Understanding heart failure with preserved ejection fraction: where are we today?

Heart failure with preserved ejection fraction (HFpEF) represents a complex and heterogeneous clinical syndrome, which is increasingly prevalent and associated with poor outcome. In contrast to heart failure with reduced ejection fraction (HFrEF), modern heart failure pharmacotherapy did not improve outcome in HFpEF, which was attributed to incomplete understanding of HFpEF pathophysiology, patient heterogeneity and lack of insight into primary pathophysiological processes. HFpEF patients are frequently elderly females and patients demonstrate a high prevalence of non-cardiac comorbidities, which independently adversely affect myocardial structural and functional remodelling. Furthermore, although diastolic left ventricular dysfunction represents the dominant abnormality in HFpEF, numerous ancillary mechanisms are frequently present, which also negatively impact on cardiovascular reserve. Over the past decade, clinical and translational research has improved insight into HFpEF pathophysiology and the importance of comorbidities and patient heterogeneity. Recently, a new paradigm for HFpEF was proposed, which states that comorbidities drive myocardial dysfunction and remodelling in HFpEF through coronary microvascular inflammation. Regarding the conceptual framework of HFpEF treatment, emphasis may need to shift from a 'one fits all' strategy to an individualised approach based on phenotypic patient characterisation and diagnostic and pathophysiological stratification of myocardial disease processes. This review will describe these novel insights from a pathophysiological standpoint.

Vitamin D in relation to myocardial structure and function after eight years of follow-up: the Hoorn study.

BACKGROUND AND AIMS: To investigate associations between baseline serum 25-hydroxyvitamin D [25(OH)D] levels and myocardial structure and function after 8 years of follow-up in older Dutch subjects. METHODS: We included 256 subjects of the Hoorn Study, a population-based cohort. They underwent a standardized 2-dimensional echocardiogram at baseline between 2000 and 2001, and again between 2007 and 2009. We studied the association of 25(OH)D quartiles with echocardiographic measures of the left ventricular mass index (LVMI), left ventricular systolic function and markers of diastolic function using linear regression analyses. RESULTS: At baseline, subjects had a mean age of 67.4 ± 5.2 years and 41.4% had prior cardiovascular disease (CVD). Low serum 25(OH)D levels were only associated with higher LVMI at 8-year follow-up in subjects without prior CVD and in subjects with low kidney function (median estimated glomerular filtration rate ≤77.5 ml/min/1.73m(2)). The associations attenuated after adjustments for parathyroid hormone (PTH), which was associated with higher LVMI (g/m(2.7)) in subjects with low kidney function (regression coefficient highest quartile 6.3, 95% CI: 0.2, 12.5). CONCLUSION: This study showed no strong associations of 25(OH)D with myocardial structure and function. However, PTH - a possible modifiable mediator in the relation between 25(OH)D and myocardial structure - was positively associated with LVMI in subjects with low kidney function.

Opposite effects of training in rats with stable and progressive pulmonary hypertension.

BACKGROUND: Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training. METHODS AND RESULTS: Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25+/-3.9 to 62+/-3.9 minutes; P<0.001). Moreover, capillary density increased significantly (from 1.21+/-0.12 to 1.51+/-0.07 capillaries per cardiomyocyte; P<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135+/-14 to 276+/-18 leukocytes per 1 mm(2); P<0.001). CONCLUSIONS: In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.

Ultrasound and microbubble-targeted delivery of therapeutic compounds: ICIN Report Project 49: Drug and gene delivery through ultrasound and microbubbles.

The molecular understanding of diseases has been accelerated in recent years, producing many new potential therapeutic targets. A noninvasive delivery system that can target specific anatomical sites would be a great boost for many therapies, particularly those based on manipulation of gene expression. The use of microbubbles controlled by ultrasound as a method for delivery of drugs or genes to specific tissues is promising. It has been shown by our group and others that ultrasound increases cell membrane permeability and enhances uptake of drugs and genes. One of the important mechanisms is that microbubbles act to focus ultrasound energy by lowering the threshold for ultrasound bioeffects. Therefore, clear understanding of the bioeffects and mechanisms underlying the membrane permeability in the presence of microbubbles and ultrasound is of paramount importance. (Neth Heart J 2009;17:82-6.).

Deteriorating glucose tolerance status is associated with left ventricular dysfunction--the Hoorn Study.

BACKGROUND: Type 2 diabetes (DM2) is associated with a greater risk of heart failure. The mechanisms underlying this association remain controversial and include diabetes-associated hypertension and obesity, impaired small and large artery function, and a distinct metabolic cardiomyopathy related to hyperglycaemia/ hyperinsulinaemia. The proximate causes of heart failure are left ventricular (LV) systolic dysfunction (SDF) and diastolic dysfunction (DDF). We investigated, in a population-based cohort (n=746), the association between glucose tolerance status and SDF and DDF . METHODS AND RESULTS: The study population consisted of 274 individuals with normal glucose metabolism (NGM), 174 with impaired glucose metabolism (IGM) and 298 with DM2 (mean age 68.5 years). All participants underwent an LV echocardiogram. SDF was defined as ejection fraction <55%. DDF was determined by a sum score of peak A velocity (abnormal, >or =97 cm/s), the difference between Apv and Amv duration (> or =41 ms), and left atrial volume (> or =57 ml), where cut-off values were based upon the 90th percentile in NGM. In addition, we analysed the ratio of early to late diastolic filling (E/A ratio) on a continuous scale using linear regression analyses. The age- and sex-standardised prevalences in NGM, IGM and DM2 were 13, 14 and 30% for SDF , and 26, 36 and 47% for DDF (P trend for both <0.001). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria, DM2 was significantly associated with both SDF (odds ratio (95% CI) 2.04 (1.24 to 3.36)) and DDF (2.42 (1.63 to 3.60)) (90th percentile definition). This was also true for the analyses with the E/A ratio on a continuous scale (regression coefficient b (95% CI) -0.05 (-0.09 to -0.01). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria IGM was not significantly associated with SDF (odds ratio (95% CI) 1.04 (0.58 to 1.88)) or DDF (1.33 (0.86 to 2.06)) using the definition based upon the 90th percentile. However, IGM was significantly associated with DDF if the E/A ratio was analysed on a continuous scale (regression coefficient beta (95% CI) -0.05 (-0.10 to -0.01). Additional adjustment for brachial artery flow-mediated vasodilation or arterial stiffness, as measures of large artery function, did not materially alter the results. Hyperglycaemia and hyperinsulinaemia together explained approximately 30% of the association of DM2 with SDF and approximately 40% of that with DDF . CONCLUSION: DM2 is independently associated with a 2.0-fold greater risk of SDF and a 2.4-fold greater risk of DDF . IGM was not associated with SDF , and the association with DDF was limited to the E/A ratio. These observations may therefore explain the increased risk of systolic and diastolic heart failure in elderly individuals with DM2.

Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy.

BACKGROUND: Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. The functional significance of this modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy. METHODS AND RESULTS: In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial expression of NOS2 was linearly correlated with LV stroke volume (P=0.001; r=0.66), LV ejection fraction (P=0.007; r=0.58), and LV stroke work (P=0.003; r=0.62). In patients with elevated LV end-diastolic pressure (>16 mm Hg), a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume (P=0.001; r=0.74), LV ejection fraction (P=0.0007; r=0.77), and LV stroke work (r=0.82; P=0.0002). LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume (P=0.01; r=0.53) and LV stroke work (P=0.01; r=0.52). To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endothelial release of NO) was infused intracoronarily (n=12). In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume from 72+/-13 to 91+/-16 mL (P=0.06) and LV stroke work from 67+/-11 to 90+/-15 g. m (P=0.03) and shifted the LV end-diastolic pressure-volume relation to the right. CONCLUSIONS: In patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve.

Orifice variability of the stenotic aortic valve: evaluation before and after balloon aortic valvuloplasty.

The effects of balloon aortic valvuloplasty on orifice variability of the stenotic sclerocalcific aortic valve were evaluated by hemodynamic measurements of aortic valve function in 14 patients before balloon aortic valvuloplasty, during nitroprusside infusion before valvuloplasty, 48 h after valvuloplasty and during nitroprusside infusion 48 h after valvuloplasty. Aortic valve function was assessed by aortic valve area calculations with use of the Gorlin and Cannon formulas. Nitroprusside infusion before balloon aortic valvuloplasty caused no change in mean aortic valve gradient but a significant increase in mean aortic transvalvular flow from 186 +/- 46 to 202 +/- 61 ml/s (p less than 0.05), in Gorlin aortic valve area from 0.49 +/- 0.17 to 0.53 +/- 0.21 cm2 (p less than 0.05) and in Cannon aortic valve area from 0.45 +/- 0.18 to 0.49 +/- 0.22 cm2 (p less than 0.05). Nitroprusside infusion 48 h after valvuloplasty induced no change in mean aortic valve gradient but a significant increase in mean aortic transvalvular flow from 214 +/- 61 to 254 +/- 78 ml/s (p less than 0.005), in Gorlin aortic valve area from 0.71 +/- 0.25 to 0.83 +/- 0.32 cm2 (p less than 0.01) and in Cannon aortic valve area from 0.78 +/- 0.33 to 0.88 +/- 0.40 cm2 (p less than 0.05). Forty-eight hours after valvuloplasty, nitroprusside infusion induced a larger increase (40 +/- 40 ml/s) in mean transvalvular flow than before valvuloplasty (16 +/- 27 ml/s; p less than 0.05) and a larger increase (0.12 +/- 0.14 cm2) in Gorlin aortic valve area than before valvuloplasty (0.05 +/- 0.07 cm2; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic function of the nonfilling human left ventricle.

OBJECTIVES: To investigate an early-diastolic left ventricular suction effect in humans, tip-micromanometer left ventricular pressure recordings were obtained in patients with mitral stenosis at the time of balloon inflations during percutaneous mitral valvuloplasty performed with a self-positioning Inoue balloon, which fits tightly in the mitral orifice. BACKGROUND: When mitral inflow was impeded in anesthetized dogs, left ventricular pressure decayed to a negative asymptote value. This negative asymptote value was consistent with an early diastolic suction effect. METHODS: Tip-micromanometer left ventricular pressure recordings were obtained in 23 patients with symptomatic mitral stenosis at the time of balloon inflations during percutaneous mitral valvuloplasty performed with a self-positioning Inoue balloon. RESULTS: The left ventricular diastolic asymptote pressure (P(asy)) was determined in 47 nonfilling beats with a sufficiently long (greater than 200 ms) diastolic time interval (that is, the interval from minimal first derivative of left ventricular pressure to left ventricular end-diastolic pressure) and equaled 2 +/- 3 mm Hg for beats with normal intraventricular conduction and 3 +/- 2 mm Hg for beats with aberrant intraventricular conduction. Left ventricular angiography was performed in five patients during the first inflation of the Inoue balloon at the time of complete balloon expansion. Left ventricular end-diastolic volume of the nonfilling beats averaged 38 +/- 14 ml and was comparable to the left ventricular end-systolic volume (39 +/- 19 ml) measured during baseline angiography before mitral valvuloplasty. Time constants of left ventricular pressure decay were calculated on 21 nonfilling beats with a diastolic time interval greater than 200 ms, normal intraventricular conduction and peak left ventricular pressure greater than 50 mm Hg. Time constants (T0 and TBF) derived from an exponential curve fit with zero asymptote pressure and with a best-fit asymptote pressure were compared with a time constant (T(asy)) derived from an exponential curve fit with the measured diastolic left ventricular asymptote pressure. The value for T(asy) (37 +/- 9 ms) was significantly smaller than that for TBF (68 +/- 28 ms, p less than 0.001) and the value for the measured diastolic left ventricular asymptote pressure (2 +/- 4 mm Hg) was significantly larger than that for the best-fit asymptote pressure (-9 +/- 11 mm Hg, p less than 0.001). T0 (44 +/- 20 ms) was significantly (p less than 0.01) different from TBF but not from T(asy). CONCLUSIONS: During balloon inflation of a self-positioning Inoue balloon, left ventricular pressure decayed continuously toward a positive asymptote value and left ventricular cavity volume was comparable to the left ventricular end-systolic volume of filling beats. In these nonfilling beats, the best-fit asymptote pressure was unrelated to the measured asymptote pressure and T0 was a better measure of T(asy) than was TBF. Reduced internal myocardial restoring forces, caused by different extracellular matrix of the human heart, reduced external myocardial restoring forces caused by low coronary perfusion pressure during the balloon inflation and inward motion of the balloon-occluded mitral valve into the left ventricular cavity could explain the failure to observe significant diastolic left ventricular suction in the human heart.

Myocardial contractile effects of L-arginine in the human allograft.

OBJECTIVES: In the present study, we investigated, in transplant recipients, whether L-arginine (L-arg) potentiates the myocardial contractile effects of receptor-mediated coronary endothelial stimulation. Moreover, because inducible nitric oxide synthase (iNOS) is frequently expressed in transplanted myocardium, we also performed intracoronary infusion of L-arg in the absence of receptor-mediated coronary endothelial stimulation to investigate whether similar left ventricular (LV) contractile effects could be induced by providing more substrate for iNOS. BACKGROUND: Nitric oxide (NO), released from coronary endothelium after receptor-mediated stimulation by substance P (SP), affects vascular smooth muscle tone and modulates LV contractile performance. L-arg augments receptor-mediated endothelium-dependent coronary vasodilation in transplant recipients by increasing substrate availability for endothelial NO production. METHODS: Sixteen transplant recipients were studied at the time of annual coronary angiography. In eight transplant recipients, microtip LV pressures were recorded before and during intracoronary (IC) SP (20 pmol/min) and after the addition of IC L-arg (160 mumol/min) to IC SP. In eight transplant recipients, microtip LV pressures were recorded before and during IC L-arg (160 mumol/min) alone, and in six of these patients, endomyocardial biopsy samples were obtained to detect the expression of iNOS gene by reverse transcription-polymerase chain reaction. RESULTS: Addition of IC L-arg to IC SP induced a fall (mean +/- SEM) in LV peak systolic pressure (-16 +/- 4 mm Hg), which was larger (p < 0.01) than that observed during IC SP (-7 +/- 2 mm Hg). During IC L-arg alone, there was no change in LV peak systolic pressure despite the presence of iNOS mRNA in five of the six biopsy samples. CONCLUSIONS: In transplant recipients, L-arg potentiates the paracrine myocardial contractile effects of receptor-mediated coronary endothelial stimulation, probably by providing more substrate for endothelial NO production. Despite the myocardial expression of iNOS gene, L-arg alone fails to elicit similar contractile effects.

Comparison of the effects of nitroprusside and nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy: altered left ventricular loading or improved muscle inactivation?

The calcium channel blocking agent, nifedipine, has been shown to improve indexes of left ventricular relaxation, diastolic filling and compliance in patients with hypertrophic cardiomyopathy. The mechanism of action of nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy is unclear and could result from an improvement in myocardial inactivation or from systemic vasodilation and left ventricular unloading. To distinguish between these mechanisms, the effects of nifedipine and the vasodilator nitroprusside on left ventricular diastolic properties were compared in 10 patients with nonobstructive hypertrophic cardiomyopathy using simultaneous micromanometer left ventricular pressure and echocardiographic measurements. Left ventricular peak systolic pressure was comparable during nitroprusside infusion (132 +/- 38 mm Hg) and after nifedipine (132 +/- 32 mm Hg). During nitroprusside infusion, the decrease in left ventricular end-diastolic pressure (22 +/- 11 to 17 +/- 11 mm Hg, p less than 0.05) was associated with a decrease in left ventricular end-diastolic dimension. In contrast, the decrease in left ventricular end-diastolic pressure after nifedipine (22 +/- 11 to 18 +/- 10 mm Hg, p less than 0.05) was associated with no reduction of left ventricular end-diastolic dimensions, suggesting an increase in left ventricular distensibility. Compared with nitroprusside, nifedipine was associated with less prolongation of the left ventricular isovolumic relaxation time and less depression of the peak left ventricular posterior wall thinning rate and peak left ventricular internal dimension filling rate. These data suggest that the effects of the calcium channel blocker, nifedipine, on diastolic mechanics in hypertrophic cardiomyopathy result not only from systemic vasodilation but also from improved cardiac muscle inactivation.

Transstenotic coronary pressure gradient measurement in humans: in vitro and in vivo evaluation of a new pressure monitoring angioplasty guide wire.

OBJECTIVES: The present study was designed to investigate 1) the feasibility and accuracy of coronary pressure measurements with a novel 0.015-in. (0.038 cm) fluid-filled guide wire, and 2) the effect of the guide wire itself on stenosis hemodynamics. BACKGROUND: To assess the functional results of coronary angioplasty, measurements of the transstenotic pressure gradient have been advocated. However, this gradient is no longer routinely measured because it is not reliable when determined with the angioplasty catheter. METHODS: A fluid-filled 0.015-in. guide wire to be connected to a conventional pressure transducer was developed. Five wires were tested for their frequency response characteristics and for their accuracy in measuring hydrostatic pressure. In an in vitro model of stenosis (reference diameter 4 mm), the pressure gradient was determined at incremental flow levels for varying stenosis severity with and without a 0.015-in. guide wire through the narrowing. In 37 patients, the transstenotic pressure gradient was measured before and after angioplasty and compared with obstruction area and percent area stenosis as determined by quantitative coronary angiography. RESULTS: The correlation between the actual pressure and the pressure recorded by the guide wire was excellent (r = 0.98) despite a slight underestimation (-3 +/- 5%). Phasic pressure recordings were precluded by a long time constant of 16 +/- 4 s. The presence of the guide wire produced a significant overestimation (> 20%) of the pressure decrease only in cases of tight stenosis (> 90% area reduction). Furthermore, a theoretic model based on the fluid dynamic equation predicted that this overestimation was inversely proportional to the reference diameter of the vessel, yet was only slightly influenced by the flow. The lesion was crossed in all but one patient (97%) and pressure gradient was recorded throughout the study in 34 (94%) of 36 patients. The mean pressure gradient decreased from 30 +/- 19 before to 3 +/- 5 mm Hg after angioplasty (p < 0.01). A curvilinear relation was found between the pressure gradient and both percent area stenosis (r2 = 0.67) and obstruction area (r2 = 0.72). A sharp increase in pressure gradient was noted once the stenosis exceeded 75% area reduction. CONCLUSIONS: Mean transstenotic pressure gradients can be easily and reliably recorded with a 0.015-in. fluid-filled guide wire. This ability should facilitate the functional assessment of coronary stenoses of intermediate severity and of immediate postangioplasty results.

Quantification of diastolic dysfunction via the age dependence of diastolic function - impact of insulin resistance with and without type 2 diabetes.

BACKGROUND: The alarming prevalence of heart failure with preserved ejection fraction requires quantification of diastolic dysfunction (DDF). Myocardial diastolic velocity E' implies that age is the most important determinant. We tested the hypothesis that age allows for quantification of DDF and assessment of the structural and metabolic determinants in patients with and without type 2 diabetes (D). METHODS: This prospective, cross-sectional study assessed cardiovascular, metabolic and ultrasound data in 409 consecutive patients (Diabetes Center, Bogenhausen-Munich) between 20 and 90 years without known cardiac disease and either with (n=204) or without D but with common prevalence of cardiovascular risk factors, including a subgroup of healthy individuals (H, n=94). RESULTS: In H, E' related to age as: E'norm=-0.163∗years+19.69 (R(2)=0.77, p<0.0001). According to this 1% reduction by annual physiologic aging, DDF was quantitated as E'-E' norm. Compared to nondiabetics, D patients were older, had greater BMI, lower E', more cardiovascular risk and greater DDF. In nondiabetics, grading of DDF by E-E'norm correlated with grading by filling pressure E/E'. Determinants of DDF by multivariate analysis included pulse wave velocity, diastolic blood pressure and the triglyceride/HDL ratio (a marker of insulin resistance) in nondiabetics and in D the same risk factors in reverse sequence and heart rate. Neither left atrial size nor left ventricular mass had significant impact. CONCLUSIONS: The physiological impact of age on myocardial function consists of a 1% annual reduction in E' and enables precise quantification of diastolic dysfunction thereby unmasking the importance of metabolic risk for DDF.

How are cytokines activated in heart failure?

In the dilated and failing heart, elevated LV end-diastolic wall stress causes myocardial expression of cytokines, which directly or indirectly influence LV contractile performance and remodeling [22]. Due to poor diffusion of cytokines into the coronary effluent, the contribution of this myocardial production to the raised plasma levels is probably limited. Raised plasma levels of cytokines in heart failure are therefore more likely the result of extramyocardial production because of altered tissue perfusion and tissue hypoxia possibly modulated by bacterial endotoxin release from the gut.

The influence of endothelium-derived nitric oxide on myocardial contractile function.

Nitric oxide released by cardiac endothelial cells modulates myocardial contractile function through elevation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). In the absence of agonist stimulation, nitric oxide typically enhances myocardial relaxation and reduces diastolic tone, without significantly altering the rate of force or pressure development. This pattern of effect is observed with nitric oxide or with cGMP analogues in isolated rat cardiac myocytes, isolated ferret papillary muscle preparations, and isolated ejecting guinea-pig hearts. In human subjects studied at cardiac catheterisation, low-dose bicoronary infusions of sodium nitroprusside or of substance P induce similar effects on left ventricular systolic and diastolic function. These changes may benefit from cardiac filling and coronary perfusion by increasing the diastolic interval, reducing extravascular compressive forces and increasing the driving pressure for filling, e.g., during exercise. Nitric oxide may also modulate inotropic and chronotropic responses to beta-adrenergic stimulation. Under pathological conditions, overproduction of nitric oxide by an inducible nitric oxide synthase may be detrimental for contractile function. Dysfunction of the constitutive nitric oxide pathway could also contribute to pathophysiology, e.g., in conditions characterised by diastolic dysfunction. The paracrine nitric oxide pathway is likely to be an important regulator of cardiac contractile function, acting in concert and interacting with other regulatory pathways.

Cytokines and heart failure.

In many forms of cardiomyopathic left ventricular (LV) dysfunction, there is a rapid myocardial expression of pro-inflammatory cytokines such as interleukin 1, interleukin 6 and tumour necrosis factor-alpha (TNF-alpha) which mediate, via specific receptors, various processes such as gene expression, cell growth or apoptosis. In the initial stages of myocarditis, the myocardial expression of proinflammatory cytokines appears to be part of an inflammatory process. In many other conditions such as ischaemic cardiomyopathy and chronic LV pressure or volume overload, myocardial expression of proinflammatory cytokines is triggered by an elevation of LV wall stress. Myocardial expression of cytokines contributes to depression of contractile performance and adverse LV remodelling. Cytokine-induced depression of contractile performance appears to result from sphingosine production, which interferes with myocardial calcium handling. In transgenic mice, the rate of progression of LV dilatation appears to correlate with the intensity of myocardial TNF-alpha overexpression. In heart failure patients, cytokine concentrations are elevated not only in the myocardium but also in plasma. Cytokines are, therefore, responsible not only for autocrine and paracrine signalling within the myocardium but also for endocrine signalling throughout the body, especially affecting striated muscle mass with induction of muscle wasting and cachexia. The source of cytokine production in heart failure remains uncertain and several mechanisms have been proposed including endotoxin-induced immune activation due to bowel oedema, myocardial production due to haemodynamic overload and peripheral extramyocardial production due to tissue hypoperfusion and hypoxia. The latter seems to be the most likely mechanism, possibly modulated by the presence of bacterial endotoxins released from the gut. Numerous drugs have meanwhile been shown to influence this cardioinflammatory response to heart failure either by reducing basal levels of cytokines (e.g. amlodipine, pentoxifylline, beta-blockers) or by reducing endotoxin-induced cytokine gene expression (e.g. ouabain, amiodarone, adenosine, angiotensin converting enzyme inhibitors, angiotensin II-receptor blockers). Direct blockade of the deleterious actions of elevated plasma levels of cytokines recently became possible through intravenous infusion of a soluble TNF-alpha receptor fusion protein, which resulted in an increase in exercise tolerance and LV performance.

Paracrine modulation of coronary vasomotor tone and myocardial performance by vascular and endocardial endothelium.

Over the last years it has become evident that endothelium is one of the most active paracrine organs releasing a number of vasoactive substances. These mediators, by acting on subjacent vascular smooth muscle, play and important role in control of vasomotor tone and of platelets aggregation. The relations between vascular endothelium and cardiovascular risk factors are complex. Functional abnormalities of vascular endothelium are probably segmental and may differ in individual cases. Experimental and clinical study has demonstrated that all cardiac endothelial cells, coronary vascular and endocardial, modulate the performance of underlying myocardium. Modulation of the left ventricular function by endothelial cells constitutes an important autoregulation of muscle-pump performance of the heart by altering the duration of contraction and diastolic function. It is likely that cardiac endothelial cells take part in extrinsic and intrinsic cardiac compensatory mechanisms and, although there is still no direct evidence, they may be closely involved in pathophysiology of heart failure in humans.

Reduction of infarct size by intravenous injection of uncultured adipose derived stromal cells in a rat model is dependent on the time point of application.

Stem cell therapy is a promising tool to improve outcome after acute myocardial infarction (AMI), but needs to be optimized since results from clinical applications remain ambiguous. A potent source of stem cells is the stromal vascular fraction of adipose tissue (SVF), which contains high numbers of adipose derived stem cells (ASC). We hypothesized that: 1) intravenous injection can be used to apply stem cells to the heart. 2) Uncultured SVF cells are easier and safer when cultured ASCs. 3) Transplantation after the acute inflammation period of AMI is favorable over early injection. For this, AMI was induced in rats by 40min of coronary occlusion. One or seven days after AMI, rats were intravenously injected with vehicle, 5×10(6) uncultured rat SVF cells or 1×10(6) rat ASCs. Rats were analyzed 35 days after AMI. Intravenous delivery of both fresh SVF cells and cultured ASCs 7 days after AMI significantly reduced infarct size compared to vehicle. Similar numbers of stem cells were found in the heart, after treatment with fresh SVF cells and cultured ASCs. Importantly, no adverse effects were found after injection of SVF cells. Using cultured ASCs, however, 3 animals had shortness of breath, and one animal died during injection. In contrast to application at 7 days post AMI, injection of SVF cells 1 day post AMI resulted in a small but non-significant infarct reduction (p=0.35). Taken together, intravenous injection of uncultured SVF cells subsequent to the acute inflammation period, is a promising stem cell therapy for AMI.