Dysphagia worsens short-term outcomes in patients with acute exacerbation of heart failure.

Dysphagia, defined as a dysfunction in any stage or process of eating, is common in patients with acute exacerbation of heart failure (HF). In some diseases, dysphagia worsens in-hospital mortality, length of hospital stay, and discharge disposition. However, it remains unclear whether dysphagia is associated with poor short-term outcomes in HF patients. The objective of the present study was to determine whether dysphagia affects short-term outcomes in patients with acute exacerbation of HF. A total of 327 patients hospitalized with acute exacerbation of HF were eligible for the study. Patients were divided into a dysphagia group (DG) or a non-dysphagia group (NDG) based on results of the functional oral intake scale (FOIS), which evaluates a patient's ability of eating and swallowing. FOIS is a 7-point scale, with a level of ≤ 5 indicating dysphagia. Following the withdrawal of 16 patients, short-term outcomes such as in-hospital mortality, length of hospital stay, and discharge disposition, of 311 patients were analyzed. All indexes of short-term outcomes were significantly worse in the DG than in the NDG. After propensity score matching, which was performed to adjust for baseline characteristics such as age, sex, height, weight, body mass index, medical history, complications, HF severity, ejection fraction, and biochemical data excluding nutritional status, all short-term outcomes remained significantly worse in the DG than in the NDG. Multivariate analysis showed that FOIS was an independent predictor of in-hospital survival, length of hospital stay, and discharge to home. The present study suggested that dysphagia affected short-term outcomes in patients with acute exacerbation of HF. Therefore, early detection and intervention of dysphagia in HF patients are important.

Dysphagia Hinders Hospitalized Patients with Heart Failure from Being Discharged to Home.

Dysphagia, defined as a dysfunction in any stage or process of eating, is common among heart failure (HF) patients. In some diseases state, dysphagia hinders patients from being discharged to home. However, it remains unclear whether dysphagia affects discharge disposition of HF patients. This study aimed to identify the impact of dysphagia on discharge disposition of HF patients. A total of 323 patients, hospitalized with acute exacerbation of HF, were eligible for the study (excluding patients who lived at nursing care facilities before admission). Following the withdrawal of 37 patients, a total of 286 patients were analyzed. Dysphagia was determined using the functional oral intake scale (FOIS), which evaluates a patient's ability to swallow. The FOIS is a 7-point scale, with a level of ≤ 5 indicating dysphagia. Of the 286 patients analyzed, 231 (80.8%) were discharged to home, and 55 were discharged to nursing care facilities or rehabilitation hospitals (non-home). FOIS level was significantly lower, and dysphagia incidence was significantly higher among patients discharged to non-home than among those discharged to home. Multivariate analysis showed that FOIS level was an independent predictor of discharge disposition. Additionally, after propensity score matching, which was performed to adjust for baseline characteristics, FOIS level remained significantly lower in patients discharged to non-home than in those discharged to home. In conclusion, dysphagia hinders patients hospitalized with HF from being discharged to home. We conclude that evaluating dysphagia and its severity on admission is useful for predicting discharge disposition in patients hospitalized with HF.

Beneficial effects of long-acting nifedipine on coronary vasomotion abnormalities after drug-eluting stent implantation: The NOVEL study.

AIMS: It is widely known that drug-eluting stents (DES) induce coronary vasomotion abnormalities. We have previously demonstrated that chronic treatment with long-acting nifedipine suppresses coronary hyperconstricting responses induced by the first-generation DES (e.g. sirolimus- and pacritaxel-eluting stents) through inhibition of vascular inflammation in pigs. To examine whether this is also the case with the second-generation DES (everolimus-eluting stents, EES) in humans, the most widely used DES in the world, we conducted a prospective, randomized, multicentre trial, termed as the NOVEL Study. METHODS AND RESULTS: We evaluated 100 patients with stable angina pectoris who underwent scheduled implantation of EES in the left coronary arteries. They were randomly assigned to receive either conventional treatments alone or additionally long-acting nifedipine (10-60 mg/day) (n = 50 each). After 8-10 months, 37 patients in the control and 38 in the nifedipine group were examined for coronary vasoreactivity to intracoronary acetylcholine (ACh) by quantitative coronary angiography after 48-h withdrawal of nifedipine. Coronary vasoconstricting responses to ACh were significantly enhanced at the distal edge of EES compared with non-stented vessel (P = 0.0001) and were significantly suppressed in the nifedipine group compared with the control group (P = 0.0044). Furthermore, the inflammatory profiles were also improved only in the nifedipine group, which evaluated by serum levels of high-sensitivity CRP (P = 0.0001) and adiponectin (P = 0.0039). CONCLUSIONS: These results indicate that DES-induced coronary vasomotion abnormalities still remain an important clinical issue even with the second-generation DES, for which long-acting nifedipine exerts beneficial effects associated with its anti-inflammatory effects. TRIAL REGISTRATION: This study is registered at the UMIN Clinical Trial Registry (UMIN-CTR; ID=UMIN000015147).

Effect of Respiratory Therapy on the Prognosis of Chronic Heart Failure Patients Complicated With Sleep-Disordered Breathing　- A Pilot Efficacy Trial.

BACKGROUND: Sleep-disordered breathing (SDB) has been reported to influence mortality and occurrence of ventricular tachyarrhythmia in patients with chronic heart failure (CHF). It remains to be elucidated, however, whether respiratory therapy (RT) can affect the occurrence of fatal ventricular tachyarrhythmia in CHF patients with SDB. METHODS AND RESULTS: We prospectively examined whether the severity of SDB was associated with fatal cardiac events in CHF patients and, if so, whether RT for SDB improved prognosis. We enrolled 95 patients with stable CHF, in whom SDB was examined on overnight polygraphy. The severity of SDB was quantified using the apnea-hypopnea index (AHI). All patients with AHI ≥10 (n=42) at initial evaluation were recommended to have RT, such as home oxygen therapy and continuous positive airway pressure, and 24 agreed to this. During the follow-up period of 29±17 months, 8 ventricular tachyarrhythmias occurred and 14 of the 95 patients died. On multivariate proportional hazard analysis AHI ≥5 was a risk factor for fatal arrhythmic events (P=0.026). Although RT significantly reduced AHI, it did not significantly reduce the event rates, but 4 patients with AHI <5 on RT had no fatal arrhythmic events or death. CONCLUSIONS: SDB is an independent prognostic factor and thus an important therapeutic target in CHF patients.

Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

End-Tidal CO2 Tension Is Predictive of Effective Nocturnal Oxygen Therapy in Patients with Chronic Heart Failure and Central Sleep Apnea.

Central sleep apnea (CSA) is characterized by recurring cycles of crescendo-decrescendo ventilation during sleep, and enhances sympathetic nerve activity. Thus CSA has a prognostic impact in patients with chronic heart failure (CHF). Although nocturnal oxygen (O2) therapy decreases frequency of CSA and improves functional exercise capacity, it is also known that some non-responders to the therapy exist. We thus aimed to identify predictors of responders to nocturnal O2 therapy in CHF patients with CSA. In 12 CHF patients with CSA hospitalized at our department, sleep study was performed at 2 consecutive nights. Patients nasally inhaled O2 at either the first or second night in a randomized manner. To predict the percentage reduction in apnea-hypopnea index (%ΔAHI) in response to the nocturnal O2 therapy, we performed multiple regression analysis with a stepwise method with variables including age, brain-natriuretic peptide, circulation time, baseline AHI, hypercapnic ventilatory response and end-tidal carbon dioxide tension (PETCO2). Nocturnal O2 therapy significantly decreased AHI (from 32 ± 13 /h to 12 ± 10 /h, P < 0.0001). Among the possible predictors, PETCO2 was the only variable that is predictive of % changes in AHI. Receiver operating characteristics analysis determined 4.25% as the optimal cutoff PETCO2 level to identify responder to nocturnal O2 therapy (> 50% reduction of AHI), with 88.9% of sensitivity and 66.7% of specificity. In conclusion, PETCO2 is useful to predict the efficacy of O2 therapy in CHF patients with CSA, providing important information to the current nocturnal O2 therapy.

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and ß-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and ß-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

Effect of the Great East Japan Earthquake on cardiovascular diseases--report from the 10 hospitals in the disaster area.

BACKGROUND: We reported an increased occurrence of cardiovascular diseases (CVDs) after the Great East Japan Earthquake by examining ambulance records, but it had to be confirmed by cardiologists. METHODS AND RESULTS: We enrolled patients admitted to the cardiology department of the 10 hospitals in the disaster area from 4 weeks prior to 15 weeks after March 11 in the years 2008-2011 (n=14,078). The weekly occurrence of several CVDs, including heart failure (HF), pulmonary thromboembolism (PTE) and infectious endocarditis (IE), was sharply and significantly increased after the Earthquake. CONCLUSIONS: The Disaster caused significantly increases in the occurrence of HF, PTE and IE.

Repetitive afterglow in zirconia by pulsed near-infrared irradiation toward biological temperature sensing.

Photoluminescence provides information about the surrounding environment. In this study, aiming to develop a non-invasive deep body-temperature sensing method, we investigated photoluminescence properties of afterglow zirconia (ZrO2) by pulsed near-infrared (NIR) light irradiation based on the biological temperature. Pulsed light irradiation produced optically stimulated luminescence, followed by afterglow, with the property of repeating 100 times or more. Furthermore, the basic principle of temperature measurement was demonstrated through afterglow decay curve measurements. The use of harmless ZrO2 as a sensing probe and NIR light, which is relatively permeable to living tissues, is expected to realize temperature measurements in the brain and may also facilitate optogenetic treatment.

Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED-J Study.

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

Soluble vascular endothelial growth factor receptor 2 and prognosis in patients with chronic heart failure.

AIMS: Endothelial cell vascular endothelial growth factor receptor 2 (VEGFR-2) plays a pivotal role in angiogenesis, which induces physiological cardiomyocyte hypertrophy via paracrine signalling between endothelial cells and cardiomyocytes. We investigated whether a decrease in circulating soluble VEGFR-2 (sVEGFR-2) levels is associated with poor prognosis in patients with chronic heart failure (HF). METHODS AND RESULTS: We performed a multicentre prospective cohort study of 1024 consecutive patients with HF, who were admitted to hospitals due to acute decompensated HF and were stabilized after initial management. Serum levels of sVEGFR-2 were measured at discharge. Patients were followed up over 2 years. The outcomes were cardiovascular death, all-cause death, major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death and HF hospitalization, and HF hospitalization. The mean age of the patients was 75.5 (standard deviation, 12.6) years, and 57% were male. Patients with lower sVEGFR-2 levels were older and more likely to be female, and had greater proportions of atrial fibrillation and anaemia, and lower proportions of diabetes, dyslipidaemia, and HF with reduced ejection fraction (<40%). During the follow-up, 113 cardiovascular deaths, 211 all-cause deaths, 350 MACE, and 309 HF hospitalizations occurred. After adjustment for potential clinical confounders and established biomarkers [N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein], a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death [hazard ratio (HR), 1.79; 95% confidence interval (CI), 1.16-2.74] and all-cause death (HR, 1.43; 95% CI, 1.04-1.94), but not with MACE (HR, 1.11; 95% CI, 0.86-1.43) or HF hospitalization (HR, 1.03; 95% CI, 0.78-1.35). The stratified analyses revealed that a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death (HR, 1.76; 95% CI, 1.07-2.85) and all-cause death (HR, 1.49; 95% CI, 1.03-2.15) in the high-NT-proBNP group (above the median), but not in the low-NT-proBNP group. Notably, the patients with high-NT-proBNP and low-sVEGFR-2 (below the 25th percentile) had a 2.96-fold higher risk (95% CI, 1.56-5.85) for cardiovascular death and a 2.40-fold higher risk (95% CI, 1.52-3.83) for all-cause death compared with those with low-NT-proBNP and high-sVEGFR-2. CONCLUSIONS: A low sVEGFR-2 value was independently associated with cardiovascular death and all-cause death in patients with chronic HF. These associations were pronounced in those with high NT-proBNP levels.

Temperature dependence of afterglow in zirconia and its optically-stimulated luminescence by bone-through irradiation for biological temperature probe.

Development of minimally invasive and site-selective biological temperature sensing is quite important in medical field. This study presents a novel temperature sensing technique based on afterglow and optically-stimulated luminescence (OSL). The dependence of afterglow photoluminescent intensity on the environmental temperature of zirconia (ZrO2) phosphor is examined to validate its use as a sensing probe. In addition, assuming the measurement in deep-part of human body, we have applied the information gathered from our validation to observe OSL from the ZrO2 by irradiation with near-infrared laser through a bone sample. This study demonstrates an alternative medical application of phosphor, and introduces an elemental-technology for the temperature sensing.

Impact of Smoking Status on Growth Differentiation Factor 15 and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study.

Background Whether circulating growth differentiation factor 15 (GDF-15) levels differ according to smoking status and whether smoking modifies the relationship between GDF-15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF-15 and the impact of smoking status on the association between GDF-15 and all-cause death. GDF-15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF-15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log-transformed GDF-15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF-15. The prognostic value of GDF-15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

Distinct Characteristics of VEGF-D and VEGF-C to Predict Mortality in Patients With Suspected or Known Coronary Artery Disease.

Background VEGF-D (vascular endothelial growth factor D) and VEGF-C are secreted glycoproteins that can induce lymphangiogenesis and angiogenesis. They exhibit structural homology but have differential receptor binding and regulatory mechanisms. We recently demonstrated that the serum VEGF-C level is inversely and independently associated with all-cause mortality in patients with suspected or known coronary artery disease. We investigated whether VEGF-D had distinct relationships with mortality and cardiovascular events in those patients. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The serum level of VEGF-D was measured. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death and major adverse cardiovascular events defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. During the 3-year follow-up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for possible clinical confounders, cardiovascular biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-I, and high-sensitivity C-reactive protein), and VEGF-C, the VEGF-D level was significantly associated with all-cause death and cardiovascular death but not with major adverse cardiovascular events.. Moreover, the addition of VEGF-D, either alone or in combination with VEGF-C, to the model with possible clinical confounders and cardiovascular biomarkers significantly improved the prediction of all-cause death but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within patients over 75 years old. Conclusions In patients with suspected or known coronary artery disease undergoing elective coronary angiography, an elevated VEGF-D value seems to independently predict all-cause mortality.

Sarcomere mechanics in uniform and non-uniform cardiac muscle: a link between pump function and arrhythmias.

Starling's Law and the well-known end-systolic pressure-volume relationship (ESPVR) of the left ventricle reflect the effect of sarcomere length (SL) on stress (sigma) development and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL-[Ca2+]free relationships (sigma-SL-CaR) at submaximal [Ca2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-CaR using a kinetic model where we assumed that the rates of Ca2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C-Ca2+ affinity, XB kinetics or, unitary XB-force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C-Ca2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the sigma-SL-CaR and the time course of twitch-stress as well as the time course of intracellular [Ca2+]i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca2+ waves arise from weakened areas in cardiac muscle. These Ca2+ waves can reversibly be induced in muscle with non-uniform excitation contraction coupling (ECC) by the cycle of stretch and release in the border zone between the damaged and intact regions. Stimulus trains induced propagating Ca2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). These observations suggest the unifying hypothesis that force feedback to Ca2+ binding by Tn-C is responsible for Starling's Law and the ESPVR in uniform myocardium and leads in non-uniform myocardium to a surge of Ca2+ released by the myofilaments during relaxation, which initiates arrhythmogenic propagating Ca2+ release by the SR.

Lamin A/C gene mutations in familial cardiomyopathy with advanced atrioventricular block and arrhythmia.

Lamin A and C proteins, encoded by the lamin A/C gene (LMNA), are inner nuclear membrane proteins predominantly expressed in terminally differentiated cells. Mutations in LMNA can cause various forms of cardiomyopathy with arrhythmia in an autosomal dominant manner. We collected and evaluated the clinical characteristics of unclassified familial cardiomyopathy with advanced AV block and sporadic cases with advanced AV block. Mutation in LMNA was directly screened using the cycle sequencing method in 5 probands of the familial cardiomyopathy and 60 sporadic cases with advanced AV block. In four of the five familial cases (80%), we identified four distinct mutations: two protein-truncation mutations, R225X and 815_818delinsCCAGAC, and two missense mutations, Y259H and R166P. No sporadic cases carried LMNA mutation. Left ventricular end-diastolic diameter (LVEDD) was slightly enlarged in LMNA mutant carriers (123.5 +/- 9.5%) as well as in non-carriers (125.1 +/- 13.3%), while left ventricular fractional shortening (LVFS) was preserved in LMNA mutant carriers (32.3 +/- 4.8%) and non-carriers (37.6 +/- 6.8%). In LMNA mutation carriers, the average age at onset of advanced AV block is significantly lower than that in non-carriers (43.7 +/- 9.5 vs. 65.3 +/- 13 yr., p < 0.01). Ventricular tachycardia, sudden death, and poor prognosis were observed in LMNA mutation carriers. LMNA mutation could cause familial cardiomyopathy with insignificant LV remodeling, early-age onset of advanced AV block, and lethal ventricular arrhythmia. Screening of LMNA mutation might be beneficial for risk stratification and clinical management of this type of unclassified familial cardiomyopathy.

Impaired glucose tolerance and albuminuria in patients with chronic heart failure: a subanalysis of the SUPPORT trial.

AIMS: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with ß-blockers and/or angiotensin-converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all-cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with ß-blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14-4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35-1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17-3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1-year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39-38.98, P = 0.019). CONCLUSIONS: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF.

Sarcomere mechanics in uniform and nonuniform cardiac muscle: a link between pump function and arrhythmias.

Starling's law and the end-systolic pressure-volume relationship (ESPVR) reflect the effect of sarcomere length (SL) on the development of stress (sigma) and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to that of skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL -[Ca2+](free) relationships (sigma-SL-Ca relationships) at submaximal [Ca2+] in intact and skinned trabeculae were similar, although the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-Ca relationship by using a kinetic model assuming that the rates of Tn-C Ca2+ binding and/or cross-bridge (XB) cycling are determined by either the SL, [Ca2+], or sigma. We analyzed the correlation between the model results and steady-state sigma measurements at varied SL at [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that the dominant feedback mechanism is SL-, sigma-, or [Ca2+]-dependent, and that the feedback mechanism regulates Tn-C Ca2+ affinity, XB kinetics, or the unitary XB force. The analysis strongly suggests that the feedback of the number of strong XBs to cardiac Tn-C Ca2+ affinity is the dominant mechanism regulating XB recruitment. Using this concept in a model of twitch-sigma accurately reproduced the sigma-SL-Ca relationship and the time courses of twitch sigma and the intracellular [Ca2+]i. The foregoing concept has equally important repercussions for the nonuniformly contracting heart, in which arrhythmogenic Ca2+ waves arise from weakened areas in the cardiac muscle. These Ca2+ waves can reversibly be induced with nonuniform excitation-contraction coupling (ECC) by the cycle of stretch and release in the border zone between the damaged and intact regions. Stimulus trains induced propagating Ca2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by the sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). Modeling of the response of the cardiac twitch to rapid force changes using the feedback concept uniquely predicts the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. These results are consistent with the hypothesis that a force feedback to Ca2+ binding by Tn-C is responsible for Starling's law and the ESPVR in the uniform myocardium and leads to a surge of Ca2+ released by the myofilaments during relaxation in the nonuniform myocardium, which initiates arrhythmogenic propagating Ca2+ release by the SR.

VEGF-C and Mortality in Patients With Suspected or Known Coronary Artery Disease.

Background The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease. However, the relationships of vascular endothelial growth factor-C ( VEGF -C), a central player in lymphangiogenesis, with mortality and cardiovascular events in patients with suspected or known coronary artery disease are unknown. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The primary predictor was serum levels of VEGF -C. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. During the 3-year follow-up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for established risk factors, VEGF -C levels were significantly and inversely associated with all-cause death (hazard ratio for 1- SD increase, 0.69; 95% confidence interval, 0.60-0.80) and cardiovascular death (hazard ratio, 0.67; 95% confidence interval, 0.53-0.87), but not with major adverse cardiovascular events (hazard ratio, 0.85; 95% confidence interval, 0.72-1.01). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF -C levels further improved the prediction of all-cause death, but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within 1717 patients with suspected coronary artery disease. Conclusions In patients with suspected or known coronary artery disease, a low VEGF -C value may independently predict all-cause mortality.