Jens D. Hove

Cirrhotic cardiomyopathy: pathogenesis and clinical relevance

Cirrhosis is known to cause alterations in the systemic haemodynamic system. Cirrhotic cardiomyopathy designates a cardiac dysfunction that includes impaired cardiac contractility with systolic and diastolic dysfunction, as well as electromechanical abnormalities in the absence of other known causes of cardiac disease. This condition is primarily revealed by inducing physical or pharmacological stress, but echocardiography is excellent at revealing diastolic dysfunction and might also be used to detect systolic dysfunction at rest. Furthermore, measurement of circulating levels of cardiac biomarkers could improve the diagnostic assessm+ent. Cirrhotic cardiomyopathy contributes to various complications in cirrhosis, especially as an important factor in the development of hepatic nephropathy. Additionally, cirrhotic cardiomyopathy seems to be associated with the development of heart failure in relation to invasive procedures such as shunt insertion and liver transplantation. Current pharmacological treatment is nonspecific and directed towards left ventricular failure, and liver transplantation is currently the only proven treatment with specific effect on cirrhotic cardiomyopathy.

New insights into cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy designates a cardiac dysfunction, which includes reduced cardiac contractility with systolic and diastolic dysfunction, and presence of electrophysiological abnormalities in particular prolongation of the QT interval. Several pathophysiological mechanisms including reduced beta-receptor function seem involved in the autonomic and cardiac dysfunction. Cirrhotic cardiomyopathy can be revealed by tissue Doppler imaging but is best demasked by physical or pharmacological stress. Liver transplantation may revert cardiac dysfunction but surgery and shunt insertion may also aggravate the condition. Moreover, cirrhotic cardiomyopathy may contribute to heart failure after invasive procedures and to development of hepatic nephropathy as part of a cardiorenal syndrome. Whether beta-blockers have a deleterious effect in this clinical situation remains to be settled.

Cardiac computed tomography guided treatment strategy in patients with recent acute-onset chest pain: results from the randomised, controlled trial: CArdiac cT in the treatment of acute CHest pain (CATCH).

OBJECTIVES In patients admitted on suspicion of acute coronary syndrome, with normal electrocardiogram and troponines, we evaluated the clinical impact of a Coronary CT angiography (CCTA)-strategy on referral rate for invasive coronary angiography (ICA), detection of significant coronary stenoses (positive predictive value [PPV]) and subsequent revascularisations, as compared to a function-based strategy (standard care). Secondarily we assessed intermediate term clinical events. METHODS AND RESULTS We randomised 600 patients to a CCTA-guided strategy (299 patients) or standard care (301 patients). In the CCTA-guided group referral for ICA required a coronary stenosis >70% or >50% in the left main, and for intermediate stenoses (50-70%), a stress test was used. A significant stenosis on ICA was defined as a stenosis ≥70% or reduced FFR ≤0.75 in intermediate stenoses (50-70%). Referral rate for ICA was 17% with CCTA vs. 12% with standard care (p=0.1). ICA confirmed significant coronary artery stenoses in 12% vs. 4% (p=0.001), and 10% vs. 4% were subsequently revascularised (p=0.005). PPV for the detection of significant stenoses was 71% with CCTA vs 36% with standard care (p=0.001). Clinical events (cardiac death, myocardial infarction, unstable angina pectoris, revascularisation and readmission for chest pain), during 120 days of follow-up, were recorded in 8 patients (3%) in the CCTA-guided group vs. 15 patients (5%) in the standard care group (p=0.1). CONCLUSION In patients with recent acute-onset chest pain, a CCTA-guided diagnostic strategy improves PPV for the detection of significant coronary stenoses, and increases the frequency of revascularisations, when compared to a conventional functional approach.

Long-Term Clinical Impact of Coronary CT Angiography in Patients With Recent Acute-Onset Chest Pain: The Randomized Controlled CATCH Trial.

OBJECTIVES The aim of the CATCH (CArdiac cT in the treatment of acute CHest pain) trial was to investigate the long-term clinical impact of a coronary computed tomographic angiography (CTA)-guided treatment strategy in patients with recent acute-onset chest pain compared to standard care. BACKGROUND The prognostic implications of a coronary CTA-guided treatment strategy have not been compared in a randomized fashion to standard care in patients referred for acute-onset chest pain. METHODS Patients with acute chest pain but normal electrocardiograms and troponin values were randomized to treatment guided by either coronary CTA or standard care (bicycle exercise electrocardiogram or myocardial perfusion imaging). In the coronary CTA-guided group, a functional test was included in cases of nondiagnostic coronary CTA images or coronary stenoses of borderline severity. The primary endpoint was a composite of cardiac death, myocardial infarction (MI), hospitalization for unstable angina pectoris (UAP), late symptom-driven revascularizations, and readmission for chest pain. RESULTS We randomized 299 patients to coronary CTA-guided strategy and 301 to standard care. After inclusion, 24 patients withdrew their consent. The median (interquartile range) follow-up duration was 18.7 (range 16.8 to 20.1) months. In the coronary CTA-guided group, 30 patients (11%) had a primary endpoint versus 47 patients (16%) in the standard care group (p = 0.04; hazard ratio [HR]: 0.62 [95% confidence interval: 0.40 to 0.98]). A major adverse cardiac event (cardiac death, MI, hospitalization for UAP, and late symptom-driven revascularization) was observed in 5 patients (2 MIs, 3 UAPs) in the coronary CTA-guided group versus 14 patients (1 cardiac death, 7 MIs, 5 UAPs, 1 late symptom-driven revascularization) in the standard care group (p = 0.04; HR: 0.36 [95% CI: 0.16 to 0.95]). Differences in cardiac death and MI (8 vs. 2) were insignificant (p = 0.06). CONCLUSIONS A coronary CTA-guided treatment strategy appears to improve clinical outcome in patients with recent acute-onset chest pain and normal electrocardiograms and troponin values compared to standard care with a functional test. (Cardiac-CT in the Treatment of Acute Chest Pain [CATCH]; NCT01534000).

Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD.

Although there is widespread interest in fractional exhaled nitric oxide (FeNO) as a non-invasive, time and cost effective biomarker for assessing airway inflammation in chronic obstructive pulmonary disease (COPD), its usefulness is still controversial. We examined the FeNO levels in clinically meaningful subgroups of COPD in a group of 91 COPD patients with FEV(1) 17-77% of predicted. Multiple flow rates FeNO at 10, 30, 50, 100 and 200 mL/s were measured and a two-compartment model was used to estimate the diffusion Capacity (D), alveolar NO concentration (Calv) and airway wall NO concentration (Caw). All patients had spirometry, assessment of symptoms with questionnaires and low-dose CT scan as well as assessment of weight and body composition. We examined the following subgroups of COPD: Patients with 1) Severe emphysema, 2) Chronic bronchitis, 3) Frequent exacerbations, 4) Loss of lean body mass and 5) Low fat-free mass index. We used advanced non-linear mixed model adjusted for age and gender. The modelled differences in D, Calv or Caw among COPD subgroups were small and not statistically significant. The analysis showed significant effects of current smoking on Caw and of gender on D and Calv. The results were the same if the advanced non-linear mixed model was substituted by more standard analysis techniques. This study questions the relevance of using FeNO as a biomarker to evaluate local inflammation in COPD and points to a need for developing novel non-invasive biomarkers for research laboratory work and daily clinical practice.

Left atrial versus left ventricular input function for quantification of the myocardial blood flow with nitrogen-13 ammonia and positron emission tomography

Flow quantitation with nitrogen-13 ammonia (13NH3) and positron emission tomography (PET) is dependent on an accurate blood time-activity curve. This is conveniently derived from the PET images by drawing a region of interest in the left ventricular cavity. The blood time-activity curve obtained in this way, however, may contain spillover from the myocardial wall. The purpose of this study was to analyse the effect of wall to blood pool spillover. Additionally, we analysed the application of a left atrial input function. Using computer simulations, we investigated the effect of spillover from the myocardial wall to the left ventricular input function and the effect of time delay on the left ventricular input function. An oxygen-15 carbon monoxide PET study of seven normal volunteers was used to investigate possible recovery issues regarding the left atrial input function. Finally, 13NH3 studies of 31 normal volunteers during rest and dipyridamole stimulation were analysed using either a left atrial or a left ventricular input function. The simulation studies showed that myocardial wall to blood pool spillover causes a considerable underestimation of the regional blood flow values in hyperaemic flow studies. Neither time delay nor recovery issues prevent flow quantitation with a left atrial input function. The 13NH3 studies revealed no significant difference between the resting blood flow values, whereas the hyperaemic blood flow values were underestimated by 8% (P<0.01) on average (up to 40% individually) when using a left ventricular input function compared with a left atrial input function. Spillover of activity from the left ventricular wall to the blood time-activity curve is of importance in hyperaemic flow studies using 13NH3. Application of a left atrial input function is a possible solution to these issues.

Cardiac remodelling and function with primary mitral valve insufficiency studied by magnetic resonance imaging

AIMS Evaluation of patients with primary mitral valve insufficiency (MI) is best supported by quantitative measures. Cardiovascular magnetic resonance imaging (CMR) offers flow and cardiac chamber volume quantification. We studied cardiac remodelling with CMR to determine MI regurgitation volumes (MIVol) related to severe MI. METHODS AND RESULTS In total, 24, 20, and 28 patients determined to have mild, moderate, and severe primary MI, respectively, were studied. Combining cine stacks with phase-contrast velocity mapping across the ascending aorta, CMR-determined MIVol was reproducibly obtained as the difference between left ventricular (LV) stroke volume and aortic forward flow (Aoflow). With increasing MI severity, MIVol, left heart volumes, and pulmonary venous diameters increased (P < 0.01). Severe MI with LV end-systolic diameter of 40 mm was signified by MIVol >40 mL, MI regurgitant fraction >0.30, LV end-diastolic volume (LVEDV(i)) >108 mL m(-2), and a total left heart volume >188 mL m(-2) with dilated pulmonary veins and a LVEDV/right ventricular EDV ratio >1.2. In severe MI, LV ejection fraction was unaffected, but the Aoflow and the peak ejection rate indexed to LVEDV were lowered (P < 0.05). In surgical patients, the MIVol correlated to the decrease in LV dimension after valve surgery (P < 0.02). CONCLUSION CMR provides a reproducible quantitative technique for evaluation of MI, as MIVol and cardiac chamber volumes can be held against diagnostic cut-off values. The Aoflow and peak ejection rate indexed to LVEDV may reveal early LV systolic dysfunction in patients with severe MI. Severe MI is related to lower MI regurgitation volume and fraction than previously believed.

Prediction of clinical outcome by myocardial CT perfusion in patients with low-risk unstable angina pectoris

The prognostic implications of myocardial computed tomography perfusion (CTP) analyses are unknown. In this sub-study to the CATCH-trial we evaluate the ability of adenosine stress CTP findings to predict mid-term major adverse cardiac events (MACE). In 240 patients with acute-onset chest pain, yet normal electrocardiograms and troponins, a clinically blinded adenosine stress CTP scan was performed in addition to conventional diagnostic evaluation. A reversible perfusion defect (PD) was found in 38 patients (16 %) and during a median follow-up of 19 months (range 12–22 months) 25 patients (10 %) suffered a MACE (cardiac death, non-fatal myocardial infarction and revascularizations). Accuracy for the prediction of MACE expressed as the area under curve (AUC) on receiver-operating characteristic curves was 0.88 (0.83–0.92) for visual assessment of a PD and 0.80 (0.73–0.85) for stress TPR (transmural perfusion ratio). After adjustment for the pretest probability of obstructive coronary artery disease, both detection of a PD and stress TPR were significantly associated with MACE with an adjusted hazard ratio of 39 (95 % confidence interval 11–134), p < 0.0001, for visual interpretation and 0.99 (0.98–0.99) for stress TPR, p < 0.0001. Patients with a PD volume covering >10 % of the LV myocardium had a worse prognosis compared to patients with a PD covering <10 % of the LV myocardium, p = 0.0002. The optimal cut-off value of the myocardial PD extent to predict MACE was 5.3 % of the left ventricle [sensitivity 84 % (64–96), specificity 95 % (91–97)]. Myocardial CT perfusion parameters predict mid-term clinical outcome in patients with recent acute-onset chest pain.

Low whole-body insulin sensitivity in patients with ischaemic heart disease is associated with impaired myocardial glucose uptake predictive of poor outcome after revascularisation

Abstract.We tested the hypothesis that low whole-body insulin sensitivity in patients with ischaemic heart disease and impaired left ventricular (LV) function is associated with abnormalities of insulin-mediated myocardial glucose uptake affecting outcome after coronary bypass surgery (CABG). We studied 29 patients with ischaemic heart disease and impaired LV ejection fraction (EF) and age-matched healthy volunteers (n=30). As assessed by euglycaemic glucose-insulin clamp, 15 patients had a low and 14 a normal whole-body insulin sensitivity. Using positron emission tomography, patterns of fluorine-18 fluorodeoxyglucose and nitrogen-13 ammonia uptake in addition to quantified glucose uptake, blood flow and hyperaemic blood flow were assessed before CABG in 16 myocardial segments of the left ventricle. Major adverse cardiac events and LVEF were evaluated 7 months after CABG. Glucose uptake in normokinetic PET-normal myocardium was found to be higher in patients with normal whole-body insulin sensitivity (P<0.001), whereas in patients with low whole-body insulin sensitivity more segments displayed a pattern of reduced glucose uptake in normoperfused myocardium (PET-reverse mismatch) (P<0.05). Hyperaemic blood flow was impaired in both patient groups. A major cardiac event after CABG could partly be predicted by the LV extent of normoperfused segments with PET-reverse mismatch. We conclude that low whole-body insulin sensitivity in patients with ischaemic heart disease and impaired LV function is associated with impaired insulin-mediated myocardial glucose uptake, which is partially predictive of a worse outcome after CABG.

Relationship between regional 18F-fluorodeoxyglucose and 13N ammonia uptake in normal myocardium assessed by positron emission tomography: Patterns of mismatch and effects of aging

Increased regional myocardial 18F fluorodeoxyglucose (18FDG) uptake in relation to 13N ammonia (13NH3) uptake – i.e. glucose metabolism–blood flow ‘mismatch’ – appears to be a strong indicator of myocardial viability in patients with ischemic heart disease (IHD) and regionally reduced contractile function. Reference values of regional 18FDG and 13NH3 uptake have not been determined in healthy subjects with the target age for the development of IHD. We therefore studied healthy middle-aged and old men using positron emission tomography (PET). Twenty-three healthy men aged 51 to 83 years of age were studied. 18FDG and 13NH3 uptake was quantified in 16 myocardial segments with PET and circumferential profile analysis. The relative 18FDG/13NH3 uptake was considerably heterogeneous with 18FDG uptake consistently higher than 13NH3 uptake in the left lateral ventricular wall. This regional ‘mismatch’ pattern was observed in all subjects, but was most prominent in middle-aged men. The observed age-dependency was the result of a progressive increased in 13NH3 uptake with advancing age in the left ventricular lateral wall. Age-matched reference values of myocardial 18FDG and 13NH3 uptake appears to be important for the discrimination between physiological and pathological glucose metabolism–blood flow mismatch assessed by PET and circumferential profile analysis.