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Objectives The aim of this study was to determine the impact of invasive approaches and revascularization in patients with cocaine-associated non–ST-segment elevation myocardial infarction (NSTEMI). Background The role of invasive approaches in cocaine-associated NSTEMI is uncertain. Methods This retrospective cohort study identified 3,735 patients with NSTEMI and history of cocaine use from the Nationwide Readmissions Database from 2016 to 2017. Invasive approaches were defined as coronary angiography, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). Revascularization was defined as PCI and CABG. The primary efficacy outcome was major adverse cardiac events (MACE), and the primary safety outcome was emergent revascularization. Nonadherence was identified using appropriate International Classification of Diseases-Tenth Revision codes. Two propensity-matched cohorts were generated (noninvasive vs. invasive and noninvasive vs. revascularization) through multivariate logistic regression. Results In the propensity score–matched cohorts, an invasive approach (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.56 to 0.92; p = 0.008) and revascularization (HR: 0.54; 95% CI: 0.40 to 0.73; p Conclusions Invasive approaches and revascularization for cocaine-associated NSTEMI are associated with lower morbidity. A history of medical nonadherence was not associated with a difference in morbidity but was associated with an increased risk for emergent revascularization with PCI.

Background: No studies assessed impact of atrial flutter (AFL) ablation on outcomes in patients with AFL and concurrent heart failure (HF). Objectives: To assess the effect of AFL ablation on mortality and HF readmissions in patients with AFL and HF. Methods: This retrospective cohort study identified 15,952 patients with AFL and HF from the 2016–17 Nationwide Readmissions Database. The primary outcome was a composite of all-cause mortality and/or HF readmission at 1 year. Secondary outcomes included HF readmission, all-cause mortality, and atrial fibrillation (AF) readmission at 1 year. Propensity score match (1:2) algorithm was used to adjust for confounders. Cox proportional hazard regression was used to generate hazard ratios. Results: Of the 15,952 patients, 9889 had heart failure with reduced ejection fraction (HFrEF) and 6063 had heart failure with preserved ejection fraction (HFpEF). In the matched HFrEF cohort (n = 5421), the primary outcome was significantly lower in patients undergoing ablation (HR 0.72, 95% CI 0.61–0.85, P < .001). HF readmission (HR 0.73, 95% CI 0.61–0.89, P = .001), all-cause mortality (HR 0.62, 95% CI 0.46–0.85, P = .003), and AF readmission (HR 0.63, 95% CI 0.48–0.82, P = .001) were also significantly reduced. In the matched HFpEF cohort (n = 2439), the primary outcome was lower in the group receiving ablation but was not statistically significant (HR 0.80, 95% CI 0.63–1.01, P = .065). Conclusion: In patients with AFL and HFrEF, AFL ablation was associated with lower mortality and HF readmissions at 1 year. Patients with AFL and HFpEF did not show a similar significant reduction in the primary outcome.

Background The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality, not only through devastating lung injury, but also due to multiple malfunctions in the cardiovascular system. The primary aetiology is believed to be mediated through lung alveolar injury; however, a few published reports have linked SARS-CoV-2 to significant organ dysfunction, venous thrombo-embolism, and coagulopathy. In view of the fact that the utility of tissue plasminogen activator in this population is not well studied, we present this case of rapid improvement in oxygenation after successful lytic therapy for thrombus in transit in this patient with SARS-CoV-2. Case summary We discuss a patient admitted with SARS-CoV-2 pneumonia. Due to the development of dramatic hypoxia, he underwent echocardiography which demonstrated extensive thrombus in transit. He received successful thrombolytic therapy with tissue plasminogen activator, with subsequent improvement in oxygenation. The patient was successfully discharged home on 2 L of oxygen via nasal cannula, and continues to improve at follow-up with his cardiologist and primary care physician. Conclusion This case not only highlights embolic causes of hypoxia in SARS-CoV-2, but demonstrates the important utility of an echocardiogram and tissue plasminogen activator in this population.

ObjectivesTo examine the relationship between pericardial fat (PCF) and cardiac structure and function among HIV-infected patients in the sub-Saharan African country of Uganda. People living with HIV (PLHIV) have altered fat distribution and an elevated risk for heart failure. Whether altered quantity and radiodensity of fat surrounding the heart relates to cardiac dysfunction in this population is unknown.MethodsOne hundred HIV-positive Ugandans on antiretroviral therapy were compared with 100 age and sex-matched HIV-negative Ugandans; all were >45 years old with >1 cardiovascular disease risk factor. Subjects underwent ECG-gated non-contrast cardiac CT and transthoracic echocardiography with speckle tracking strain imaging. Multivariable linear and logistic regression models were used to explore the association of PCF with echocardiographic outcomes.ResultsMedian age was 55% and 62% were female. Compared with uninfected controls, PLHIV had lower body mass index (27 vs 30, p=0.02) and less diabetes (26% vs 45%, p=0.005). Median left ventricular (LV) ejection fraction was 67%. In models adjusted for traditional risk factors, HIV was associated with 10.3 g/m2 higher LV mass index (LVMI) (95% CI 3.22 to 17.4; p=0.005), 0.87% worse LV global longitudinal strain (GLS) (95% CI −1.66 to −0.07; p=0.03) and higher odds of diastolic dysfunction (OR 1.96; 95% CI 0.95 to 4.06; p=0.07). In adjusted models, PCF volume was significantly associated with increased LVMI and worse LV GLS, while PCF radiodensity was associated with worse LV GLS (all pConclusionsIn Uganda, HIV infection, PCF volume and density are associated with abnormal cardiac structure and function.

Pericarditis is a rare but debilitating complication of cytarabine therapy. While echocardiography can aid with the diagnosis, cardiac MRI has superior accuracy in establishing the diagnosis. In this case, we describe a 65-year-old patient receiving cytarabine as part of induction chemotherapy for acute myeloid leukemia who developed acute pericarditis. Her cardiac MRI revealed pericardial edema on T2-weighted STIR imaging and pericardial late gadolinium enhancement which confirmed the diagnosis.

Accurate identification of left ventricular masses (LVM) can be challenging, and if incorrect, may have devastating consequences. While transthoracic echocardiography is often the first test to identify intracardiac masses, cardiac MRI (CMRI) allows for better anatomical definition and tissue characterisation. We present a case of a 51-year-old man who presented with 4 weeks of shortness of breath, found on echocardiogram to have severely reduced LV function and a 2.5×4.0 cm LVM with a hypolucent/cystic core. Due to the unusual appearance, CMRI was required for confirmation of an LV thrombus. This case highlights the importance of multimodality imaging in the discovery and identification of LVM.

Background: Transcatheter aortic valve replacement (TAVR) may be an effective option for high-risk AR patients. Although international experiences of TAVR for AR are published, U.S. data is limited. The primary objective of this study was to investigate periprocedural and 30-days outcomes in terms of mortality and post-procedural complications in patients undergoing TAVR for AR using large national U.S. databases. Hypothesis: TAVR is a promising option in AR Methods: Study cohorts were derived from Nationwide Inpatient Sample (NIS) and Nationwide Readmissions Database (NRD) 2016-17. TAVR and AR were identified using ICD-10-CM-codes. The key outcomes were all-cause mortality, disabling stroke, valvular complications, complete heart block (CHB)/ permanent pacemaker placement (PPM), open heart surgery, acute kidney injury (AKI) requiring dialysis, and vascular complications. Multivariate logistic regression was used to adjust for confounders. Results: 915 patients from the NIS (male-71%, age 65-84.2%) and 822 patients from the NRD (male-69.3%, age 65-80.5%) underwent TAVR for AR. The median length of stay (LOS) was 4 days for both cohorts. In-hospital mortality was 2.7% in NIS and 30-day mortality was 3.3% in NRD. Disabling strokes were noted in 0.6% peri-procedurally and 1.8% at 30-days. Valve-related complications were 18-19% with paravalvular leak being the most common. Approximately 11% of patients developed CHB and/or needed PPM in both cohorts. In NRD, 2.2% of patients required dialysis for AKI, 1.5% developed vascular complications, and 0.6% required open-heart surgery within 30-days post-procedure. Anemia was predictive of increased overall complications and valvular complications, whereas, peripheral vascular disease was predictor of increased valvular complications and CHB/PPM. Conclusion: TAVR is a promising option in AR. Further studies are necessary for the expansion of TAVR as standard treatment in AR.

Introduction: Impact of an invasive approach in patients with cocaine associated non-ST-elevation myocardial infarction (CANSTEMI) is unknown. Hypothesis: To determine the effects of an invasive approach on patients with CANSTEMI. Methods: Nationwide Readmissions Database (NRD) from years 2016-2017 was utilized for hypothesis. We utilized ICD-10 CM codes I21.4 in primary diagnosis field and F14 in secondary fields to identify CANSTEMI. Coronary angiogram (CA) with or without percutaneous coronary intervention (PCI) was considered an invasive approach. The primary outcome was a composite of major adverse cardiac events (MACE) at one year. Secondary outcomes included all-cause mortality, MI readmission, stroke readmission, and emergent revascularization at one year. Cox-Proportional Hazard regression was used to adjust for demographic and comorbid confounders. Results: A total of 7,372 patients were identified of which 4,332 (58.8%) underwent invasive treatment. Patients with obesity, hyperlipidemia, tobacco use, and a personal and family history of CAD were more likely to undergo an invasive approach. Conversely, patients with CKD stage 3 or more and anemia were less likely to undergo invasive treatment. The primary outcome was significantly reduced with an invasive approach compared to a non-invasive approach. Similarly, all-cause mortality and MI readmission were also significantly reduced with an invasive approach. An invasive approach was associated with increased emergent revascularization compared to a noninvasive approach. On further stratification of an invasive approach, CA and PCI both were individually associated with improved MACE outcomes and PCI only was associated with increased emergent revascularization. Conclusions: In conclusion, an invasive approach with CA with or without PCI for CANSTEMI was associated with reductions in morbidity and mortality. PCI only was associated with an increase in emergent revascularization.

Aim Human Immunodeficiency Virus (HIV) patients commonly experience dyspnea for which an immediate cause may not be always apparent. In this prospective cohort study of HIV patients with exercise limitation, we use cardiopulmonary exercise testing (CPET) coupled with exercise cardiovascular magnetic resonance (CMR) to elucidate etiologies of dyspnea. Methods and results Thirty-four HIV patients on antiretroviral therapy with dyspnea and exercise limitation (49.7 years, 65% male, mean absolute CD4 count 700) underwent comprehensive evaluation with combined rest and maximal exercise treadmill CMR and CPET. The overall mean oxygen consumption (VO2) peak was reduced at 23.2 ± 6.9 ml/kg/min with 20 patients (58.8% of overall cohort) achieving a respiratory exchange ratio > 1. The ventilatory efficiency (VE)/VCO2 slope was elevated at 36 ± 7.92, while ventilatory reserve (VE: maximal voluntary ventilation (MVV)) was within normal limits. The mean absolute right ventricular (RV) and left ventricular (LV) contractile reserves were preserved at 9.0% ± 11.2 and 9.4% ± 9.4, respectively. The average resting and post-exercise mean average pulmonary artery velocities were 12.2 ± 3.9 cm/s and 18.9 ± 8.3 respectively, which suggested lack of exercise induced pulmonary artery hypertension (PAH). LV but not RV delayed enhancement were identified in five patients. Correlation analysis found no relationship between peak VO2 measures of contractile RV or LV reserve, but LV and RV stroke volume correlated with PET CO2 (p = 0.02, p = 0.03). Conclusion Well treated patients with HIV appear to have conserved RV and LV function, contractile reserve and no evidence of exercise induced PAH. However, we found evidence of impaired ventilation suggesting a non-cardiopulmonary etiology for dyspnea.

This review examines the current status of measuring left atrial mechanical functions and the ability of atrial functional analysis to predict cardiovascular outcomes. Increasing data support the use of echocardiography, computed tomography, and cardiac magnetic resonance in this regard. This review will discuss the various techniques used to assess left atrium reservoir, conduit, and booster pump functions and will focus on their ability to predict cardiovascular events in general and referral populations, and in patients with atrial fibrillation and other heart diseases.

Prolylcarboxypeptidase (PRCP) is a carboxypeptidase that cleaves angiotensin II (AngII) forming Ang(1-7). The impact of genetic PRCP deficiency on AngII metabolism, blood pressure (BP), kidney histology, and cardiac phenotype was investigated in two lines of PRCP-deficient mice: KST302 derived in C57BL/6 background and GST090 derived in FVB/N background. The GST090 line had increased mean arterial pressure (MAP) (113.7 ± 2.07 vs. WT 105.0 ± 1.23 mmHg; p 0.01) and left ventricular hypertrophy (LVH) (ratio of diastolic left ventricular posterior wall dimension to left ventricular diameter 0.239 ± 0.0163 vs. WT 0.193 ± 0.0049; p 0.05). Mice in the KST302 line also had mild hypertension and LVH. Cardiac defects, increased glomerular size, and glomerular mesangial expansion were also observed. After infusion of AngII to mice in the KST302 line, both MAP and LVH increased, but the constitutive differences between the gene trap mice and controls were no longer observed. Plasma and cardiac AngII and Ang(1-7) were not significantly different between PRCP-deficient mice and controls. Thus, PRCP deficiency is associated with elevated blood pressure and cardiac alterations including LVH and cardiac defects independently of systemic or cardiac AngII and Ang(1-7). An ex vivo assay showed that recombinant PRCP, unlike recombinant ACE2, did not degrade AngII to form Ang(1-7) in plasma at pH 7.4. PRCP was localized in α-intercalated cells of the kidney collecting tubule. The low pH prevailing at this site and the acidic pH preference of PRCP suggest a role of this enzyme in regulating AngII degradation in the collecting tubule where this peptide increases sodium reabsorption and therfore BP. However, there are other potential mechanisms for increased BP in this model that need to be considered as well. PRCP converts AngII to Ang(1-7) but only at an acidic pH. Global PRCP deficiency causes heart and kidney alterations and a moderate rise in BP. PRCP is abundant in the kidney collecting tubules, where the prevailing pH is low. In collecting tubules, PRCP deficiency could result in impaired AngII degradation. Increased AngII at this nephron site stimulates Na reabsorption and increases BP.Prolylcarboxypeptidase (PRCP) converts AngII to Ang (1-7) but only at an acidic pH. Global PRCP deficiency causes heart and kidney alterations and a moderate rise in BP. PRCP is abundant in the kidney collecting tubules, where the prevailing pH is low. In collecting tubules, PRCP deficiency could result in impaired AngII degradation. Increased AngII at this nephron site stimulates Na reabsorption and increases BP.

Background Pulmonary arterial hypertension (PAH) is a potentially serious cause of dyspnea and exercise limitation in patients with HIV infection. In this trial, we propose using exercise MRI in conjunction with cardiopulmonary testing to delineate PAH from other causes of cardiovascular dysfunction, identify individuals with exercise-induced PAH who are at high risk of developing resting PAH, and provide longitudinal estimates of progression of PAH and right ventricular function. Methods In this prospective observational study, HIV patients with dyspnea and exercise limitation in the absence of identifiable causes and those who meet the inclusion criteria will be enrolled based on resting pulmonary artery pressure (≤ or >40 mmHg) on a screening echocardiogram and exercise limitation on the Modified Medical Research Council dyspnea scale. Patients without evidence of resting PAH will be enrolled into both rest and exercise MRI and cardiopulmonary testing protocol, whereas patients with evidence of PAH on resting echocardiograms will undergo only resting cardiac MRI studies to evaluate right ventricular function and fibrosis. Both patient subgroups will be followed for 24 months to obtain longitudinal progression of the disease. In a sub-study, we will further analyze inflammatory variables that may predict these changes, thus allowing early identification of these patients. Implications and conclusions This trial will be the first study to provide an understanding of the mechanisms underpinning the functional deterioration of the right ventricle in patients with HIV and will impart insight into the immune mediators of PAH progression and right ventricular functional deterioration in patients with HIV-PAH.

> Form follows function—this has been misunderstood. Form and function should be one, joined in a spiritual union. > > —Frank Lloyd Wright Left atrial (LA) remodeling refers to the spectrum of pathophysiological changes in atrial structure and mechanical function and the electric, ionic, and molecular milieu of the LA that most often occurs in response to stresses imposed by conditions such as hypertension, heart failure, diabetes mellitus, and obesity. Remodeling is initially adaptive, but when it occurs in response to a chronic pathological stimulus (as opposed to remodeling of the athlete’s heart), it often becomes maladaptive and associated with an increased risk of cardiovascular events and mortality.1 Remodeling forms the basis of atrial cardiomyopathy, defined recently by a multisociety, expert consensus statement as any complex of structural, architectural, contractile, or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations.2 See Article by Oliver et al LA structural remodeling is the complex phenotypic expression that results from changes in LA size, shape,3 and architecture and alterations in the cardiomyocyte, fibroblast, and noncollagen infiltrative compartments of the atrium.2 LA enlargement, which is simple to measure, is the default clinical hallmark of structural remodeling that occurs most often in response to LA pressure and volume overload; in the absence of atrial fibrillation, mitral valvular disease, and high cardiac output states, it is an excellent biomarker for the presence and severity of left ventricular (LV) diastolic dysfunction.4 Moreover, LA enlargement portends a poor prognosis in a variety of cardiovascular diseases.1 Indices of LA size are also markers of cardiovascular risk in the general population.5,6 The strength of the association between atrial remodeling as determined by increased maximal indexed LA volume (LAVi) and cardiovascular risk reported in the literature is influenced by the nature …

The author examines the ability of left atrial size and function to predict cardiovascular outcomes. Data are sufficient to recommend evaluation of left atrial volume in certain populations, and although analysis of atrial reservoir, conduit, and booster pump function trails in that regard, the gap is rapidly closing. In this state-of-the-art paper, the author reviews the methods used to assess left atrial size and function and discusses their role in predicting cardiovascular events in general and referral populations and in patients with atrial fibrillation, cardiomyopathy, ischemic heart disease, and valvular heart disease.

Aims The transcription factor hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) regulates myocardial vascularization and growth during cardiogenesis. Our aim was to determine whether HEXIM1 also has a beneficial role in modulating vascularization, myocardial growth, and function within the adult heart. Methods and results To achieve our objective, we created and investigated a mouse line wherein HEXIM1 was re-expressed in adult cardiomyocytes to levels found in the foetal heart. Our findings support a beneficial role for HEXIM1 through increased vascularization, myocardial growth, and increased ejection fraction within the adult heart. HEXIM1 re-expression induces angiogenesis, that is, essential for physiological hypertrophy and maintenance of cardiac function. The ability of HEXIM1 to co-ordinate processes associated with physiological hypertrophy may be attributed to HEXIM1 regulation of other transcription factors (HIF-1-α, c-Myc, GATA4, and PPAR-α) that, in turn, control many genes involved in myocardial vascularization, growth, and metabolism. Moreover, the mechanism for HEXIM1-induced physiological hypertrophy appears to be distinct from that involving the PI3K/AKT pathway. Conclusion HEXIM1 re-expression results in the induction of angiogenesis that allows for the co-ordination of tissue growth and angiogenesis during physiological hypertrophy.

Background: Conflicting evidence exists on the ideal choice of non-invasive pharmacologic stress imaging for coronary artery disease (CAD) diagnosis in patients with left bundle branch block (LBBB). The aim of this meta-analysis is to compare data that examine the sensitivity and specificity of non-invasive pharmacologic stress imaging in patients with LBBB for obstructive CAD diagnosis. Methods: We performed a literature search in MEDLINE, embase.com and Cochrane (CENTRAL) without publication type or language restrictions. Both pharmacologic stress echocardiography (SE) and nuclear myocardial perfusion imaging (MPI) searches were restricted to the period between January 2004 and review time. Exclusion criteria included studies that lacked sensitivity and specificity data. The primary objective was to compare the sensitivities and specificities of all pharmacologic SE, MPI, myocardial contrast echocardiography (MCE), stress cardiac magnetic resonance (CMR) and positron emission tomography (PET) for identifying significant CAD in patients with LBBB. Results: 10 studies met the inclusion criteria for analysis. The sensitivity and specificity odds ratio of MCE was 92% (95% CI 81-97%), 93% (95% CI 86- 97%); Dobutamine (D)-CMR 64% (95% CI 42-82%), 94% (95% CI 85-98%); pharmacologic SE 73% (95% CI 55-86%), 84% (95% CI 75-91%); and pharmacologic MPI 83% (95% CI 72-91%), 56% (95% CI 42-70%). Conclusion: MCE and D-CMR appear to have improved diagnostic accuracy in comparison to pharmacologic SE and MPI in patients with LBBB. Additional MCE and D-CMR studies are warranted given their potential to become the non-invasive gold standard for the diagnosis of CAD in this population.

Background— Decreased expression of cardiac myosin binding protein C (cMyBPC) as a result of genetic mutations may contribute to the development of hypertrophic cardiomyopathy (HCM); however, the mechanisms that link cMyBPC expression and HCM development, especially contractile dysfunction, remain unclear. Methods and Results— We evaluated cardiac mechanical function in vitro and in vivo in young mice (8–10 weeks of age) carrying no functional cMyBPC alleles (cMyBPC −/− ) or 1 functional cMyBPC allele (cMyBPC ± ). Skinned myocardium isolated from cMyBPC −/− hearts displayed significant accelerations in stretch activation cross-bridge kinetics. Cardiac MRI studies revealed severely depressed in vivo left ventricular (LV) magnitude and rates of LV wall strain and torsion compared with wild-type (WT) mice. Heterozygous cMyBPC ± hearts expressed 23±5% less cMyBPC than WT hearts but did not display overt hypertrophy. Skinned myocardium isolated from cMyBPC ± hearts displayed small accelerations in the rate of stretch induced cross-bridge recruitment. MRI measurements revealed reductions in LV torsion and circumferential strain, as well reduced circumferential strain rates in early systole and diastole. Conclusions— Modest decreases in cMyBPC expression in the mouse heart result in early-onset subtle changes in cross-bridge kinetics and in vivo LV mechanical function, which could contribute to the development of HCM later in life.

Objective Pulmonary arterioles respond to hypoxia with constriction that raises vascular resistance and pulmonary artery blood pressure. The response is sustained indefinitely by the chronic hypoxia of high-altitude residence among highlanders of European and Andean descent, but not Tibetans. The objective of this study was to identify the consequences of lifelong hypoxia exposure for the pulmonary vasculature among Amhara high-altitude natives from Ethiopia. Methods A three-way static group comparison tested for the effect of Amhara ancestry and high residence altitude on pulmonary hemodynamics measured using echocardiography in samples of 76 healthy adult Amhara lifelong residents at 3700 m, 54 Amhara lifelong residents at 1200 m, and 46 U.S. low-altitude residents at 282 m. Results Amhara at 3700 m had average Doppler-estimated pulmonary artery systolic pressure (tricuspid regurgitant gradient) of 27.9 ± 8.4 (SD) mm Hg as compared with 21.9 ± 4.0 among Amhara at low altitude and 16.5 ± 3.6 in the U.S. low-altitude reference sample. However, there was no residence altitude effect on pulmonary blood flow or vascular resistance. Amhara ancestry was associated with greater pulmonary artery systolic pressure and pulmonary blood flow, yet lower pulmonary vascular resistance. Conclusions The Amhara at 3700 m had elevated pulmonary artery pressure, but without the elevated pulmonary vascular resistance characteristic of the classic model of the response to long-term hypoxia by the pulmonary vasculature. The elevated pressure among Amhara may be a consequence of high pulmonary blood flow regardless of altitude and represent a newly identified pattern of response. Am. J. Hum. Biol., 2011. © 2010 Wiley-Liss, Inc.

Impaired myocardial contractile function is a hallmark of heart failure (HF), which may present under resting conditions and/or during physiological stress. Previous studies have reported that high fat feeding in mild to moderate HF/left ventricular (LV) dysfunction is associated with improved contractile function at baseline. The goal of this study was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat after infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal chow (NC; 10% kcal fat; Sham + NC and HF + NC groups) or high-fat chow (SAT; 60% kcal saturated fat; Sham + SAT and HF + SAT groups) for 8 wk. Myocardial contractile function was assessed using a Millar pressure-volume conductance catheter at baseline and during inferior vena caval occlusions and dobutamine stress. Steady-state indexes of systolic function, LV +dP/d tmax, stroke work, and maximal power were increased in the HF + SAT group versus the HF + NC group and reduced in the HF + NC group versus the Sham + NC group. Preload recruitable measures of contractility were decreased in HF + NC group but not in the HF + SAT group. β-Adrenergic responsiveness [change in LV +dP/d tmax and change in cardiac output with dobutamine (0–10 μg·kg−1·min−1)] was reduced in HF, but high fat feeding did not further impact the contractile reserve in HF. The contractile reserve was reduced by the high-fat diet in the Sham + SAT group. Microarray gene expression analysis revealed that the majority of significantly altered pathways identified contained multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts but may negatively impact the contractile reserve under nonpathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways revealed promising targets through which high saturated fat potentially mediates cardioprotection in mild to moderate HF/LV dysfunction.

The pericardium is composed of visceral and parietal components. In view of the pericardium's simple structure, pathologic processes involving it are understandably few. However, despite a limited number of clinical syndromes, the pericardium is affected by virtually every category of disease, including infectious, neoplastic, immune-inflammatory, metabolic, iatrogenic, and traumatic. Thus, the recognition of pericardial heart disease remains challenging. Treatment of pericardial disease is also problematic in that there is a paucity of randomized, placebo-controlled trials from which appropriate therapy may be selected and important clinical decisions assisted. This article reviews pericarditis and its sequelae, pericardial effusions, cardiac tamponade and constrictive pericarditis.

Dyspnea and exercise intolerance are common symptoms among patients with HIV. Cardiac magnetic resonance imaging (CMR) has emerged as a versatile tool in the evaluation of cardiovascular disorders including pulmonary arterial hypertension (PAH). We sought to determine the utility of a novel

Previous studies have reported that elevated myocardial lipids in a model of mild-to-moderate heart failure increased mitochondrial function, but did not alter left ventricular function. Whether more prolonged exposure to high dietary lipids would promote a lipotoxic phenotype in mitochondrial and myocardial contractile function has not been determined. We tested the hypothesis that prolonged exposure to high dietary lipids, following coronary artery ligation, would preserve myocardial and mitochondrial function in heart failure. Rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM, HF) or high fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for sixteen weeks. Although high dietary fat was accompanied by myocardial tissue triglyceride accumulation (SHAM 1.47+/-0.14; SHAM+FAT 2.32+/-0.14; HF 1.34+/-0.14; HF+FAT 2.21+/-0.20 micromol/gww), fractional shortening was increased 16% in SHAM+FAT and 28% in HF+FAT compared to SHAM and HF, respectively. Despite increased medium-chain acyl-CoA dehydrogenase (MCAD) activity in interfibrillar mitochondria (IFM) of both SHAM+FAT and HF+FAT, dietary lipids also were associated with decreased state 3 respiration using palmitoylcarnitine (SHAM 369+/-14; SHAM+FAT 307+/-23; HF 354+/-13; HF+FAT 366+/-18 nAO min(-1) mg(-1)) in SHAM+FAT compared to SHAM and HF+FAT. State 3 respiration in IFM also was decreased in SHAM+FAT relative to SHAM using succinate and DHQ. In conclusion, high dietary lipids promoted myocardial lipid accumulation, but were not accompanied by alterations in myocardial contractile function typically associated with lipotoxicity. In normal animals, high dietary fat decreased mitochondrial respiration, but also increased MCAD activity. These studies support the concept that high fat feeding can modify multiple cellular pathways that differentially affect mitochondrial function under normal and pathological conditions.

Background It is not known how carbohydrate and fat intake affect the development of left ventricular (LV) hypertrophy and contractile dysfunction in response to pressure overload. We hypothesized that a low-carbohydrate/high-fat diet prevents LV hypertrophy and dysfunction compared with high-carbohydrate diets. Methods and Results Rats were fed high-carbohydrate diets composed of either starch or sucrose, or a low-carbohydrate/high-fat diet, and underwent abdominal aortic banding (AAB) for 2 months. AAB increased LV mass with all diets. LV end-diastolic and systolic volumes and the ratio of the mRNA for myosin heavy chain β/α were increased with both high-carbohydrate diets but not with the low-carbohydrate/high-fat diet. Circulating levels of insulin and leptin, both stimulants for cardiac growth, were lower, and free fatty acids were higher with the low-carbohydrate/high-fat diet compared with high-carbohydrate diets. Among animals that underwent AAB, LV volumes were positively correlated with insulin and LV mass correlated with leptin. Conclusion A low-carbohydrate/high-fat diet attenuated pressure overload-induced LV remodeling compared with high-carbohydrate diets. This effect corresponded to lower insulin and leptin concentrations, suggesting they may contribute to the development of LV hypertrophy and dysfunction under conditions of pressure overload.

Aims Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure. Methods and results Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high-fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed. Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared with SHAM+FAT and HF, respectively (242 ± 21, 246 ± 21 vs. 183 ± 8, 181 ± 6 and 193 ± 17, 185 ± 16 nAO min−1 mg−1). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1 ± 2.7 vs. HF+FAT, 81.5 ± 5.4 nmoles min−1 mg−1). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +d P /d t max. Conclusion Administration of a high-fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.

Dietary lipid content effects activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and may accelerate cardiac hypertrophy and dysfunction in response to pressure overload. This study investigated the effects of a high-fat diet on the development of cardiac hypertrophy.C57BL/6J mice (n = 14-16/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either standard low-fat diet (STD; 10% fat) or a high-fat diet (HFD; 60% fat) for 16 weeks. Sham mice showed no differences between STD and HFD for heart mass or echocardiographic parameters despite greater plasma free fatty acid and leptin concentrations with HFD. TAC increased heart mass and decreased ejection fraction similarly in both groups. Left ventricular end systolic and diastolic diameters with TAC were increased compared with shams on the HFD (P.05), but were not different from STD TAC mice. High-fat feeding increased expression of PPAR-alpha-regulated genes. The activity of medium chain acyl-coenzyme A dehydrogenase (MCAD), a marker of fatty acid oxidation capacity, was increased in HFD TAC mice compared with STD, consistent with PPAR-alpha activation.Increased fat intake prevented the fall in MCAD activity and did not exacerbate the hypertrophic response to TAC compared with a low-fat diet.

Objective Epidemiological studies suggest that consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFA) decreases the risk of heart failure. We assessed the effects of dietary supplementation with ω-3 PUFA from fish oil on the response of the left ventricle (LV) to arterial pressure overload. Methods Male Wistar rats were fed a standard chow or a ω-3 PUFA-supplemented diet. After 1 week rats underwent abdominal aortic banding or sham surgery ( n =9–12/group). LV function was assessed by echocardiography after 8 weeks. In addition, we studied the effect of ω-3 PUFA on the cardioprotective adipocyte-derived hormone adiponectin, which may alter the pro-growth serine–threonine kinase Akt. Results Banding increased LV mass to a greater extent with the standard chow (31%) than with ω-3 PUFA (18%). LV end diastolic and systolic volumes were increased by 19% and 105% with standard chow, respectively, but were unchanged with ω-3 PUFA. The expression of adiponectin was up-regulated in adipose tissue, and the plasma adiponectin concentration was significantly elevated. Treatment with ω-3 PUFA increased total Akt protein expression in the heart, but decreased the fraction of Akt in the active phosphorylated form, and thus did not alter the amount of active phospho-Akt. Conclusion Dietary supplementation with ω-3 PUFA attenuated pressure overload-induced LV dysfunction, which was associated with elevated plasma adiponectin.

> You can’t prevent what you can’t predict > > –K.M. Mac Aulay Atrial fibrillation (AF) is a global public health problem characterized by dramatically increasing prevalence, significantly associated morbidity and mortality, and ominously spiraling healthcare costs. Thus, the lifetime risk for AF in individuals over the age of 40 in the United States is ≈1 in 4 and the risk of stroke, heart failure, and death is increased in affected individuals.1–5 Although currently estimated to be present in ≈2 million persons, it is expected that as many as 12 million people will have AF by 2050.6 Not surprisingly, AF is responsible for significant US healthcare costs, which are estimated to exceed 6 billion dollars annually.7 Accordingly, identifying the risk factors for the development of AF and strategies to reduce risk and, thereby prevent AF is a high priority of the American Heart Association.8 See Article by Russo et al The established modifiable risk factors for AF include hypertension, diabetes mellitus, previous cardiovascular disease, obesity, and cigarette smoking.9 However, after considering these risk factors, considerable residual risk remains. In the Framingham cohort, hypertension, prevalent heart disease, diabetes mellitus, and cigarette smoking accounted for 44% of the risk in men and 58% of the risk in women.10 In the Atherosclerosis Risk in Communities (ARIC) study, 57% of incident AF cases during a 17-year follow-up could be explained by having at least 1 borderline or elevated risk factor (hypertension, obesity, diabetes mellitus, cigarette smoking, and previous heart disease); the most important contributor was hypertension, which accounted for approximately a quarter of the AF burden.11 A heritable component undoubtedly accounts for some of the residual risk. …

Studies in advanced heart failure show down-regulation of fatty acid oxidation genes, possibly due to decreased expression of the nuclear transcription factors peroxisome proliferator activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha). We assessed mRNA and protein expression of PPARalpha and RXRalpha, and for several PPAR/RXR regulated metabolic proteins at 8 and 20 weeks following myocardial infarction induced by coronary artery ligation. Infarction resulted in heart failure, as indicated by reduced LV fractional shortening and increased end diastolic area compared to sham. There was a progressive increase in LV end systolic area, myocardial ceramide content and atrial natriuretic peptide mRNA, and a deterioration in LV fractional area of shortening from 8 to 20 weeks. Protein and mRNA expression of PPARalpha and RXRalpha were not different among groups. The mRNA for PPAR/RXR regulated genes (e.g. medium chain acyl-CoA dehydrogenase (MCAD)) was down-regulated at 8 and 20 weeks post-infarction; however, neither the protein expression nor activity of MCAD was reduced compared to sham. In conclusion, reduced mRNA expression of PPAR/RXR regulated genes is not dependent on reduced PPAR/RXR protein expression.

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) ( n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC ( P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 ± 0.2 vs. 1.4 ± 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 ± 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 ± 0.05 vs. 0.17 ± 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content ( P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.

Echocardiographic techniques are commonly utilized to describe the rodent cardiovascular phenotype. These approaches are contrasted with other in vivo methods and are positioned in the assay selection process by a review of studies from our laboratory and others. Although not conventionally considered a biomarker, the technique has the potential to be exploited as a marker of intentional or unanticipated toxic biological effects in the preclinical development of drugs and chemicals.

When O2 availability is reduced unavoidably, as it is at high altitude, a potential mechanism to improve O2 delivery to tissues is an increase in blood flow. Nitric oxide (NO) regulates blood vessel diameter and can influence blood flow. This field study of intrapopulation variation at high altitude tested the hypothesis that the level of exhaled NO (a summary measure of pulmonary synthesis, consumption, and transfer from cells in the airway) is directly proportional to pulmonary, and thus systemic, blood flow. Twenty Tibetan male and 37 female healthy, nonsmoking, native residents at 4,200 m (13,900 ft), with an average O2 saturation of hemoglobin of 85%, participated in the study. The geometric mean partial pressure of NO exhaled at a flow of 17 ml/s was 23.4 nmHg, significantly lower than that of a sea-level reference group. However, the rate of NO transfer out of the airway wall was seven times higher than at sea level, which implied the potential for vasodilation of the pulmonary blood vessels. Mean pulmonary blood flow (measured by cardiac index) was 2.7 ± 0.1 (SE) l/min, and mean pulmonary artery systolic pressure was 31.4 ± 0.9 (SE) mmHg. Higher exhaled NO was associated with higher pulmonary blood flow; yet there was no associated increase in pulmonary artery systolic pressure. The results suggest that NO in the lung may play a key beneficial role in allowing Tibetans at 4,200 m to compensate for ambient hypoxia with higher pulmonary blood flow and O2 delivery without the consequences of higher pulmonary arterial pressure.

Echocardiography is widely used in both patient care and clinical research because of its entirely noninvasive nature, versatility, availability, portability, and suitability for serial studies. In clinical trials, echocardiography is used to determine study enrollment eligibility, to measure

Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide (NO)–mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3′ exon produces leucine zipper positive and negative (LZ +/− ) MYPT1 isoforms. Expression of a LZ + MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ +/− MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ +/− MYPT1 isoforms were determined. In control animals, the expression of the LZ + MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30±5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ + MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ + MYPT1 isoform and the sensitivity to 8-Br-cGMP–mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ + MYPT1 isoform.

Background: The bases for the association between sleep-disordered breathing (SDB) and cardiovascular disease are poorly understood. Endothelial dysfunction, assessed with brachial artery ultrasonography, may predict cardiovascular risk and represent preclinical vascular disease. We determined whether flow-mediated dilation (FMD) and peak blood flow (PBF) increase after cuff occlusion is altered with SDB. Methods: 193 participants (58% women) in a cohort study were studied with overnight polysomnography and subsequent brachial artery ultrasonography. SDB was quantified using the apnea-hypopnea index (AHI) and indexes of overnight desaturation and arousal frequency. Two-dimensional and Doppler-velocity measurements of the brachial artery were obtained at baseline and after 5 minutes of upper-arm cuff occlusion. FMD and PBF were defined as the percentage changes from baseline in brachial artery diameter and flow, respectively. Results: In the entire sample, the AHI was inversely associated with both FMD (r = -0.30, P

Background— Matrix metalloproteinase (MMP) and cardiac inhibitor of metalloproteinase (CIMP) are coexpressed in the heart. Although it is known that oxidative stress activates MMP and CIMP inhibits MMP, it is unclear whether CIMP administration attenuates oxidative stress and MMP-mediated cardiac dilatation. Methods and Results— Arteriovenous fistula (AVF) was created in C57BL/J6 mice, and CIMP was administered to AVF and sham mice by protein transfer into peritoneal cavity by minipump for 4 weeks. Mice were grouped as follows: sham; sham+CIMP; AVF; and AVF+CIMP (n=6). In vivo left ventricular (LV) pressure was measured. Plasma and LV tissue levels of CIMP were measured by Western analysis. LV levels of NADPH oxidase activity, marker of oxidative stress, were increased in AVF mice and decreased in AVF mice treated with CIMP. Compared with sham, CIMP was decreased in AVF mice, and CIMP protein transfer increased plasma and LV tissue levels of CIMP in AVF mice; there was no increase in sham animals. In situ zymography demonstrated a robust increase in MMP activity in the hearts from AVF mice compared with sham, and treatment with CIMP decreased MMP activity. In AVF mice, the cardiac pressure-length relationship was similar to that observed in sham mice after administration of CIMP. Contractile responses of normal LV rings were measured in the presence and absence of CIMP. CIMP shifted the pressure-length relationship to the left, attenuated LV dilatation, and had no effect on CaCl 2 -mediated contraction. Conclusions— Treatment of AVF mice with CIMP significantly abrogated the contractile dysfunction and decreased the oxidative stress in volume overload–induced heart failure.

Cardiac dysfunction in AIDS is an important problem. Cocaine is an epidemic associated with sudden death, cardiac dysfunction, and congestive heart failure. Cocaine use and HIV infection frequently coexist in the same patient, yet the combined impact of both is poorly understood. The present study uses cocaine treatment of an established murine AIDS transgenic model (NL4-3Delta gag/pol; TG) to define the combined effects of AIDS and cocaine on cardiac pathophysiology. To determine the effects of cocaine and HIV-1 proteins on mortality, wild-type and NL4-3Delta gag/pol mice received saline or cocaine via continuous infusion by Alzet osmotic pumps for 28 days (chronic). Acute cocaine administration (10 days; 40 mg/kg/day) was used to study the nonlethal effects of cocaine in TGs. Echocardiograms and single time point electrocardiograms were performed at the termination of each experiment. Hearts were removed and examined histopathologically. Chronic cocaine treatment (80 mg/kg/day; 28 days) markedly decreased median survival in both wild-type and TG; however, TG survival was significantly more decreased. In acute studies, TG echocardiographic changes included increased left ventricular mass and increased left ventricular fractional shortening compared with all cohorts. Electrocardiographic changes were absent among the groups. Histopathologically, perivascular fibrosis and interstitial fibrosis were evident in cocaine-treated TG. Data suggest that additive cardiac insults (from AIDS and cocaine) result in combined deleterious effects.

Certainty is the most vivid condition of ignorance and the most necessary condition for knowledge. —Kedar Joshi ([1][1]) Growing interest in left atrial (LA) size is motivated by the recognition of its importance as: 1) a predictor of cardiovascular morbidity and mortality ([2][2]); 2) a

Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process. Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level. Results: NMR analysis revealed a defined alteration in the α-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 μM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to β-adrenergic stimulation. Importantly, a blunted force–frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality. Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB’s regulatory effects on SERCA.

The goal of the study was to determine whether defects in intracellular Ca2+ signaling contribute to cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Depression in cardiac systolic and diastolic function was traced from live diabetic rats to isolated individual myocytes. The depression in contraction and relaxation in myocytes was found in parallel with depression in the rise and decline of intracellular free Ca2+ concentration ([Ca2+]i). The sarcoplasmic reticulum (SR) Ca2+ store and rates of Ca2+ release and resequestration into SR were depressed in diabetic rat myocytes. The rate of Ca2+ efflux via sarcolemmal Na+/Ca2+ exchanger was also depressed. However, there was no change in the voltage-dependent L-type Ca2+ channel current that triggers Ca2+ release from the SR. The depression in SR function was associated with decreased SR Ca2+-ATPase and ryanodine receptor proteins and increased total and nonphosphorylated phospholamban proteins. The depression of Na+/Ca2+ exchanger activity was associated with a decrease in its protein level. Thus it is concluded that defects in intracellular Ca2+ signaling caused by alteration of expression and function of the proteins that regulate [Ca2+]i contribute to cardiomyopathy in STZ-induced diabetic rats. The increase in phospholamban, decrease in Na+/Ca2+ exchanger, and unchanged L-type Ca2+ channel activity in this model of diabetic cardiomyopathy are distinct from other types of cardiomyopathy.

Cited2 is a cAMP-responsive element-binding protein (CBP)/p300 interacting transcriptional modulator and a proposed negative regulator for hypoxia-inducible factor (HIF)-1α through its competitive binding with HIF-1α to CBP/p300. Disruption of the gene encoding Cited2 is embryonic lethal because of defects in the development of heart and neural tube. Morphological and Doppler echocardiographic analyses of Cited2 −/− embryos reveal severe cardiovascular abnormalities, including pulmonic arterial stenosis and ventricular septal defects accompanied by high peak outflow velocities, features of the human congenital cardiac defect termed tetralogy of Fallot. The mRNA levels of several HIF-1α-responsive genes, such as vascular endothelial growth factor (VEGF), Glut1, and phosphoglycerate kinase 1, increased in the Cited2 −/− hearts. The increase of VEGF levels is significant, because defects in the Cited2 −/− embryos closely resemble the major defects observed in the VEGF transgenic embryos. Finally, compared with wild-type, cultured fibroblasts from Cited2 −/− embryos demonstrate an enhanced expression of HIF-1α-responsive genes under hypoxic conditions. These observations suggest that functional loss of Cited2 is responsible for defects in heart and neural tube development, in part because of the modulation of HIF-1 transcriptional activities in the absence of Cited2. These findings demonstrate that Cited2 is an indispensable regulatory gene during prenatal development.