Sudden Cardiac Death in the General Population: Can We Improve Risk Stratification and Prevention?

A total of 15 to 20% of deaths worldwide are sudden (within 1 hour of symptom onset). Our ability to predict and prevent sudden cardiac death (SCD) in the general population, in which 85% have no known organic heart disease (OHD) or stable OHD with left ventricular ejection fraction >40%, is limited to poor. The purpose of this commentary is to suggest a new approach to SCD in this population. Oxidative stress is a common thread in development and progression of the major cardiac diseases associated with SCD. It has a profound adverse effect upon heart rate variability (HRV), sympathetic tone (S), and parasympathetic tone (P). Recently, developed technology finally has allowed accurate measures of S and P. Using this technique, the general population can be screened, those at risk for SCD can be identified with a higher degree of success, and preventative measures instituted. For example, in 133 geriatric type 2 diabetics with S and/or P abnormalities upon screening, the potent and natural antioxidant (r)α lipoic acid reduced SCD (relative risk reduction) 43% ( p = 0.0076), mean follow-up 6.31 years. Diabetes mellitus patients have high glycemic oxidative stress. Addressing oxidative stress S and P abnormalities can reduce SCD. S and P screening of the general population will be discussed.

(r)Alpha Lipoic Acid Is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone.

Chronic orthostatic hypotension (OH), affecting 10 to 30% of the elderly, is associated with falls, and increased morbidity and mortality. Current pharmacologic therapy can cause or worsen hypertension and fluid retention. (r)α lipoic acid (ALA), a powerful natural antioxidant, avoids those complications and may assist management of chronic neurogenic orthostatic hypotension (NOH). The purpose of this study is to demonstrate improvement in the symptoms of orthostatic dysfunction with r-ALA, including improved sympathetic (S) and blood pressure (BP) responses to head-up postural change (standing). A cohort of 109 patients with low S tone upon standing was detected using the ANX -3.0, Autonomic Monitor, ANSAR Medical Technologies, Inc., Philadelphia, PA. From the cohort, 29 patients demonstrated NOH (change in (∆) standing BP ≥ -20/-10 mm Hg); 60 patients demonstrated orthostatic intolerance (OI, ∆ standing systolic BP between -6 and -19 mm Hg). These 89 were given ALA orally: either 590 to 788 mg (r)ALA or 867 to 1,500 mg of the less expensive 50 to 50% mixture (r)ALA and inactive (s)ALA. Changes in their S and parasympathetic (P) tone, and BPs, were compared with 20 control patients during mean follow-up of 2.28 years. Nineteen of 29 (66%) NOH patients responded with a ∆ standing BP from -28/-6 mm Hg to 0/+2 mm Hg. Forty of 60 (67%) of patients with OI responded with a ∆ standing BP of -9/+1 mm Hg to +6/+2 mm Hg. Although all patients treated with ALA increased S tone, the ∆ BP depended upon the pretreatment of S tone. Those with the lowest S tone responded the least well. The only treatment side effects were nausea, intolerable in only 5%. Nausea improved with routine gastrointestinal medications. Glucose levels improved in the 28% of patients who were diabetic. Also, resting hypertension improved. Control patients had no ∆ BP and no increase in S tone. (r)ALA improves S-, and BP, responses to head-up postural change, and thereby NOH/OI, in a majority of patients without causing harmful side effects.

Revising the structure of a new eicosanoid from human platelets to 8,9-11,12-diepoxy-13-hydroxyeicosadienoic acid.

Eicosanoids are critical mediators of fever, pain, and inflammation generated by immune and tissue cells. We recently described a new bioactive eicosanoid generated by cyclooxygenase-1 (COX-1) turnover during platelet activation that can stimulate human neutrophil integrin expression. On the basis of mass spectrometry (MS/MS and MS3), stable isotope labeling, and GC-MS analysis, we previously proposed a structure of 8-hydroxy-9,11-dioxolane eicosatetraenoic acid (DXA3). Here, we achieved enzymatic synthesis and 1H NMR characterization of this compound with results in conflict with the previously proposed structural assignment. Accordingly, by using LC-MS, we screened autoxidation reactions of 11-hydroperoxy-eicosatetraenoic acid (11-HpETE) and thereby identified a candidate sharing the precise reverse-phase chromatographic and MS characteristics of the platelet product. We optimized these methods to increase yield, allowing full structural analysis by 1H NMR. The revised assignment is presented here as 8,9-11,12-diepoxy-13-hydroxyeicosadienoic acid, abbreviated to 8,9-11,12-DiEp-13-HEDE or DiEpHEDE, substituted for the previous name DXA3 We found that in platelets, the lipid likely forms via dioxolane ring opening with rearrangement to the diepoxy moieties followed by oxygen insertion at C13. We present its enzymatic biosynthetic pathway and MS/MS fragmentation pattern and, using the synthetic compound, demonstrate that it has bioactivity. For the platelet lipid, we estimate 16 isomers based on our current knowledge (and four isomers for the synthetic lipid). Determining the exact isomeric structure of the platelet lipid remains to be undertaken.

Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE1 Series EP4 Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE1 Analog (KMN-159) as a Potent EP4 Agonist.

A series of small-molecule full agonists of the prostaglandin E2 type 4 (EP4) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.

Ranolazine Therapy Reduces Non-ST-Segment-Elevation Myocardial Infarction and Unstable Angina in Coronary Disease Patients with Angina.

High sympathetic tone and cardiac autonomic neuropathy (CAN) are associated with major adverse cardiac events (MACE). We have shown ranolazine (RAN) improves autonomic function. RAN was introduced to 51 successive anginal CD patients (RANCD). A control group of 54 successive nonanginal CD patients (NORANCD) continued baseline therapy. Mean study duration was 6.1 years, which included semi-annual autonomic function measures (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA) and yearly myocardial perfusion SPECT studies (MPI). MACE were experienced by 29% RANCD patients versus 46% NORANCD patients (p = 0.0105). The patients from both groups with abnormal parasympathetic and sympathetic (P&S) measures and MACE totaled 52 of those patients with MACE versus 17% of those patients without MACE (p = 0.0274). Abnormal MPI was demonstrated in 35% of those with abnormal (P&S) measures and MACE versus 12% without MACE. Sympathovagal balance (SB) was lower, indicating higher, relative parasympathetic tone (known to be cardioprotective) in the RANCD group. Acute coronary syndromes occurred 4.5 times as often in NORANCD patients. High SB occur more frequently than abnormal MPI in CD patients experiencing MACE. In addition to increased myocardial blood flow as its proposed mechanism of angina relief, RAN improves P&S measures, a potentially new mechanism whereby RAN improves outcomes.

Cardiac autonomic testing and treating heart disease. "A clinical perspective".

BACKGROUND: Coronary heart disease (CHD) is a major health concern, affecting nearly half the middle-age population and responsible for nearly one-third of all deaths. Clinicians have several major responsibilities beyond diagnosing CHD, such as risk stratification of patients for major adverse cardiac events (MACE) and treating risks, as well as the patient. This second of a two-part review series discusses treating risk factors, including autonomic dysfunction, and expected outcomes. METHODS: Therapies for treating cardiac mortality risks including cardiovascular autonomic neuropathy (CAN), are discussed. RESULTS: While risk factors effectively target high-risk patients, a large number of individuals who will develop complications from heart disease are not identified by current scoring systems. Many patients with heart conditions, who appear to be well-managed by traditional therapies, experience MACE. Parasympathetic and Sympathetic (P&S) function testing provides more information and has the potential to further aid doctors in individualizing and titrating therapy to minimize risk. Advanced autonomic dysfunction (AAD) and its more severe form cardiovascular autonomic neuropathy have been strongly associated with an elevated risk of cardiac mortality and are diagnosable through autonomic testing. This additional information includes patient-specific physiologic measures, such as sympathovagal balance (SB). Studies have shown that establishing and maintaining proper SB minimizes morbidity and mortality risk. CONCLUSIONS: P&S testing promotes primary prevention, treating subclinical disease states, as well as secondary prevention, thereby improving patient outcomes through (1) maintaining wellness, (2) preventing symptoms and disorder and (3) treating subclinical manifestations (autonomic dysfunction), as well as (4) disease and symptoms (autonomic neuropathy).

Ranolazine improves autonomic balance in heart failure when added to guideline-driven therapy.

BACKGROUND: The effect of ranolazine (RAN) on cardiac autonomic balance in congestive heart failure (CHF) was studied. METHODS: Fifty-four CHF patients were randomized to (1) open-label RAN (RANCHF) added to usual therapy vs. (2) usual therapy (NORANCHF). Parasympathetic and sympathetic (P&S) measurements were taken at baseline and at 12 months. RESULTS: A total of 16/27 (59%) patients in both groups had initially abnormal P&S measures, including high sympathovagal balance (SB), cardiovascular autonomic neuropathy (CAN) or both. High SB normalized in 10/12 (83%) RANCHF patients vs. 2/11 (18%) NORANCHF patients. SB became high in 5/11 (45%) NORANCHF vs. 1/11 (9%) RANCHF patients. CAN improved in 4/6 (67%) RANCHF patients vs. 5/7 (45%) NORANCHF patients. CAN developed in 1/11 (9%) RANCHF vs. 4/11 (36%) NORANCHF patients. Since improved P&S in RANCHF patients seemed independent of improved brain natriuretic peptide and impedance cardiography (BioZ) measurements, 5 day RAN was given to 30 subjects without CHF but with high SB or CAN. P&S improved in 90% of these subjects. CONCLUSIONS: RAN improves unfavorable P&S activity in CHF possibly by a direct effect upon autonomic sodium channels.

Cardiac autonomic testing and diagnosing heart disease. "A clinical perspective".

BACKGROUND: Coronary heart disease (CHD) is a major health concern, affecting nearly half the middle-age population and responsible for nearly one-third of all deaths. Clinicians have responsibilities beyond diagnosing CHD, including risk stratification of patients for major adverse cardiac events (MACE), modifying the risks and treating the patient. In this first of a two-part review, identifying risk factors is reviewed, including more potential benefit from autonomic testing. METHODS: Traditional and non-traditional, and modifiable and non-modifiable risk factors for MACE where compared, including newer risk factors, such as inflammation, carotid intimal thickening, ankle-brachial index, CT calcium scoring, and autonomic function testing, specifically independent measurement of parasympathetic and sympathetic (P&S) activity. RESULTS: The Framingham Heart Study, and others, have identified traditional risk factors for the development of CHD. These factors effectively target high-risk patients, but a large number of individuals who will develop CHD and MACE are not identified. Many patients with CHD who appear to be well-managed by traditional therapies still experience MACE. In order to identify these patients, other possible risk factors have been explored. Advanced autonomic dysfunction, and its more severe form, cardiac autonomic neuropathy, have been strongly associated with an elevated risk of cardiac mortality and are diagnosable through P&S testing. CONCLUSIONS: Independent measures of P&S activity, provides additional information and has the potential to incrementally add to risk assessment. This additional information enables physicians to (1) specifically target more high-risk patients and (2) titrate therapies, with autonomic testing guidance, in order to minimize risk of cardiac mortality and morbidity.

Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure.

BACKGROUND: Ranolazine (RAN) reduces cardiac sodium channel 1.5's late sodium current in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular (LV) function. RAN blocks neuronal sodium channel 1.7, potentially altering parasympathetic and sympathetic (P&S) activity. The effects of RAN on LV ejection fraction (LVEF) and P&S function in CHF were studied. METHODS: Matched CHF patients were given open-label RAN (1000 mg po-bid) added to guideline-driven therapy (RANCHF, 41 systolic, 13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Echocardiographic LVEF and P&S measures were obtained at baseline and follow-up (mean 23.7 months). RESULTS: LVEF increased in 70% of RANCHF patients, an average of 11.3 units. Mean LVEF remained unchanged in NORANCHF patients. P&S measures indicated cardiovascular autonomic neuropathy (P≤0.1 bpm(2)) in 20% of NORANCHF patients at baseline and in 29% at follow-up (increasing in both groups). At baseline, 28% of patients had high sympathovagal balance (SB), RAN normalized SB over 50% of these; in contrast, the NORANCHF group had a 20% increase in patients with high SB. CONCLUSIONS: RAN preserves or improves LVEF and decreases high SB in CHF.

Noninvasive monitoring of the autonomic nervous system and hemodynamics of patients with blunt and penetrating trauma.

BACKGROUND: To describe early effects of sympathetic (SNS) and parasympathetic nervous system (PSNS) activities measured by heart rate (HR) and respiratory rate variabilities simultaneously with noninvasive hemodynamic patterns in patients with blunt and penetrating trauma. METHODS: Descriptive study of 168 monitored trauma patients in a level I university-run trauma service. We studied HR and respiratory rate variability by spectral analysis as a measure of autonomic nervous system (ANS) activity in severe blunt and penetrating injuries beginning shortly after their admission to the emergency department. The low frequency area is the area under the HR spectral analysis curve within the frequency range of 0.04 Hz to 0.10 Hz. This area primarily reflects the tone of the SNS as mediated by the vagus nerve. The respiratory frequency area, sometimes referred to as the high frequency area, is a 0.12 Hz-wide frequency range centered around the fundamental respiratory frequency defined by the peak mode of the respiratory activity power spectrum. It is indicative of vagal outflow reflecting PSNS activity. The low frequency area/respiratory frequency area, or L/R ratio, reflects the balance of the SNS and the PSNS. ANS was studied simultaneously with noninvasive hemodynamic patterns after blunt and penetrating thoracic or abdominal injury beginning shortly after admission. We measured cardiac index by bioimpedance, HR, and mean arterial pressure (MAP) to evaluate cardiac function, pulse oximetry (SapO2) to reflect changes in respiratory function, and transcutaneous oxygen indexed to fractional inspired oxygen (PtcO2/FIO2) to reflect tissue perfusion. RESULTS: ANS activity markedly increased especially in the nonsurvivors at 12 hours to 24 hours after admission. Compared with survivors, the nonsurvivors had lower MAP, CI, and PtcO2/FIO2 values associated with increased ANS activity. CONCLUSIONS: In the nonsurvivors, low flow, low MAP, and reduced tissue perfusion were associated with pronounced increases in PSNS and lesser increases in SNS activity. In the survivors, higher CI, MAP, and PtcO2/FIO2 values were associated with lesser increases in both PSNS and SNS activities.

Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV). METHODS: We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an alpha(1)-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the alpha(1)-agonist was discontinued; and 61 (45 female) who were on an alpha(1)-agonist, but for whom no drug changes were made. The tests averaged 3.1 +/- 1.4 months apart; midodrine (ProAmatine) was the alpha(1)-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension. RESULTS: Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term alpha(1)-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed. CONCLUSIONS: The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA. The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.

Autonomic activity in trauma patients based on variability of heart rate and respiratory rate.

OBJECTIVE: To evaluate the effects of sympathetic and parasympathetic nervous system activity on the heart rate and other hemodynamic variables in acute emergency patients with mild to moderately severe trauma. DESIGN: Clinical study. SETTING: Level 1 university-run trauma service. PATIENTS: Fourteen trauma patients studied immediately after admission to the emergency department. INTERVENTIONS: We measured heart rate and respiratory rate variability by spectral analysis in the early period of mildly to moderately injured patients and compared the patterns of the low- (Lfa) and high-frequency (Hfa) areas of variability. MEASUREMENTS AND MAIN RESULTS: The Lfa is the area under the spectral analysis curve within the frequency range of 0.04-0.10 Hz. This area reflects primarily the tone of the sympathetic nervous system as mediated by the cardiac nerve. The respiratory area or Hfa is a 0.12 Hz-wide frequency range centered around the fundamental respiratory frequency defined by the peak mode of the respiratory power spectrum. It is indicative of vagal outflow reflecting parasympathetic nervous system activity. The Lfa/Hfa, or "L/R ratio," reflects the balance between the sympathetic and parasympathetic nervous systems. The hemodynamic effects of bursts of autonomic activity in response to injury were explored by heart rate and respiratory rate variability measured with non-invasive hemodynamic monitoring consisting of bioimpedance cardiac output, heart rate, and mean arterial pressure to measure cardiac function and transcutaneous oxygen (PtcO2) to reflect tissue perfusion. During sudden surges of autonomic activity, we described increased heart rate variability reflecting increased Lfa and to a lesser degree to Hfa. Slightly later there was increased heart rate, mean arterial pressure, and cardiac index but decreased tissue perfusion indicated by the decreased PtcO2/FIO2 ratio. CONCLUSIONS: Surges in autonomic activity in the period immediately after emergency department admission of trauma patients were associated with pronounced increases in cardiac index, mean arterial pressure, and heart rate and reduced tissue oxygenation.