Mario Kasner

Utility of Doppler Echocardiography and Tissue Doppler Imaging in the Estimation of Diastolic Function in Heart Failure With Normal Ejection Fraction A Comparative Doppler-Conductance Catheterization Study

Background— Various conventional and tissue Doppler echocardiographic indexes were compared with pressure–volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF). Methods and Results— Diastolic dysfunction was confirmed by pressure–volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (&tgr;, dP/dtmin), LV end-diastolic pressure, and LV end-diastolic pressure–volume relationship (stiffness, b [dP/dV], and stiffness constant, &bgr;) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, &tgr; (E/A: r=−0.36, P=0.013; isovolumic relaxation time: r=0.31, P=0.040) and b (deceleration time: r=0.39, P=0.012) but not with &bgr;, in contrast to the tissue Doppler imaging indexes E’/A’lateral (r=−0.37, P=0.008) and E/E’lateral (r=0.53, P<0.001). Diastolic dysfunction was detected in 70% of the HFNEF patients by mitral flow Doppler but in 81% and 86% by E’/A’lateral, and E/E’lateral, respectively. Conclusions— Of all echocardiographic parameters investigated, the LV filling index E/E’lateral was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.

Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction

Background— Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results— Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. Conclusions— Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.

Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction

Background—The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results—We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-&bgr;. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-&bgr;, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-&bgr; resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. Conclusions—Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.

High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction

Background—The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction. Methods and Results—In 70 patients (mean±SD age, 43±11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fraction=68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (P<0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive. Conclusions—PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.

Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure

Aims We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output. Methods and results In 17 patients with HFNEF (median age 69 years, 13 female) and seven age-matched control patients, systolic and diastolic function was analysed by pressure–volume loops at baseline heart rate and during atrial pacing to 100 and 120 min−1. At baseline, relaxation was prolonged and end-diastolic left ventricular stiffness was higher in HFNEF, whereas all parameters of systolic function were not different from control patients. This resulted in smaller end-diastolic volumes, higher end-diastolic pressure, and a lower stroke volume and cardiac index in HFNEF vs. control patients. During pacing, frequency-dependent upregulation of contractility indices (+dP/dtmax and Ees) occurred similarly in HFNEF and control patients, but frequency-dependent acceleration of relaxation (dP/dtmin) was blunted in HFNEF. In HFNEF, end-diastolic volume and stroke volume decreased with higher heart rates while both remained unchanged in control patients. Conclusion In HFNEF, frequency-dependent upregulation of cardiac output is blunted. This results from progressive volume unloading of the left ventricle due to limited relaxation reserve in combination with increased LV passive stiffness, despite preserved force–frequency relation.

Left ventricular dysfunction induced by nonsevere idiopathic pulmonary arterial hypertension: a pressure-volume relationship study.

RATIONALE Severe increase in right ventricular pressure can compromise left ventricular (LV) function because of impaired interventricular interaction and aggravate the symptoms. OBJECTIVES To elucidate how nonsevere idiopathic pulmonary arterial hypertension (IPAH) influences LV function because of impaired interventricular interaction. METHODS Invasive pressure-volume (PV) loop analysis obtained by conductance catheterization was performed at rest and during atrial pacing in patients with mild IPAH (n = 10) compared with patients with isolated LV diastolic dysfunction (DD) (n = 10) and control subjects without heart failure symptoms (n = 9). MEASUREMENTS AND MAIN RESULTS Patients with nonsevere IPAH (pulmonary artery pressure mean 29 ± 5 mm Hg) and patients with DD showed preserved systolic (ejection fraction 63 ± 12% and 62 ± 9%) and impaired LV diastolic function at rest (LV stiffness 0.027 ± 0.012 ml(-1) and 0.029 ± 0.014 ml(-1)). During pacing at 120 per minute patients with IPAH and DD decreased their stroke volume (-25% and -30%; P < 0.05) and failed to increase cardiac output significantly. Opposite to patients with DD and control subjects, temporary preload reduction during inferior vena cava occlusion initially induced an expansion of LV end-diastolic volume in IPAH (+7%; P < 0.05), whereas end-diastolic pressure continuously dropped. This resulted in an initial downward shift to the right of the PV loop indicating better LV filling, which was associated with a temporary improvement of cardiac output (+11%; P < 0.05) in the patients with IPAH, but not in patients with DD and control subjects. CONCLUSIONS Mild idiopathic pulmonary arterial pressure impairs LV diastolic compliance even in the absence of the intrinsic LV disease and contributes to the reduced cardiac performance at stress.

Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.

Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction

BACKGROUND Functional iron deficiency (FID) is an independent risk factor for poor outcome in advanced heart failure with reduced EF, but its role in heart failure with preserved EF (HFPEF) remains unclear. We aimed to investigate the impact of FID on cardiac performance determined by pressure-volume loop analysis in HFPEF. METHODS 26 HFPEF patients who showed an increase in LV stiffness by pressure-volume (PV) loop analysis obtained by conductance-catheterization, performed exercise testing, echocardiographic examination including tissue Doppler and determination of iron metabolism: serum iron, ferritin and transferrin saturation. HFPEF patients who provided ferritin <100 μg/l or ferritin of 100-299 μg/l in combination with transferrin saturation <20% were defined as having FID. In 14 patients the expression of transferrin receptor was determined from available endomyocardial biopsies. RESULTS Fifteen out of 26 HFPEF patients showed FID without anemia. Compared to control subjects and HFPEF patients without FID, HFPEF patients with FID showed an up-regulation of the myocardial transferrin receptor expression (p<0.05). No differences between HFPEF patients with and without iron deficiency were found in heart dimensions, systolic and diastolic function obtained by PV-loop and echocardiography analysis. According to the linear regression analysis, LV stiffness was correlated with peak oxygen uptake (r=-0.636, p<0.001) but not with the ferritin level or transferrin saturation. No relation was found between FID and exercise capacity. The association of LV stiffness with exercise performance was independent from the level of iron deficiency. CONCLUSION In non-anemic HFPEF patients, cardiac dysfunction and impaired exercise capacity occur independently of FID.

Increased Left Ventricular Stiffness Impairs Exercise Capacity in Patients with Heart Failure Symptoms Despite Normal Left Ventricular Ejection Fraction

Aims. Several mechanisms can be involved in the development of exercise intolerance in patients with heart failure despite normal left ventricular ejection fraction (HFNEF) and may include impairment of left ventricular (LV) stiffness. We therefore investigated the influence of LV stiffness, determined by pressure-volume loop analysis obtained by conductance catheterization, on exercise capacity in HFNEF. Methods and Results. 27 HFNEF patients who showed LV diastolic dysfunction in pressure-volume (PV) loop analysis performed symptom-limited cardiopulmonary exercise testing (CPET) and were compared with 12 patients who did not show diastolic dysfunction in PV loop analysis. HFNEF patients revealed a lower peak performance (P = .046), breathing reserve (P = .006), and ventilation equivalent for carbon dioxide production at rest (P = .002). LV stiffness correlated with peak oxygen uptake (r = −0.636, P < .001), peak oxygen uptake at ventilatory threshold (r = −0.500, P = .009), and ventilation equivalent for carbon dioxide production at ventilatory threshold (r = 0.529, P = .005). Conclusions. CPET parameters such as peak oxygen uptake, peak oxygen uptake at ventilatory threshold, and ventilation equivalent for carbon dioxide production at ventilatory threshold correlate with LV stiffness. Increased LV stiffness impairs exercise capacity in HFNEF.

New Echocardiographic Findings Correlate with Intramyocardial Inflammation in Endomyocardial Biopsies of Patients with Acute Myocarditis and Inflammatory Cardiomyopathy

Background. The diagnosis of acute myocarditis (AMC) and inflammatory cardiomyopathy (DCMi) can be difficult. Speckle tracking echocardiography with accurate assessments of regional contractility could have an outstanding importance for the diagnosis. Methods and Results. N = 25 patients with clinically diagnosed AMC who underwent endomyocardial biopsies (EMBs) were studied prospectively. Speckle tracking imaging was examined at the beginning and during a mean follow-up period of 6.2 months. In the acute phase patients had markedly decreased left ventricular (LV) systolic function (mean LV ejection fraction (LVEF) 40.4 ± 10.3%). At follow-up in n = 8 patients, inflammation persists, correlating with a significantly reduced fractional shortening (FS, 21.5 ± 6.0%) in contrast to those without inflammation in EMB (FS 32.1 ± 7.1%, P < 0.05). All AMC patients showed a reduction in global systolic longitudinal strain (LS, −8.36 ± −3.47%) and strain rate (LSR, 0.53 ± 0.29 1/s). At follow-up, LS and LRS were significantly lower in patients with inflammation, in contrast to patients without inflammation (−9.4 ± 1.4 versus −16.8 ± 2.0%, P < 0.0001; 0.78 ± 0.4 versus 1.3 ± 0.3 1/s). LSR and LS correlate significantly with lymphocytic infiltrates (for CD3 r = 0.7, P < 0.0001, and LFA-1 r = 0.8, P < 0.0001). Conclusion. Speckle tracking echocardiography is a useful adjunctive assisting tool for evaluation over the course of intramyocardial inflammation in patients with AMC and DCMi.