Amyloid myopathy: expanding the clinical spectrum of transthyretin amyloidosis-case report and literature review.

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

A case report of a 40-year-old woman with endomyocardial fibrosis in a non-tropical area: from initial presentation to high urgent heart transplantation.

BACKGROUND: Endomyocardial fibrosis (EMF) represents the most common cause of restrictive cardiomyopathy worldwide. Despite a high prevalence in tropical regions, it occasionally occurs in patients who have never visited these areas. While researches have proposed various possible triggers for EMF, etiology and pathogenesis remain largely unknown. Diagnosis is based on patient history, heart failure symptoms, and echocardiographic signs of restrictive ventricular filling, atrioventricular valve regurgitation and frequently apical thrombus. Following is a case report of an Austrian patient with EMF who eventually had to undergo a heart transplant. This case report strives to promote awareness for this in non-tropical areas uncommon but nevertheless detrimental disease. CASE PRESENTATION: A 40-year-old woman was presented at our emergency department with chest pain and fever up to 38.1° Celsius. Plasma troponin-T levels and inflammatory markers were slightly elevated, but the echocardiogram was without pathological findings. The patient was hospitalized on the suspicion of acute myocarditis and discharged soon after improvement. Eight months later, she was presented again with chest pain and symptoms of heart failure. The echocardiogram showed normal systolic left ventricular (LV) function with LV wall thickening and severe restrictive mitral regurgitation as well as aortic and tricuspid regurgitation. Coronary angiogram was normal but right heart catheterization showed pulmonary hypertension due to left heart disease. Further diagnostic workup with cardiac magnetic resonance imaging revealed subendocardial late enhancement and apical thrombus formation in the left ventricle compatible with the diagnosis of EMF. A comprehensive diagnostic workup showed no evidence of infection, systemic immunologic or hematological disease, in particular hypereosinophilic syndrome. After a multidisciplinary consideration of several therapeutic options, the patient was listed for heart transplantation. On the waiting list, she deteriorated rapidly due to progressive heart failure and finally underwent a heart transplantation. Histological examination confirmed the diagnosis of EMF. Six years after her heart transplantation, the patient was presented in an excellent clinical condition. CONCLUSIONS: Even in non-tropical regions, the diagnosis of EMF should always be considered in restrictive cardiomyopathy. Knowledge of the distinct phenotype of EMF facilitates diagnosis, but comprehensive workup and therapeutic management remain challenging and require a multidisciplinary approach.

Cardiohepatic syndrome.

Accumulating evidence shows that acute as well as chronic heart disease can directly contribute to an acute or chronic worsening of liver function and vice versa. Description and definition of cardiohepatic syndrome (CHS) in this review are based on the cardiorenal syndrome (CRS) concept. The eye-catching analogy between CHS and CRS is applied to facilitate an understanding of the pathophysiology and overall burden of disease for each of the proposed CHS subtypes, their natural course, and associated morbidity and mortality.

FGF23 is associated with disease severity and prognosis in chronic heart failure.

BACKGROUND: Elevated levels of fibroblast growth factor 23 (FGF23) are associated with incident heart failure in individuals with or without chronic kidney disease. We aimed to investigate the association between serum FGF23 concentrations and disease severity and long-term outcome in patients with stable heart failure. MATERIALS AND METHODS: Serum levels of C-term FGF23 (Ct-FGF23) concentrations, inorganic phosphate (Pi ), parathormone (PTH) and 25-hydroxyvitamin D (25(OH)D) were measured in 208 patients with nonischaemic heart failure (age 48 ± 15 years; 70% male; NYHA Class I 27·8%, NYHA Class II 43·4%, NYHA Class III/IV 28·8%; LV-EF 34 ± 15%; eGFR ≥60 mL/min/1·73 m(2) in 86%). RESULTS: Median Ct-FGF23 levels were 18·2 RU/mL (7·5-40·8RU/mL). A dose-response relationship was found between median Ct-FGF23 levels and increasing NYHA class (I: 11·9 RU/mL, II: 15·8 RU/mL, III/IV: 38·8 RU/mL; P < 0·001). Ct-FGF23 correlated with NTproBNP (r = 0·307, P < 0·001), central venous pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure and inversely correlated with cardiac output after adjustment for renal function (eGFR) and Pi . LnCt-FGF23 was related with the combined endpoint of death or heart transplantation (hazard ratio 1·452 [1·029-2·048]; P = 0·034) independent of Pi , PTH, 25(OH)D, age and sex. CONCLUSION: The phosphatonin FGF23 is strongly associated with disease severity and long-term outcome in patients with nonischaemic heart failure and preserved renal function. Further studies are needed to evaluate the pathophysiologic role of FGF23 and its potential as a biomarker in heart failure.

Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis.

OBJECTIVE: Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality. METHODS: Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects. RESULTS: For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF. CONCLUSIONS: The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.

Imbalance of Iron Availability and Demand in Patients With Acute and Chronic Heart Failure.

BACKGROUND: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand. METHODS AND RESULTS: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF. CONCLUSIONS: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.

Correlation of 99mTc-DPD bone scintigraphy with histological amyloid load in patients with ATTR cardiac amyloidosis.

BACKGROUND: The significance of measuring 99mTc-labelled-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in transthyretin (ATTR) cardiac amyloidosis has not been adequately studied. This single-centre observational study evaluated the correlation between 99mTc-DPD scintigraphy and histological amyloid load in endomyocardial biopsy (EMB). METHODS: Twenty-eight patients with biopsy-proven ATTR amyloidosis and concomitantly available 99mTc-DPD scintigraphy were included. Visual Perugini scoring, and (semi-)quantitative analysis of cardiac 99mTc-DPD uptake by planar whole-body imaging and single photon emission computed tomography (SPECT/CT) using regions of interest (ROI) were performed. From this, heart-to-whole-body ratio (H/WB) and heart-to-contralateral-chest ratio (H/CL) were calculated. The histological amyloid load was quantified using two different staining methods. RESULTS: Increased cardiac tracer uptake was documented in all patients (planar: ROImean 129 ± 37 cps; SPECT/CT: ROImean 369 ± 142 cps). Histological amyloid load (19 ± 13%) significantly correlated with Perugini score (r = 0.69, p < .001) as well as with cardiac 99mTc-DPD uptake (planar: r = 0.64, p < .001; H/WB: r = 0.50, p = .014; SPECT/CT: r = 0.53, p = .008; H/CL: r = 0.43, p = .037) (results are shown for correlations with Congo Red-staining). CONCLUSION: In ATTR, cardiac 99mTc-DPD uptake significantly correlated with histological amyloid load in EMB. Further studies are needed to implement thresholds in cardiac 99mTc-DPD uptake measurements for risk stratification and guidance of therapy.

Serum phosphate and long-term outcome among patients with stable heart failure.

BACKGROUND: Elevated serum phosphate levels are associated with excess risk for cardiovascular mortality in patients with and without chronic kidney disease and with increased risk for incident heart failure. We determined the association of serum phosphate concentrations with disease severity and long-term outcome in patients with overt heart failure. METHODS AND RESULTS: Clinical and laboratory parameters of 974 ambulatory heart failure patients were evaluated. Prevalence of elevated phosphate levels (>4.5 mg/dL) was 5.8% in men and 6.0% in women. Phosphate was significantly correlated with disease severity as assessed by New York Heart Association class, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide (P < .01, respectively). Multivariate sex-stratified Cox regression analysis adjusted for various clinically relevant covariates revealed baseline phosphate to be independently associated with death from any cause or heart transplantation (HR 1.26 [95% CI 1.04-1.52]; P < .001). This relation was maintained in patients with and without chronic kidney disease. After categorization based on quartiles of phosphate levels, a graded, independent relation between phosphate and outcome was observed (P for trend <.001). CONCLUSIONS: We found a graded, independent relation between serum phosphate and adverse outcome in patients with stable heart failure. Also, serum phosphate was related to disease severity. These findings further highlight the clinical importance of serum phosphate in cardiovascular disease.

Renal effects of levosimendan: a consensus report.

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).

Unicentric Castleman's disease associated with malignant cardiac Amyloid-A amyloidosis: a case report.

Background: Unicentric Castleman's disease (UCD), a lymphoproliferative disorder characterized by enlargement of the lymph nodes, is a rare cause of Amyloid-A amyloidosis. While patients usually present with impaired kidney function and proteinuria, heart involvement is neither common nor the main cause of signs and symptoms. Case summary: We present a patient who was admitted to the hospital for impaired exercise capacity. Diagnostic work-up revealed severe left ventricular hypertrophy suggestive of cardiac amyloidosis. Although Congo red staining of endomyocardial biopsies was initially negative, subsequent immunohistochemical staining against serum amyloid A finally confirmed the diagnosis of cardiac amyloidosis. 18F-fluorodeoxyglucose positron emission tomography/computed tomography revealed a tumour located in dorsal of the duodenum. Fine-needle aspiration biopsy of the tumour was suggestive but could not confirm the presence of UCD beyond reasonable doubt. Rapid worsening of heart failure symptoms warranted urgent surgical tumourectomy, which resulted in immediate post-operative lowering of serum amyloid protein. However, post-operative cardiogenic shock could not be stabilized even with veno-arterial extracorporeal membrane oxygenation, and the patient eventually died. The UCD of the hyaline vascular (HV) subtype was confirmed by pathologic work-up of the excised tumour. Discussion: This case report presents for the first time a patient with malignant cardiac Amyloid-A amyloidosis caused by unicentric Castleman's disease of the HV subtype. Since the disease progresses swiftly, rapid diagnosis is essential for potential curative treatment.

RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.

Impact of Professional Background on Inter-Annotator Variability and Accuracy During Annotation of Clinical Notes.

BACKGROUND: The aging population's need for treatment of chronic diseases is exhibiting a marked increase in urgency, with heart failure being one of the most severe diseases in this regard. To improve outpatient care of these patients and reduce hospitalization rates, the telemedical disease management program HerzMobil was developed in the past. OBJECTIVE: This work aims to analyze the inter-annotator variability among two professional groups (healthcare and engineering) involved in this program's annotation process of free-text clinical notes using categories. METHODS: A dataset of 1,300 text snippets was annotated by 13 annotators with different backgrounds. Inter-annotator variability and accuracy were evaluated using the F1-score and analyzed for differences between categories, annotators, and their professional backgrounds. RESULTS: The results show a significant difference between note categories concerning inter-annotator variability (p<0.0001) and accuracy (p<0.0001). However, there was no statistically significant difference between the two annotator groups, neither concerning inter-annotator variability (p=0.15) nor accuracy (p=0.84). CONCLUSION: Professional background had no significant impact on the annotation of free-text HerzMobil notes.

Liver dysfunction in chronic heart failure: prevalence, characteristics and prognostic significance.

BACKGROUND: Although abnormal liver morphology and function have long been recognized, characterization and importance of liver dysfunction in heart failure are poorly defined. This study sought to investigate the relevance of circulating liver function tests (LFTs) in an unselected chronic heart failure (CHF) cohort. MATERIALS AND METHODS: A total of 1032 consecutive ambulatory patients with CHF were enrolled from 2000 to 2008. Clinical and laboratory variables including LFTs were collected at study entry. Follow-up (median 36 months) was available in 1002 (97·1%) patients. The endpoint was defined as death from any cause or heart transplantation. Hazard ratios (HR) for transplant-free survival were estimated per log unit using Cox proportional hazard regression models for sex-stratified data. RESULTS: Sex-specific prevalence of cholestatic enzyme elevation was 19·2% as opposed to elevated transaminases in 8·3%. Cholestatic enzymes, but not transaminases, were significantly associated with severity of heart failure syndrome and backward failure. The endpoint was recorded in 339 patients (33·8%). T-Bil, γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) were associated with adverse outcome in bivariate models. Of these, GGT [HR 1·22 (1·06, 1·41); P = 0·006] and ALP [HR 1·52 (1·09, 2·12); P = 0·014] were independently associated with the endpoint after adjustment for a wide array of clinical and laboratory predictors. CONCLUSIONS: Liver dysfunction is frequent in CHF and characterized by a predominantly cholestatic enzyme profile that is associated with disease severity and prognosis. Thus, we propose a cardio-hepatic syndrome in CHF. Future studies are needed to clarify the exact mechanisms of organ interaction.

Eosinophilic myocarditis complicated by permanent atrioventricular nodal block: a case report.

Background: Eosinophilic myocarditis (EM) is a rare disease with different clinical pictures and disease courses. Little literature is available on the various courses of the disease. Case summary: A previously healthy 44-year-old male patient presented with acute heart failure and developed complete atrioventricular (AV) block requiring pacing. Acute heart failure was managed with inotropic support, non-invasive ventilation, and implantation of a permanent AV-sequential pacemaker. Cardiac magnetic resonance imaging was suggestive of myocarditis and endomyocardial biopsy diagnosed EM histologically. Endomyocardial biopsy was essential for definite aetiologic assignment, thus dispelling initial reservations about immunosuppressive therapy. Final treatment strategy consisted of steroids and Azathioprine. Discussion: Endomyocardial biopsy is essential to establish diagnosis and targeted treatment in EM, which can rapidly lead to life-threatening conditions. Left ventricular function recovered within 2 weeks in response to immunosuppression and the patient was consistently well during follow-up. Despite the otherwise good response to immunosuppression, complete AV block continued over time.

γ-Glutamyltransferase rather than total bilirubin predicts outcome in chronic heart failure.

BACKGROUND: Gamma-glutamyltransferase (GGT) and total bilirubin (T-Bil) are elevated and of prognostic significance in chronic heart failure (CHF). This study sought to compare these novel cardiovascular risk markers in CHF. METHODS AND RESULTS: We evaluated 1,087 ambulatory patients from our heart failure program. Long-term follow-up was available in 1,056 patients. The combined end point was defined as death of any cause or heart transplantation. Prevalence of elevated GGT was 43% in men and 48% in women, that of T-Bil 17% and 8%, respectively. Both variables were significantly correlated with severity of heart failure. GGT and T-Bil were associated with transplant-free survival in bivariate analysis (P values <.001 and .006, respectively). However, GGT (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.13-1.44; P < .001), but not T-Bil, remained an independent predictor of prognosis in the multivariate model. Also, categorized GGT levels beyond the gender-specific normal ranges were predictive of the combined end point (HR 1.55, 95% CI 1.23-1.95). Elevation of both GGT and T-Bil further increased the risk of reaching the end point (HR 2.57, 95% CI 1.74-3.18). CONCLUSIONS: GGT and T-Bil are associated with disease severity in CHF. However, only GGT is independently associated with adverse outcome. Our findings further highlight the clinical importance of GGT in cardiovascular disease.

Heart failure from ATTRwt amyloid cardiomyopathy is associated with poor prognosis.

AIMS: Amyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild-type cardiomyopathy (ATTRwt-CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt-CM and other heart failure aetiologies. METHODS AND RESULTS: This was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long-term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light-chain amyloidosis (AL) 3.1%], dilated CM (dCMP) (46.4%), ischaemic heart disease (IHD) (24.4%), hypertensive heart disease (HHD) (14.6%), hypertrophic CM (HCM) (5.1%), and valvular heart disease (VHD) (3.4%). Median duration of follow-up was 7.1 years (interquartile range 3.4-11.3). Five-year overall survival in the whole cohort was 80.1%. In multivariate analysis, individuals with amyloid CM were 3.74 times [95% confidence interval (CI) 2.72-5.14; P < 0.001] more likely to die of any reason than were individuals with dCMP. Mortality was higher in AL-CM compared with ATTRwt-CM [hazard ratio (HR) 2.88; 95% CI 1.48-5.58; P = 0.002]. Mortality rates in patients with ATTRwt-CM were higher than in patients with dCMP (HR 1.96; 95% CI 1.24-3.22; P = 0.007), HCM (HR 2.94; 95% CI 1.28-6.67; P = 0.011), HHD (HR 2.08; 95% CI 1.27-3.45; P = 0.004), VHD (HR 2.38; 95% CI 1.30-4.35; P = 0.005), or left ventricular ejection fraction ≥ 40% (HR 1.99; 95% CI 1.12-3.52; P = 0.018). CONCLUSIONS: Our study demonstrates that amyloid CM is independently associated with poor survival among patients with various causes of heart failure. ATTRwt-CM had a better long-term prognosis than did AL-CM, but was associated with higher mortality than were dCMP, HCM, HHD, VHD, and heart failure with preserved or mid-range ejection fraction.

Heart failure disease management programs in Austria 2019 : A systematic survey of the Heart Failure Working Group and the Working Group for Cardiological Assistance and Care Personnel of the Austrian Society of Cardiology.

Heart failure (HF) is common and is associated with high morbidity, mortality and high health expenditure. A multidisciplinary disease management plan (DMP) can reduce morbidity and mortality, save costs and improve the quality of life. In Austria, three HF-specific DMPs are currently in a project phase and four established DMPs are active. Although programs are widely heterogeneous with respect to their intervention type, they pursue the same interventional goal by supporting seamless care between inpatient and community care settings with a multidisciplinary team. This survey presents a systematic survey of the HF-specific DMPs in Austria. Disparities between programs are highlighted and discussed. The nationwide establishment of HF-specific DMPs that integrate primary care and cardiology services including a regulation of the remuneration of stakeholders and program infrastructure is needed to decrease the burden of HF for both the individual and society.

Cardiac Inflammation Impedes Response to Cardiac Resynchronization Therapy in Patients With Idiopathic Dilated Cardiomyopathy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of nonresponse to CRT in patients with DCM using endomyocardial biopsies. METHODS: Within the Maastricht and Innsbruck registries of patients with DCM, 99 patients underwent endomyocardial biopsies before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm2. Echocardiographic left ventricular end-systolic volume reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and nonresponders. RESULTS: Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation before implantation was negatively associated with response to CRT (25% of responders, 47% of nonresponders; odds ratio 0.3 [0.12-0.76]; P=0.01). Endomyocardial biopsies fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test P<0.001). Cardiac transcriptomic profiling of endomyocardial biopsies reveals a strong proinflammatory and profibrotic signature in the hearts of nonresponders compared with responders. In particular, COL1A1, COL1A2, COL3A1, COL5A1, POSTN, CTGF, LOX, TGFß1, PDGFRA, TNC, BGN, and TSP2 were significantly higher expressed in the hearts of nonresponders. CONCLUSIONS: Cardiac inflammation along with a transcriptomic profile of high expression of combined proinflammatory and profibrotic genes are associated with a poor response to CRT in patients with DCM.

Impact of all-day physical activity on ventilatory perfusion coupling in patients undergoing cardiac resynchronization therapy.

OBJECTIVES: There is still little information about the cardiorespiratory effects of cardiac resynchronization therapy (CRT) in patients undergoing all-day physical activity. This study aimed to assess the effects of CRT on ventilatory perfusion coupling during submaximal exercise. METHODS: Metabolic and hemodynamic parameters were obtained during treadmill exercise testing as well as during rest for each single-right (RV), -left (LV) and biventricular (BiV) pacing mode as well as during intrinsic conduction (VVI 30) in 37 patients. Only responders to CRT (>10% increase in cardiac output (CO) during BiV pacing; n = 27) were included into the evaluation. RESULTS: LV and BiV pacing increased systolic (144 +/- 25 and 142 +/- 28 vs. 118 +/- 29 mm Hg, p < 0.05) and mean blood pressure (108 +/- 19 and 109 +/- 19 vs. 94 +/- 25 mm Hg, p < 0.05) as well as CO (7.0 +/- 0.6 and 7.2 +/- 0.8 vs. 6.0 +/- 0.6 l/min, p < 0.05 and p < 0.01) during exercise as compared to VVI 30. Simultaneously, LV and BiV pacing decreased dead space ventilation (18 +/- 3 and 17 +/- 3 vs. 20 +/- 4, p < 0.01) and the ventilatory equivalent for oxygen (31 +/- 4 and 31 +/- 5 vs. 36 +/- 6; p < 0.05) compared to intrinsic conduction. CONCLUSION: The improvement in ventilatory efficacy during CRT, which is demonstrated by the decrease in the ventilatory equivalent for oxygen, results from an increase in CO and thus from a reduction in the ventilatory perfusion mismatch.