Rapid shifts in circulation and biogeochemistry of the Southern Ocean during deglacial carbon cycle events.

The Southern Ocean plays a crucial role in regulating atmospheric CO2 on centennial to millennial time scales. However, observations of sufficient resolution to explore this have been lacking. Here, we report high-resolution, multiproxy records based on precisely dated deep-sea corals from the Southern Ocean. Paired deep (∆14C and δ11B) and surface (δ15N) proxy data point to enhanced upwelling coupled with reduced efficiency of the biological pump at 14.6 and 11.7 thousand years (ka) ago, which would have facilitated rapid carbon release to the atmosphere. Transient periods of unusually well-ventilated waters in the deep Southern Ocean occurred at 16.3 and 12.8 ka ago. Contemporaneous atmospheric carbon records indicate that these Southern Ocean ventilation events are also important in releasing respired carbon from the deep ocean to the atmosphere. Our results thus highlight two distinct modes of Southern Ocean circulation and biogeochemistry associated with centennial-scale atmospheric CO2 jumps during the last deglaciation.

Anomalously weak Labrador Sea convection and Atlantic overturning during the past 150 years.

The Atlantic meridional overturning circulation (AMOC) is a system of ocean currents that has an essential role in Earth's climate, redistributing heat and influencing the carbon cycle1, 2. The AMOC has been shown to be weakening in recent years 1 ; this decline may reflect decadal-scale variability in convection in the Labrador Sea, but short observational datasets preclude a longer-term perspective on the modern state and variability of Labrador Sea convection and the AMOC1, 3-5. Here we provide several lines of palaeo-oceanographic evidence that Labrador Sea deep convection and the AMOC have been anomalously weak over the past 150 years or so (since the end of the Little Ice Age, LIA, approximately AD 1850) compared with the preceding 1,500 years. Our palaeoclimate reconstructions indicate that the transition occurred either as a predominantly abrupt shift towards the end of the LIA, or as a more gradual, continued decline over the past 150 years; this ambiguity probably arises from non-AMOC influences on the various proxies or from the different sensitivities of these proxies to individual components of the AMOC. We suggest that enhanced freshwater fluxes from the Arctic and Nordic seas towards the end of the LIA-sourced from melting glaciers and thickened sea ice that developed earlier in the LIA-weakened Labrador Sea convection and the AMOC. The lack of a subsequent recovery may have resulted from hysteresis or from twentieth-century melting of the Greenland Ice Sheet 6 . Our results suggest that recent decadal variability in Labrador Sea convection and the AMOC has occurred during an atypical, weak background state. Future work should aim to constrain the roles of internal climate variability and early anthropogenic forcing in the AMOC weakening described here.

Soil disturbance effects on the composition of seed-dispersing ants in roadside environments.

Myrmecochory (the dispersal of seeds by ants) is a significant ecological process in sclerophyll woodlands, but habitat disturbance is known to alter the extent and success of this mutualism. We investigated the influence of soil disturbance on the composition of the seed-dispersing ant community. Surveys were conducted in roadside verges where soils are regularly disturbed by road maintenance activities. Using a 'cafeteria' bait station approach, we selected 24 roads of different widths to investigate ant composition and abundance in relation to soil disturbance. We found ant species richness was greater in non-disturbed than disturbed zones, where road verge width significantly influenced results. The composition and abundance of individual seed-dispersing ant species varied between disturbed and non-disturbed zones. Rhytidoponera metallica were more abundant in non-disturbed sites, whereas Melophorus bruneus and Monomorium rothseini were more frequently recorded in disturbed areas. Commonly found Iridomyrmex purpureus was significantly more abundant in disturbed zones in narrow roadsides and vice versa in wide roadsides, and strongly influenced total community composition. Variation in the abundance of commonly recorded Iridomyrmex and Monomorium genera were related more to site conditions (roadside width and habitat) than soil disturbance. The rich composition of seed dispersing ants in roadside environments, and the effects of soil disturbances on these ant communities that we describe, provide a key insight to important seed dispersal vectors occurring in fragmented rural landscapes.

Screening for Cardiac Magnetic Resonance Scar Features by 12-Lead ECG, in Patients with Preserved Ejection Fraction.

BACKGROUND: Increased QRS score and wide spatial QRS-T angle are independent predictors of cardiovascular mortality in the general population. Our main objective was to assess whether a QRS score ≥ 5 and/or QRS-T angle ≥ 105° enable screening of patients for myocardial scar features. METHODS: Seventy-seven patients of age ≤ 70 years with QRS score ≥ 5 and/or spatial QRS-T angle ≥ 105° as well as left ventricular ejection fraction (LVEF) >35% were enrolled in the study. All participants underwent complete clinical examination, signal-averaged ECG (SAECG), 30-minute ambulatory ECG recording for T-wave alternans (TWA), and late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Relationship between QRS score, QRS-T angle with scar presence and pattern, as well as gray zone, core, and total scar size by LGE-CMR were assessed. RESULTS: Myocardial scar was present in 41 (53%) patients, of whom 19 (46%) exhibited a typical ischemic pattern. QRS score but not QRS-T angle was related to total scar size and gray zone size (R(2) = 0.12, P = 0.002; R(2) = 0.17; P ≤ 0.0001, respectively). Patients with QRS scores ≥ 6 had significantly greater myocardial scar and gray zone size, increased QRS duration and QRS-T angle, a higher prevalence of late potentials (LPs) presence, increased LV end-diastolic volume and decreased LVEF. There was a significant independent and positive association between TWA value and total scar (P = 0.001) and gray zone size (P = 0.01). CONCLUSION: Patients with preserved LVEF and myocardial scar by CMR also have electrocardiographic features that could be involved in ventricular arrhythmogenesis.

Synchronous centennial abrupt events in the ocean and atmosphere during the last deglaciation.

Antarctic ice-core data reveal that the atmosphere experienced abrupt centennial increases in CO2 concentration during the last deglaciation (~18 thousand to 11 thousand years ago). Establishing the role of ocean circulation in these changes requires high-resolution, accurately dated marine records. Here, we report radiocarbon data from uranium-thorium-dated deep-sea corals in the Equatorial Atlantic and Drake Passage over the past 25,000 years. Two major deglacial radiocarbon shifts occurred in phase with centennial atmospheric CO2 rises at 14.8 thousand and 11.7 thousand years ago. We interpret these radiocarbon-enriched signals to represent two short-lived (less than 500 years) "overshoot" events, with Atlantic meridional overturning stronger than that of the modern era. These results provide compelling evidence for a close coupling of ocean circulation and centennial climate events during the last deglaciation.

Number of P-wave fragmentations on P-SAECG correlates with infiltrated atrial fat.

BACKGROUND: Although atrial fibrillation (AF) triggers are known, the underlying AF substrate is less well understood. The goal of our study was to explore correlations between electrophysiological and structural characteristics of atria in patients with paroxysmal AF and individuals at AF risk. METHODS: Patients in sinus rhythm (N = 90; age 57 ± 10 year; 55 men [63.2%]) with structural heart disease and paroxysmal AF (n = 12 [13%]), or with AF risk factors and LVEF > 35% (n = 78), underwent SAECG and cardiac magnetic resonance study. Interatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. All local P-wave extrema were identified on SAECG leads during sinus rhythm. A P-wave fragmentation (Pf) was defined as an absolute difference between adjacent extrema which was above three standard deviations of noise, and was normalized by the duration of the P wave in the corresponding lead. RESULTS: The Pf was greater on the filtered than on the unfiltered P-SAECG signal (13.1 ± 3.8 vs. 3.4 ± 1.2; P < 0.0001). Pf was the greatest on the Y lead (13.0 ± 3.5 on Y lead vs. 12.1 ± 3.4 on Z lead; P = 0.003. Pf on Z lead correlated with interatrial fat index (r = 0.544; P = 0.001). Epicardial fat significantly correlated with body mass index (BMI; r = 0.302; P = 0.015). After adjustment for BMI, left atrium (LA) size, epicardial fat, and interatrial septum width, interatrial fat independently associated with the Pf on Z lead (ß-coefficient 0.009 [95%CI 0.0003-0.019]; P = 0.043). CONCLUSIONS: Infiltrated atrial fat correlates with discontinuous conduction on posterior LA wall and represents AF early substrate.

Infiltrated atrial fat characterizes underlying atrial fibrillation substrate in patients at risk as defined by the ARIC atrial fibrillation risk score.

BACKGROUND: It is known that expanded epicardial fat is associated with atrial fibrillation (AF). However, infiltrated intraatrial fat has not been previously quantified in individuals at risk as determined by the ARIC AF risk score. METHODS: Patients in sinus rhythm (N=90, age 57 ± 10 years; 55 men [63.2%]), in 3 groups at risk of AF as determined by the ARIC AF risk score [low (≤ 11 points; n=15), moderate (12-18 points; n=40), high (≥ 19 points; n=23) risk of AF], and paroxysmal AF (n=12) underwent cardiac magnetic resonance study. Intraatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. OsiriX DICOM viewer (Geneva, Switzerland) was used to quantify the intraatrial fat area. Width of the cephalad portion of the interatrial septum was measured at the level of the fossa ovalis. RESULTS: Intraatrial fat monotonically increased with growing AF risk in study groups (low AF risk 16 ± 4 vs. moderate AF risk 32 ± 18 vs. high AF risk 81 ± 83 mm(2); ANOVA P=0.012). Log-transformed intraatrial fat predicted ARIC AF risk score in multivariate ordered probit regression after adjustment for sex, race, left and right atrial area indices, and body mass index (ß-coefficient 0.50 [95% CI 0.03-0.97]; P=0.037), whereas epicardial fat did not. Interatrial septum width showed similar association (3.0 ± 1.4 vs. 5.0 ± 1.8 vs. 7.1 ± 2.7 mm; ANOVA P<0.001; adjusted ß-coefficient 2.80 [95% CI 1.19-4.41]; P=0.001). CONCLUSIONS: Infiltrated intraatrial fat characterizes evolving substrate in individuals at risk of AF.

Screening entire health system ECG databases to identify patients at increased risk of death.

BACKGROUND: Current methods to identify patients at higher risk for sudden cardiac death, primarily left ventricular ejection fraction ≤35%, miss ≈80% of patients who die suddenly. We tested the hypothesis that patients with elevated QRS-scores (index of myocardial scar) and wide QRS-T angles (index abnormal depolarization-repolarization relationship) have high 1-year all-cause mortality and could be further risk stratified with clinical characteristics. METHODS AND RESULTS: We screened all 12-lead ECGs over 6 months at 2 large hospital systems and analyzed clinical characteristics and 1-year mortality. Patients with ECGs obtained in hospital areas with known high mortality rates were excluded. At the first hospital, QRS-score ≥5 and QRS-T angle ≥105° identified 8.0% of patients and was associated with an odds ratio of 2.79 (95% confidence interval, 2.10-3.69) for 1-year mortality compared with patients below both ECG thresholds (13.9% versus 5.5% death rate). Left ventricular ejection fraction was >35% in 82% of the former group of patients, and addition of ECG measures to left ventricular ejection fraction increased the discrimination of death risk (P<0.0001). At the second hospital, the odds ratio was 2.42 (1.95-3.01) for 1-year mortality (8.8% versus 3.8%). Adjustment for patient characteristics eliminated interhospital differences. Multivariable adjusted odds ratio combining data from both hospitals was 1.53 (1.28-1.83). Increasing heart rate and chronic renal impairment further predicted mortality. CONCLUSIONS: Screening hospital ECG databases with QRS-scoring and QRS-T angle analysis identifies patients with high 1-year all-cause mortality and predominantly preserved left ventricular ejection fraction. This approach may represent a widely available method to identify patients at increased risk of death.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.

BACKGROUND: Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD. METHODS AND RESULTS: We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values <0.01) in the initial study sample. These SNPs were subsequently tested for replication in an independent case-control study sample from the Ore-SUDS (n=688). The association analysis in the replication stage revealed 6 SNPs associated with SCD: CASQ2 region (rs17500488, P=0.04; rs3010396, P=0.007; rs7366407; P=0.04), NOS1AP (rs12084280, P=0.04; rs10918859, P=0.02), and 1 SNP located ≈26 kb upstream of GPD1L (rs9862154, P=0.04). CONCLUSIONS: Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted.

Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome.

OBJECTIVES: We investigated the role of nitric oxide 1 adaptor protein (NOS1AP) as a genetic modifier of long QT syndrome (LQTS). BACKGROUND: LQTS risk stratification is complicated by the phenotype variability that limits prediction of life-threatening arrhythmic events based on available metrics. Thus, the identification of new markers is desirable. Recent studies have shown that NOS1AP variations in the gene modulate QT interval in healthy and 1 LQTS kindred, and occurrence of cardiac events in healthy subjects. METHODS: The study included 901 patients enrolled in a prospective LQTS registry. Three NOS1AP marker SNPs (rs4657139, rs16847548, and rs10494366) were genotyped to assess the effect of variant alleles on QTc and on the incidence of cardiac events. We quantified the association between variant alleles, QTc, and outcomes to assess whether NOS1AP is a useful risk stratifier in LQTS. RESULTS: Variant alleles tagged by SNPs rs4657139 and rs16847548 were associated with an average QTc prolongation of 7 and 8 ms, respectively (p < 0.05; p < 0.01); whereas rs4657139 and rs10494366 were associated with increased incidence of cardiac events (25.2% vs. 18.0%, p < 0.05 and 24.8% vs. 17.8% p < 0.05). Cox multivariate analysis identified rs10494366 minor allele as an independent prognostic marker among patients with QTc <500 ms (hazard ratio: 1.63; 95% confidence interval: 1.06 to 2.5; p < 0.05) but not in the entire cohort. CONCLUSIONS: Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01). CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations.

BACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks. CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.

Sudden cardiac death: The larger problem... The larger genome.

This perspective considers progress in understanding how genetic influences modulate susceptibility to lethal ventricular arrhythmias in cardiac patients and the population at large, as opposed to those with rare inherited arrhythmic conditions, such as the Long-QT and Brugada syndromes. It addresses largely unresolved issues, such as how important these effects may be and what we know of underlying mediators and pathways. Attention is given to newly revealed mechanisms of genomic function and the problem of identifying new susceptibility genes and targets useful in developing improved strategies for sudden death prevention.

Using a state-and-transition approach to manage endangered Eucalyptus albens (White Box) woodlands.

Eucalyptus albens (White Box) woodlands are among the most poorly conserved and threatened communities in Australia. Remnants are under further threat from stock grazing, deteriorating soil conditions, weed invasion, and salinity. There is an urgent need to restore degraded White Box and other woodland ecosystems to improve landscape function. However, there is still a poor understanding of the ecology of degraded woodland ecosystems in fragmented agricultural landscapes, and consequently a lack of precise scientific guidelines to manage these ecosystems in a conservation context. State and Transition Models (STMs) have received a great deal of attention, mainly in rangeland applications, as a suitable framework for understanding the ecology of complex ecosystems and to guide management. We have developed a STM for endangered White Box woodlands and discuss the merits of using this approach for land managers of other endangered ecosystems. An STM approach provides a greater understanding of the range of states, transitions, and thresholds possible in an ecosystem, and provides a summary of processes driving the system. Importantly, our proposed STM could be used to clarify the level of "intactness" of degraded White Box woodland sites, and provide the impetus to manage different states in complementary ways, rather than attempting to restore ecosystems to one pristine stable state. We suggest that this approach has considerable potential to integrate researcher and land manager knowledge, focus future experimental studies, and ultimately serve as a decision support tool in setting realistic and achievable conservation and restoration goals.

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

Thyroid hormone analog, DITPA, improves endothelial nitric oxide and beta-adrenergic mediated vasorelaxation after myocardial infarction.

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3 versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus 3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P < 0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.

Genomics in sudden cardiac death.

Sudden cardiac death (SCD) remains a public health problem of major magnitude. Contrary to earlier expectations, and despite decreased overall cardiac mortality, SCD rates appear to be rising in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. With the exception of the implantable defibrillator, there are few effective approaches to SCD prevention and even fewer clues concerning patient phenotypes predisposed to life-threatening arrhythmias. Clinical variables such as ejection fraction predict mortality but are not sensitive enough to identify many high SCD risk patients. The predictive power of autonomic dysregulation and markers such as lipid levels, hypertension, diabetes, and smoking is quite low in subclinical heart disease, the population in which the majority of SCDs occur. This review addresses advances in genomic science applicable to the SCD public health problem in both rare and common forms of heart disease. These include novel bioinformatic approaches to both identify candidate genes/pathways and identify previously unknown functional genetic elements, as well as methods to comprehensively screen these elements. We also discuss the possibility of applying high-density genome-wide SNP analyses to examine genetic contributions to arrhythmia susceptibility in community-based, case-control studies of common forms of SCD. The development of novel strategies to identify contributors to susceptibility in common cardiac phenotypes is most likely to lead to new and relevant therapeutic targets for SCD.

Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure.

Thyroid hormone has unique actions that make it a novel and possibly useful agent for treatment of heart failure. Because of potential adverse effects of thyroid hormone, however, there has been interest in developing analogues with fewer undesirable side effects. Screening of compounds structurally related to levothyroxine identified 3,5-diiodothyropropionic acid (DITPA) as an analogue with inotropic selectivity and low metabolic activity in hypothyroid rats. When DITPA was administered alone or in combination with captopril in rat and rabbit postinfarction models of heart failure, cardiac output was increased and left ventricular end-diastolic pressure (LV EDP) was decreased without increasing heart rate. A pilot clinical study was undertaken to evaluate the safety and efficacy of DITPA. In a dose-ranging study in 7 normal volunteers the drug was well tolerated. A double-blind comparison then was made of DITPA versus placebo in a group of 19 patients with moderately severe heart failure. Patients were randomly assigned to receive either 1.875 mg/kg of DITPA or placebo daily. After 2 weeks the drug was increased to 3.75 mg/kg daily for an additional 2 weeks. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Total serum cholesterol (p = 0.013) and triglycerides (p = 0.005) also were decreased significantly. These results indicate that DITPA is well tolerated and could represent a useful new agent for treatment of congestive heart failure.