypertensive, and 42 normotensive adults with normal LV ejection fraction. Time-resolved central pressure, flow, and LV geometry were measured with carotid tonometry, Doppler, and speckle-tracking echocardiography for computation of arterial load and time-varying circumferential and longitudinal myocardial stress. In all 3 groups, peak myocardial stress typically occurred in early systole (within the first 100 milliseconds of ejection), followed by a marked midsystolic shift in the pressure-stress relationship, which favored lower late systolic stress values (P<0.001) relative to pressure. The mean magnitude of this midsystolic shift was quantitatively important in all 3 groups (circumferential stress, 144 to 148 kdynes/cm(2)) and was independently predicted by a higher LV ejection fraction and ratio of LV end-diastolic cavity to wall volume. Time of peak myocardial stress independently correlated with time of the first systolic but not with time of the second systolic central pressure peak. CONCLUSIONS: Peak myocardial stress occurs in early systole, before important contributions of reflected waves to central pressure. In the presence of normal LV ejection fraction, a midsystolic shift in the pressure-stress relationship protects cardiomyocytes against excessive late systolic stress (despite pressure augmentation associated with wave reflections), a coupling mechanism that may be altered in various disease states.

Systemic telomere length and preclinical atherosclerosis: the Asklepios Study.

AIMS: Peripheral blood leucocyte (PBL) telomere length (TL) is a systemic ageing biomarker and has been proposed to be an independent predictor of cardiovascular disease (CVD). We aimed at providing an explanation for this association by the evaluation of the biomarker value of PBL-TL in preclinical atherosclerosis. METHODS AND RESULTS: Peripheral blood leucocyte telomere length was assessed by telomere restriction fragment analysis in 2509 volunteers free from established CVD, aged approximately 35-55 years old, from the Asklepios Study cohort. Intima-media thickness (IMT) and plaque presence were determined by ultrasonography in both left and right carotid and femoral arteries. Peripheral blood leucocyte telomere length was not a significant independent determinant of IMT (P > 0.3) or plaque presence (P > 0.05), in either artery or either sex. In women but not in men, PBL-TL was a weak determinant of combined (carotid or femoral) plaque presence, adjusted for other risk factors (women: P = 0.03, men: P > 0.4). However, even in women presenting plaques, PBL-TL was still longer than in men. CONCLUSION: Since systemic TL is not a substantial underlying determinant of preclinical atherosclerosis, the association between CVD and TL cannot be explained by the fact that subjects with shorter inherited TL are predisposed to atherosclerosis.

Allometric versus ratiometric normalization of left ventricular stroke volume by Doppler-echocardiography for outcome prediction in severe aortic stenosis with preserved ejection fraction.

BACKGROUND: Appropriate normalization methods to scale Doppler-derived stroke volume (SV) to body size in patients with aortic stenosis (AS) are poorly defined and reference values are lacking. We aim to establish reference values of normalized SV in adults, and to compare the prognostic value of SV normalized by different methods in AS patients. METHODS: In 2781 normotensive, non-obese adults without cardiovascular disease we defined normal relationships between SV and body size by nonlinear regression. Reference SV values were calculated by quantile regression. We subsequently analyzed by Cox analysis the prognostic performance of ratiometric and allometric normalized SV in 1450 patients with severe AS and preserved LVEF under medical and surgical management. RESULTS: Unlike ratiometric normalization, allometric indexation eliminated the residual relationships between normalized SV and body size. The allometric exponents that adequately described the SV-height (H) and SV-body surface area (BSA) relationships were 1.32, and respectively 0.88. In males, low-flow (LF) reference values were: <28 ml/m2, <30 ml/m, <30ml/(m2)0.88, and, respectively, <26 ml/m1.32, and in females <27 ml/m2, <28 ml/m, <29ml/(m2)0.88, and, respectively, <24 ml/m1.32. In patients with severe AS, SV/H1.32 was most consistently associated with mortality and showed better prognostic performance than other normalized SV parameters (adjusted hazard ratios: 1.86 for SV/H1.32, 1.72 for SV/H, 1.64 for SV/BSA, and 1.61 for SV/BSA0.88). Compared to H-normalization, BSA-normalization markedly overestimated the frequency of LF (3% vs. 9%). CONCLUSIONS: We provide normative reference values and appropriate normalization methods for SV by Doppler-echocardiography. In severe AS, SV/H1.32 seems the most appropriate indexation method, especially in obese individuals.

Feasibility and agreement of a novel combined echocardiographic method to measure global longitudinal strain and strain rate compared to speckle tracking and tissue Doppler imaging.

Background: Currently, two echocardiographic techniques are used to measure deformation: tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). Recently, a technique combining STE and TDI (on TDI overlay images) has become available, allowing derivation of STE/TDI results from a single acquisition/reading (combined-STE/combined-TDI). We tested the feasibility and agreement of this novel technique to measure left ventricular deformation in the general population compared to STE and TDI.Methods: We examined a subsample of 106 consecutive subjects of the Asklepios Study, a population-based random sample of male/female volunteers without overt clinical disease (mean age: 55.9 years). Left ventricular deformation measurements were assessed with transthoracic echocardiography using the combined method, STE and TDI.Results: Almost all deformation parameters significantly differed between all methods. Global systolic longitudinal strain (GS) and strain rate (GSRs) values measured by combined-TDI were significantly higher (GS -17.2% ± 3.0, GSRs -0.9 s-1 ± 0.2) compared to TDI (GS -21.1% ± 2.2, GSRs -1.3 s-1 ± 0.2). Measurements by combined-STE were significantly lower (GS -19.1% ± 2.9, GSRs -1.0 s-1 ± 0.2) compared to STE (GS -18.2% ± 3.0, GSRs -0.9 s-1 ± 0.1). Overall, the smallest differences and highest agreement were observed between STE and combined-STE (GS r = 0.84, p < .001; GSRs r = 0.70, p < .001).Conclusions: The comparison of methods showed different values and poor agreement between the echocardiographic modalities. Regrettably, the combined method does not make it possible to obtain in a single image/measurement results that are comparable to STE and TDI data in the general population.

Muscle strength is a major determinant of the blood pressure response to isometric stress testing: the Asklepios population study.

AIM: Maximal handgrip strength is a strong predictor of cardiovascular mortality in economically and socioculturally diverse countries, yet the main determinants of cardiovascular response to change in afterload during handgrip are not well known. We examined the blood pressure (BP) responses during submaximal handgrip (at 25% of grip strength) and the determinants of grip strength. METHODS: We studied 2215 participants from a population-based random sample without overt clinical disease (Asklepios Study; mean age 56.2 years). Handgrip testing was performed using a modified Jamar dynamometer with direct visual feedback. Simultaneously, a validated finger plethysmographic device measured continuous BP and heart rate. RESULTS: During handgrip, SBP and DBP rose by, respectively, 20 ±â€Š13 and 10 ±â€Š6 mmHg. These changes were normally distributed and consistently higher in men. The main independent determinants of mean arterial pressure response during handgrip were: grip strength (F = 191.4; P < 0.001), baseline pulse pressure (F = 32.0; P < 0.001), height (F = 16.4; P < 0.001) and age (F = 12.8; P < 0.001). Grip strength was associated with muscle mass, better metabolic health, but also with higher baseline DBP. There was a significant graded increase in maximum pressure achieved and in the magnitude of pressure change during handgrip with increasing BP categories (P for trend <0.001). CONCLUSION: The population BP response to handgrip is variable and its predominant determinant turned out to be grip strength itself, which should be accounted for in future analyses. Higher baseline BP, even within the normotensive range, acted as an independent and graded predictor of BP increase during handgrip.

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension.

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

Femoral plaques confound the association of circulating oxidized low-density lipoprotein with carotid atherosclerosis in a general population aged 35 to 55 years: the Asklepios Study.

OBJECTIVE: Reported associations of oxidized low-density lipoprotein (oxLDL) with noninvasive measures of atherosclerosis are inconsistent. In the Asklepios Study cohort of asymptomatic subjects aged 35 to 55 years, we evaluated the relationship of circulating oxLDL with subclinical atherosclerosis in the carotid and femoral arteries. METHODS AND RESULTS: Participants (n=2524, 51.5% females) completed a study questionnaire and underwent a clinical examination, blood analysis of oxLDL (mAb-4E6) and other risk markers, and ultrasound examination of intima-media thickness (IMT) and plaques in the left and right carotid and femoral arteries. oxLDL concentrations were highest in subjects with femoral plaques (n=658). In the group of subjects with carotid plaques (n=476), elevated oxLDL concentrations are related to concomitant femoral plaques detected in 54% of these subjects. Multivariate regression analyses (including anthropometric, hemodynamic, biochemical, and lifestyle variables) showed that femoral plaques are independently related to oxLDL whereas femoral IMT, carotid IMT, or carotid plaques were not independently associated with oxLDL. CONCLUSIONS: Circulating oxLDL is independently associated with femoral plaque and not with carotid artery wall damage.

Effect of Obesity on Left Atrial Strain in Persons Aged 35-55 Years (The Asklepios Study).

Obesity increases the risk of heart failure and atrial fibrillation. Left atrial (LA) dysfunction is increasingly recognized as a mediator of cardiovascular disease. Early effects of obesity on LA function have not been examined in large population samples. We quantified LA strain and strain rate (SR) through speckle tracking echocardiography in 1,531 middle-aged community-based participants enrolled in the Asklepios study. We compared LA function between individuals with body mass index (BMI) < 25 kg/m2 (n = 779), 25 to 29.9 kg/m2 (n = 618) and ≥ 30 kg/m2 (n = 134). Significant differences in reservoir longitudinal LA strain (BMI < 25 kg/m2 = 35.3%, BMI 25-29.9 kg/m2 = 33.1%, and BMI ≥ 30 kg/m2 = 30.9%; p < 0.00001) strain rate ([SR] BMI < 25 kg/m2 = 151; BMI 25 to 29.9 kg/m2 = 141; and BMI ≥ 30 kg/m2 = 135 %/s; p <0.00001) and expansion index (BMI < 25 kg/m2 = 1.6, BMI 25 to 29.9 kg/m2 = 1.4, and BMI ≥ 30 kg/m2 = 1.4; p <0.00001) were seen, indicating reduced reservoir function with increasing BMI. Obesity was also associated with impaired LA conduit function, including conduit longitudinal LA strain (BMI < 25 kg/m2 = 21.6%, BMI 25 to 29.9 kg/m2 = 18.9%, and BMI ≥ 30 kg/m2 = 16.7%; p <0.00001), SR (BMI < 25 kg/m2 = -189, BMI 25 to 29.9 kg/m2 = 166, and BMI ≥ 30 kg/m2 = 150 %/s; p <0.0001) and passive LA emptying fraction (BMI < 25 kg/m2 = 40.5, BMI 25 to 29.9 kg/m2 = 36.5, and BMI ≥ 30 kg/m2 = 36%, p <0.00001). These differences persisted after adjustment for age, gender and other potential confounders. In contrast to reservoir and conduit function, obesity was associated with increased booster pump function (active LA emptying fraction: BMI < 25 kg/m2 = 19.4%, BMI 25 to 29.9 kg/m2 = 20.5%, and BMI ≥ 30 kg/m2 = 21.5%; p <0.00001). In middle-aged adults, obesity is associated with impaired reservoir and conduit LA function and higher booster function, which may be compensatory. Loss of booster LA function, either because of more advanced LA dysfunction or atrial fibrillation, may play an important role in precipitating heart failure in obese individuals.

NMR-based characterization of metabolic alterations in hypertension using an adaptive, intelligent binning algorithm.

As with every -omics technology, metabolomics requires new methodologies for data processing. Due to the large spectral size, a standard approach in NMR-based metabolomics implies the division of spectra into equally sized bins, thereby simplifying subsequent data analysis. Yet, disadvantages are the loss of information and the occurrence of artifacts caused by peak shifts. Here, a new binning algorithm, Adaptive Intelligent Binning (AI-Binning), which largely circumvents these problems, is presented. AI-Binning recursively identifies bin edges in existing bins, requires only minimal user input, and avoids the use of arbitrary parameters or reference spectra. The performance of AI-Binning is demonstrated using serum spectra from 40 hypertensive and 40 matched normotensive subjects from the Asklepios study. Hypertension is a major cardiovascular risk factor characterized by a complex biochemistry and, in most cases, an unknown origin. The binning algorithm resulted in an improved classification of hypertensive status compared with that of standard binning and facilitated the identification of relevant metabolites. Moreover, since the occurrence of noise variables is largely avoided, AI-Binned spectra can be unit-variance scaled. This enables the detection of relevant, low-intensity metabolites. These results demonstrate the power of AI-Binning and suggest the involvement of alpha-1 acid glycoproteins and choline biochemistry in hypertension.

Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population.

BACKGROUND: The relationship between aortic (carotid-femoral) pulse wave velocity and stiffness measures based on local diameter and pressure readings is not yet fully understood. METHODS: We compared the relationship with age and gender of aortic pulse wave velocity to stiffness indices (compliance and distensibility coefficient) evaluated at the common carotid and femoral arteries in 2195 (1131 women) apparently healthy subjects, aged 35-55 years participating in the Asklepios study. Aortic pulse wave velocity was further compared with previously reported central arterial stiffness parameters on the same population. Subjects were divided into four age groups for analysis. RESULTS: Femoral arterial stiffness was higher in men than in women (P < 0.001) but did not change with age and no age-gender interaction was evident. Carotid arterial stiffness increased with age (P < 0.001) and showed a significant (P < 0.001) age-gender interaction, with carotid stiffness increasing more rapidly in women than in men, crossing over around the age of 45. Aortic pulse wave velocity did not differ between men and women, but did increase with age (P < 0.001). No age-gender interaction was evident. CONCLUSION: The relation with age and gender of local and central stiffness measures is not the same over the age range 35-55 in apparently healthy men and women. Depending on the central stiffness parameter used, age-gender effects evident at the carotid artery are or are not found centrally. Though the relevance of these differences requires further evaluation in a longitudinal study with outcome data, they need to be kept in mind when designing or interpreting results from arterial stiffness evaluation studies.

Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease.

Evidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.