The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase.

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 ± 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 ± 7.0% over the preceding baseline during saline infusion (P < 0.01), and this was reduced to 26 ± 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 µmol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 ± 3.7% (P = 0.02) and 0.5 ± 2.8% (P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress (r2 = -0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels.NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental-stress/.

Hypoglycemia and Cardiac Arrhythmia; Mechanisms, Evidence Base a nd Current Recommendations.

BACKGROUND: With the use of intensive insulin therapy and insulin secretagogues to optimize glycemic control in diabetes, hypoglycemia continues to present a clinical challenge. Hypoglycemia has been implicated in nocturnal sudden death in type 1 diabetes, and the mechanism underlying this is postulated to be cardiac arrhythmia. OBJECTIVE: This article reviews the evidence surrounding hypoglycemia and cardiac arrhythmia. METHODS: A structured search of the Pubmed bibliographic database was undertaken, and relevant peerreviewed articles on the topic were included in the review. RESULTS: Since the initial description of nocturnal sudden death in type 1 diabetes over twenty years ago, numerous studies have been performed to try and improve our understanding of the effects of hypoglycemia on cardiac rhythm. This includes animal models of diabetes that have permitted valuable insights into the pathophysiology of arrhythmia generation, involving direct effects of hypoglycemia on the cardiac myocyte, effects from sympatho-adrenal activation and a reduced arrhythmia threshold. In humans, the use of tools such as the hypoglycemic clamp or subcutaneous continuous glucose monitoring have helped explore the interaction between hypoglycemia and cardiac rhythm in both controlled and real world settings. Proving a causal link with fatal cardiac arrhythmia is clearly more difficult, as simultaneous monitoring of cardiac rhythm and blood glucose level is rarely performed in this setting. However substantial circumstantial evidence, including that from large randomized clinical trials, exists to support the theoretical risk of arrhythmic death conferred by hypoglycemia. This has reshaped opinion surrounding intensive glucose lowering in patients with diabetes and heart disease, and is reflected in recent international guidelines. CONCLUSION: This article reviews the postulated mechanisms, the extensive evidence base and the current recommendations around hypoglycemia and arrhythmia.

Clinical utility of speckle-tracking echocardiography in cardiac resynchronisation therapy.

Cardiac resynchronisation therapy (CRT) can profoundly improve outcome in selected patients with heart failure; however, response is difficult to predict and can be absent in up to one in three patients. There has been a substantial amount of interest in the echocardiographic assessment of left ventricular dyssynchrony, with the ultimate aim of reliably identifying patients who will respond to CRT. The measurement of myocardial deformation (strain) has conventionally been assessed using tissue Doppler imaging (TDI), which is limited by its angle dependence and ability to measure in a single plane. Two-dimensional speckle-tracking echocardiography is a technique that provides measurements of strain in three planes, by tracking patterns of ultrasound interference ('speckles') in the myocardial wall throughout the cardiac cycle. Since its initial use over 15 years ago, it has emerged as a tool that provides more robust, reproducible and sensitive markers of dyssynchrony than TDI. This article reviews the use of two-dimensional and three-dimensional speckle-tracking echocardiography in the assessment of dyssynchrony, including the identification of echocardiographic parameters that may hold predictive potential for the response to CRT. It also reviews the application of these techniques in guiding optimal LV lead placement pre-implant, with promising results in clinical improvement post-CRT.

Physiological Reduction in Left Ventricular Contractile Function in Healthy Postpartum Women: Potential Overlap with Peripartum Cardiomyopathy.

AIMS: Peripartum cardiomyopathy is a potentially life-threatening cause of heart failure, commoner in Afro-Caribbean than Caucasian women. Its diagnosis can be challenging due to physiological changes in cardiac function that also occur in healthy women during the early postpartum period. This study aimed to (i) establish the overlap between normal cardiac physiology in the immediate postpartum period and pathological changes in peripartum cardiomyopathy ii) identify any ethnicity-specific changes in cardiac function and cardiac biomarkers in healthy postpartum women. METHODS AND RESULTS: We conducted a cross-sectional study of 58 healthy postpartum women within 48 hours of delivery and 18 matched non-pregnant controls. Participants underwent cardiac assessment by echocardiography and strain analysis, including 3D echocardiography in 40 postpartum women. Results were compared with 12 retrospectively studied peripartum cardiomyopathy patients. Healthy postpartum women had significantly higher left ventricular volumes and mass, and lower ejection fraction and global longitudinal strain than non-pregnant controls. These parameters were significantly more impaired in peripartum cardiomyopathy patients but with overlapping ranges of values. Healthy postpartum women had higher levels of adrenomedullin, placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt1) compared to controls. The postpartum state, adrenomedullin, sFlt1 and the sFlt1:PlGF ratio were independent predictors of LV remodelling and function in healthy postpartum women. CONCLUSION: Healthy postpartum women demonstrate several echocardiographic indicators of left ventricular remodelling and reduced function, which are associated with altered levels of angiogenic and cardiac biomarkers.

Impaired neuronal nitric oxide synthase-mediated vasodilator responses to mental stress in essential hypertension.

Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 µmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events.