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.

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.

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.

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.

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart.

Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article. Meta-analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that "left" and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature. As in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensin-converting enzyme inhibition or ß-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well. In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials.

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.

A refined radio-telemetry technique to monitor right ventricle or pulmonary artery pressures in rats: a useful tool in pulmonary hypertension research.

Implantable radio-telemetry methodology, allowing for continuous recording of pulmonary haemodynamics, has previously been used to assess effects of therapy on development and treatment of pulmonary hypertension. In the original procedure, rats were subjected to invasive thoracic surgery, which imposes significant stress that may disturb critical aspects of the cardiovascular system and delay recovery. In the present study, we describe and compare the original trans-thoracic approach with a new, simpler trans-diaphragm approach for catheter placement, which avoids the need for surgical invasion of the thorax. Satisfactory overall success rates up to 75% were achieved in both approaches, and right ventricular pressures and heart and respiratory rates normalised within 2 weeks. However, recovery was significantly faster in trans-diaphragm than in trans-thoracic operated animals (6.4+/-0.5 vs 9.5+/-1.1 days, respectively; p<0.05). Stable right ventricular pressures were recorded for more than 4 months, and pressure changes, induced by monocrotaline or pulmonary embolisms, were readily detected. The data demonstrate that right ventricular telemetry is a practicable procedure and a useful tool in pulmonary hypertension research in rats, especially when used in combination with echocardiography. We conclude that the described trans-diaphragm approach should be considered as the method of choice, for it is less invasive and simpler to perform.

Pulmonary embolism causes endomyocarditis in the human heart.

BACKGROUND: Pulmonary embolism (PE) is a significant cause of morbidity and mortality. In a recent study in patients with PE, an increased level of macrophages was found in the right ventricle. OBJECTIVE: To evaluate the presence of inflammatory cells, myocytolysis and intracavitary thrombi in the left and right ventricle of patients who died because of PE as a putative new source of heart failure. PATIENTS AND METHODS: 22 patients with PE were studied. For comparison, eight controls and 11 patients who died of chronic pulmonary hypertension (PHT) were used. Slides of the left and right ventricle were stained with antibodies, identifying neutrophilic granulocytes, lymphocytes and macrophages, which were subsequently quantified. Myocytolysis was visualised using complement staining. Thrombi were identified by conventional staining. RESULTS: Compared with controls, in patients with PE a significant increase in extravascular localisation of all three inflammatory cells was found both in the right and left ventricle, coinciding with myocytolysis, indicative for myocarditis. No increase in inflammatory cells was found in patients with PHT. Endocardial cellular infiltration was also found, partly coinciding with the presence of ventricular thrombi. CONCLUSIONS: In patients with PE, endomyocarditis and intracavitary thrombi in the left and right ventricle were found. These abnormalities may be an additional new explanation for the observed cardiac enzyme release and functional abnormalities of the heart in these patients and may contribute to the morbidity and mortality of the disease.

Myocardial cytokine gene expression is higher in aortic stenosis than in idiopathic dilated cardiomyopathy.

OBJECTIVE: To investigate cytokine gene expression in patients with aortic valve stenosis (AS) and with idiopathic dilated cardiomyopathy (DCM), and to correlate wall stress with myocardial proinflammatory cytokine gene expression. METHODS: Human left ventricular (LV) myocardial biopsies were obtained for subsequent reverse transcription polymerase chain reaction of tumour necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, and IL-6 mRNA. The study population consisted of 24 patients with AS and 10 patients with idiopathic DCM. RESULTS: Patients with AS had a larger ejection fraction (56 (5) v 37 (4)%, p < 0.01), smaller LV end diastolic volumes (146 (11) v 267 (21) ml, p < 0.01), and lower end systolic wall stress (44 (7) v 112 (11) kdyn/cm2, p < 0.001). Upregulation of TNFalpha, IL-1beta, and IL-6 gene expression was detected in both groups. However, TNFalpha gene expression was significantly higher in AS than in DCM (p = 0.009). No correlation was found between haemodynamic parameters and TNFalpha gene expression. In patients with AS there was a strong inverse relation between circulating TNFalpha and TNFalpha gene expression (r = -0.685, p = 0.014), between circulating TNFalpha and IL-1beta gene expression (r = -0.664, p = 0.018), and between soluble TNF receptor 2 and TNFalpha gene expression (r = -0.685, p = 0.020). Myocardial gene expression of TNFalpha was significantly higher in patients with well compensated AS than in patients with decompensated AS (p = 0.017). Similarly, patients with decompensated DCM were characterised by significantly lower TNFalpha gene expression than were patients with well compensated DCM (p = 0.011). CONCLUSION: TNFalpha gene expression is significantly higher in patients with pressure overload than in normal hearts, in patients with idiopathic DCM, and in patients with compensated versus decompensated heart failure. Secondly, in patients with AS proinflammatory cytokine gene expression did not affect systolic performance. The higher TNFalpha gene expression in patients with compensated heart failure suggests that cytokine gene expression has an adaptive role in the early phase of LV remodelling.

The role of nitric oxide in the failing heart.

Nitric oxide (NO) has effects on contractility, energetics and gene expression of failing myocardium. Initial studies on isolated cardiomyocytes showed NO to reduce systolic shortening but intracoronary infusions of NO-donors or of NO synthase (NOS) inhibitors failed to elicit changes in baseline LV contractility indices such as LVdP/dt(max). Intracoronary infusions of NO-donors or of substance P, which releases NO from the coronary endothelium, however demonstrated NO to induce a downward displacement of the left ventricular (LV) diastolic pressure-volume relation, consistent with increased LV diastolic distensibility. In end-stage failing myocardium, the increased oxygen consumption is related to reduced NO production and in isolated cardiomyocytes, NO blunts the norepinephrine-induced expression of the fetal gene programme thereby preserving myocardial calcium homeostasis.In dilated cardiomyopathy, changed endomyocardial NOS gene expression has been reported. Because of lower endomyocardial NOS gene expression in patients with higher functional class and lower LV stroke work, increased endomyocardial NOS gene expression seems to be beneficial rather than detrimental for the failing heart. A beneficial effect of increased NOS gene expression could result from NO's ability to increase LV diastolic distensibility, to augment LV preload reserve, to reduce myocardial oxygen consumption and to prevent downregulation of calcium ATPase. Upregulated endomyocardial NOS gene expression has also been reported in athlete's heart and could therefore play a role in physiological LV remodeling. Reduced endomyocardial NO content because of decreased NO or increased superoxide production could lower LV diastolic distensibility and contribute to diastolic heart failure. In many conditions such as aging, hypertension, diabetes or posttransplantation, the increased incidence of diastolic heart failure is indeed paralleled by reduced endothelium-dependent vasodilation.

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.

Beneficial effects of nitric oxide on cardiac diastolic function: 'the flip side of the coin'.

Modulation by NO of systolic myocardial function received widespread attention but most studies focused on potential negative inotropic properties of NO. The very original observations on the effects of NO on myocardial contraction already provided evidence that NO modified myocardial contractile performance mainly through a relaxation-hastening effect (i.e. earlier onset of relaxation) and through an increase in myocardial distensibility. The present review discusses the relaxation hastening and distensibility-increasing effects of NO in experimental preparations, in the normal human heart, in left ventricular hypertrophy of aortic stenosis, in the human allograft and in dilated nonischemic cardiomyopathy. This 'diastolic flip side' of the myocardial effects of NO appears to be beneficial especially for patients who are dependent on the LV Frank-Starling response to maintain cardiac output.

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.