Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Larry H Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Association of heart rate variability and inflammatory response in patients with cardiovascular diseases: current strengths and limitations
V Papaioannou, I Pneumatikos and N Maglaveras
Front Phys 2013.
http://dx.doi.org:/10.3389/fphys.2013.00174

A few clinical studies have assessed the possible inter-relation between neuro-autonomic output, estimated with heart rate variability analysis, which is the variability of R-R in the electrocardiogram, and different inflammatory biomarkers, in patients suffering from stable or unstable coronary artery disease (CAD) and heart failure. Moreover, different indices derived from heart rate signals’ processing, have been proven to correlate strongly with severity of heart disease and predict final outcome. In this review article we will summarize major findings from different investigators, evaluating neuro-immunological interactions through heart rate variability analysis, in different groups of cardiovascular patients. We suggest that markers originating from variability analysis of heart rate signals seem to be related to inflammatory biomarkers.
Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation  

DM. Hodgson-Zingman, ML. Karst, LV. Zingman, DM. Heublein, et al.
N Engl J Med. 2008 July 10; 359(2): 158–165  http://www.nejm.org/doi/full/10.1056/NEJMoa0706300

We mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide–cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability.
Impact of anemia on clinical outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention: insights from the AFCAS registry.
M Puurunen, T Kiviniemi, W Nammas, A Schlitt, A Rubboli, K Nyman, et al.
BMJ Open 2014; 4:e004700.
http://dx.doi.org:/10.1136/bmjopen-2013-004700

The study adds to our knowledge on the prevalence and impact of anemia in patients with AF undergoing PCI and thus requiring combination antithrombotic medication. It shows that anemia is a frequent finding and that even mild anemia has an adverse impact on outcome.
Atrial Natriuretic Peptide Single Nucleotide Polymorphisms in Patients with Nonfamilial Structural Atrial Fibrillation.
P Francia, A Ricotta, A Frattari, R Stanzione, A Modestino, et al.
Clinical Medicine Insights: Cardiology 2013:7 153–159
http://dx.doi.org:/10.4137/CMC.S12239

We report lack of association between the rs5065 and −G664C ANP gene SNPs and AF in a Caucasian population of patients with structural AF. Further studies will clarify whether these or other ANP gene variants affect the risk of different subpheno-types of AF driven by distinct pathophysiological mechanisms.
Gene Expression and Genetic Variation in Human Atria.

H Lin, EV. Dolmatova, MP. Morley, KL. Lunetta, et al.
Heart Rhythm HRTHM5533.
http://dx.doi.org/10.1016/j.hrthm.2013.10.051

We studied the gene expression profiles and genetic variations in 53 left atrial and 52 right atrial tissue samples collected from the Myocardial Applied Genomics Network (MAGNet) repository. The tissues were collected from heart failure patients undergoing transplantation and from unused organ donor hearts with normal ventricular function.
A total of 187 and 259 significant cis-associations between transcript levels and genetic variants were identified in left and right atrial tissues, respectively. We also found that a SNP at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right atrial tissues. Our results implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF. 

Global Left Atrial Strain Correlates with CHADS2 Risk Score in Patients with Atrial Fibrillation
SK. Saha, PL. Anderson, G Caracciolo, A Kiotsekoglou, S Wilansky, et al.

J Am Soc Echocardiogr 2011;24:506-12.
http://dx.doi.org:/10.1016/j.echo.2011.02.012

Global longitudinal LA strain was reduced in patients with AF compared with controls (P < .001) and was a predictor of high risk for thromboembolism (CHADS2 score > 2; odds ratio, 0.86; P = .02). LA strain indexes showed good interobserver and intraobserver variability. In sequential Cox models, the prediction of hospitalization and/or death was improved by addition of global LA strain and indexed LA volume to CHADS2 score (P = .003).

Time and Frequency Domain Analysis of Heart Rate Variability and their Correlations in Diabetes Mellitus.
PTA Seyd, VIT Ahamed, J Jacob, P Joseph K.
Int  Biol and Life Sci  2008; 4(1).
http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.307.6260

In this paper, changes in ANS activity are quantified by means of frequency and time domain analysis of R-R interval variability. Electrocardiograms (ECG) of 16 patients suffering from DM and of 16 healthy volunteers were recorded. Frequency domain analysis of extracted normal to normal interval (NN interval) data indicates significant difference in very low frequency (VLF) power, low frequency (LF) power and high frequency (HF) power, between the DM patients and control group. Time domain measures, standard deviation of NN interval (SDNN), root mean square of successive NN interval differences (RMSSD), successive NN intervals differing more than 50 ms (NN50 Count), percentage value of NN50 count (pNN50), HRV triangular index and triangular interpolation of NN intervals (TINN) also show significant difference between the DM patients and control group.

Power Spectral Density of the RR interval of a 55 year old healthy volunteer

Power Spectral Density of the RR interval of a 55 year old healthy volunteer

Power Spectral Density of the RR interval of a 62 year old woman suffering from diabetes for the last 15 years.

Power Spectral Density of the RR interval of a 62 year old woman suffering from diabetes for the last 15 years.

Time domain and frequency domain analysis of the RR interval variability of diabetic and normal subjects shows that there is significant difference in these measures for DM patients with respect to normal subjects. Variation of the HRV parameters indicates changes in ANS activity of DM patients. This can provide valid information regarding autonomic neuropathy in people with diabetes. It may be noted that these methods can detect changes before clinical signs appear.

Quantification of Heart Rate Variability: A Measure based on Unique Heart Rates
VIT Ahamed, P Dhanasekaran, A Naseem, NG Karthick, TKA Jaleel, Paul K

It is established that the instantaneous heart rate (HR) of healthy humans keeps on changing. Analysis of heart rate variability (HRV) has become a popular non invasive tool for assessing the activities of autonomic nervous system. Depressed HRV has been found in several disorders, like diabetes mellitus (DM) and coronary artery disease, characterised by autonomic nervous dysfunction. A new technique, which searches for pattern repeatability in a time series, is proposed specifically for the analysis of heart rate data. These set of indices, which are termed as pattern repeatability measure and pattern repeatability ratio are compared with approximate entropy and sample entropy.

Cardiovascular autonomic neuropathy in patients with diabetes mellitus
International Journal of Pharma and Bio Sciences
http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.178.2974

The cardioautonomic reflexes of 82 diabetic subjects and 40 age and sex matched healthy controls were studied using blood pressure and heart rate variation in response to standing, deep breathing, isometric exercise, cold pressor test and determination of QTc interval. Among the 82 patients, 68 patients were found to have cardiac autonomic neuropathy (CAN). Results showed that diabetics had significantly impaired cardioautonomic reflexes compared to non-diabetics, which increases with the duration of diabetes. Out of 68 patients with CAN, QTc prolongation was observed in 64 patients. In conclusion the autonomic nervous system integrity is appeared to be greatly affected by diabetes mellitus and the degree of impairment was dependent on duration of the disease.

Prognostic Value of Heart Rate Variability Analysis in Patients with Depressed Left Ventricular Function Irrespective of Cardiac Rhythm
http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.377.9244
 M Sosnowski, Pw Macfarlane, R Parma, J Skrzypek-wanha, M Tendera

A new index of heart rate variability – HRF Fraction – was developed and its value for risk stratification was evaluated in 480 patients with coronary heart disease. The main purpose to introduce the HRVF was to overcome one of the most important constraints – cardiac arrhythmia, especially atrial fibrillation – that limits use of HRV measurement as a routine clinical tool. In 384 patients with sinus rhythm (SR) and 96 with AF HRV measurements from 24h ambulatory ECG were performed. Patients were followed for a median period of 28 months. The HRV indices in those who died were compared to those who survived. Authors found that HRV Fraction and- among standard time-domain indices- only SDANN, possessed properties that allow HRV measurement to be applied for risk stratification studies in unselected population of patients with cardiac arrhythmia.

Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus.
Burger AJ¹, Charlamb M, Weinrauch LA, D’Elia JA
Am J Cardiol. 1997 Nov 1;80(9):1198-202.
http://www.ncbi.nlm.nih.gov/pubmed/9359550

Using Pearson correlation, the time domain indicators of parasympathetic activity demonstrated very strong correlations at 3 and 6 months compared with baseline, with good correlations at 1 year. The average SD of all 5-minute RR intervals maintained a very strong correlation for the entire year (r >0.94). In the frequency domain, the measures of parasympathetic and sympathetic activity maintained a solid correlation for the entire study period. Reproducibility of HRV was also examined using repeated-measures analysis of variance. The time and frequency domain parameters demonstrated very little variation over the study period of 12 months. Thus, our investigation demonstrated that HRV in long-term diabetics using 24-hour ambulatory recordings is abnormal and reproducible over a 12-month interval; very little variation in all HRV parameters, especially in parameters of parasympathetic activity, occurred during the study period.