The  Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico  ( GISSI ) (Italian group for the study of the survival of myocardial infarction) is a  cardiology  research group founded as a collaboration between two Italian organisations – the  Mario Negri Institute for Pharmacological Research  and the Associazione Nazionale dei Medici Cardiologi Ospedalieri (ANMCO). [ 1 ] [ 2 ]


Four large-scale clinical trials (GISSI 1, [ 3 ]  GISSI 2, [ 3 ]  GISSI 3, [ 4 ]  GISSI Prevention [ 5 ] ) have involved over 60,000 people with  acute myocardial infarction  (AMI). [ 1 ] [ 5 ] [ 6 ]


Glycogen phosphorylase isoenzyme BB  (abbreviation:  GPBB ) is an  isoenzyme  of  glycogen phosphorylase . This isoform of the enzyme exists in cardiac (heart) and brain tissue.


The enzyme is one of the "new  cardiac markers " which are discussed to improve early diagnosis in  acute coronary syndrome . A rapid rise in blood levels can be seen in  myocardial infarction  and  unstable angina .


Other enzymes related to glycogen phosphorylase are abbreviated as  GPLL  (liver) and  GPMM  (muscle).


This  medical  diagnostic article is a  stub . You can help Wikipedia by  expanding it .


Wayne Robert Griffin  (born 1975) is the second person in Australia to be implanted with the SynCardia Total  artificial heart . [ 1 ]


The  artificial heart  surgery was performed on 20 August 2010, by Dr. Phillip Spratt, the head of the Heart and Lung Transplant Unit of  St Vincent's Hospital .
He was assisted by Dr. Paul Jantz and supervised by Dr. Jack Copeland. The surgery was filmed by  60 Minutes Australia  as "The Ultimate Bypass", which was aired in September 2010.


This biographical article related to medicine in Australia is a  stub . You can help Wikipedia by  expanding it .


Hajdu–Cheney syndrome , also called  acroosteolysis with osteoporosis and changes in skull and mandible ,  arthrodentoosteodysplasia  and  Cheney syndrome , [ 1 ]  is an extremely rare  autosomal   dominant   congenital disorder [ 2 ] [ 3 ]  of the  connective tissue  characterized by severe and excessive  bone resorption  leading to  osteoporosis  and a wide range of other possible symptoms. Mutations in the  NOTCH2  gene, identified in 2011, cause HCS. HCS is so rare that only about 50 cases have been reported worldwide since the discovery of the syndrome in 1948 [ 4 ]


Hajdu–Cheney syndrome causes many issues with an individual's connective tissues. Some general characteristics of an individual with Hajdu–Cheney syndrome include bone flexibility and deformities, short stature, delayed  acquisition of speech  and  motor skills ,  dolichocephalic  skull,  Wormian bone , small maxilla, hypoplastic frontal sinuses, basilar impression, joint laxity, bulbous finger tips and severe osteoporosis. Wormian bone occurs when extra bones appear between cranial sutures. Fetuses with Hajdu–Cheney syndrome often will not be seen to unclench their hands on obstetrical ultrasound. They may also have low-set ears and their eyes may be farther apart than on a usual child, called  hypertelorism . Children's heads can have some deformities in their shape and size ( plagiocephaly ). Early tooth loss and bone deformities, such as serpentine tibiae and fibulae, are also common in those affected. [ citation needed ]


Hajdu–Cheney syndrome is a monogenic disorder. The disorder is inherited and controlled by a single pair of genes. A single copy of the mutant gene on an autosome causes HCS. HCS is an autosomal dominant disorder, only one parent with the defective gene is needed to pass the disorder to the offspring. [ citation needed ]


Mutations within the last coding exon of  NOTCH2  that remove the  PEST  domain and escape the  nonsense-mediated mRNA decay  have been shown to be the main cause of Hajdu–Cheney syndrome. [ 5 ] [ 6 ] [ 7 ]  The NOTCH2 gene plays a very important role in skeletogenesis. Mutations of NOTCH2 that seem to cause HCS occur in the last coding exon of the gene (exon 34). These mutations remove PEST domains, which mediate proteosomal destruction of the protein. These PEST domains are removed due to the premature stop codon in the amino acid sequence. All HCS alleles are observed to have premature protein destruction before the PEST sequence is fully translated. The result is a mature  NOTCH2  gene with a partially completed PEST sequence. In some cases, no PEST sequence at all is seen. This leads to the no proteosomal destruction of the protein. [ citation needed ]


The  NOTCH2  gene is ubiquitously expressed in all embryonic tissue. When researching HCS in mice, the homozygous deletion of  NOTCH2  leads to death. This observation is important because it explains how the HCS phenotype is not isolated to only one system of the body.  NOTCH2  is also shown to regulate RANK-L osteoclastogenesis, which is the production of functional osteoclasts. Osteoclasts are the component that breaks bone down. This is why bone loss is observed in HCS patients, due to the overactivation of RANK-L. [ citation needed ]


The mechanism thought to cause HCS is an abnormality in osteoblast and osteoid function. These are major components of bone development, and the low function of each leads to the weak bones that characterize HCS. [ citation needed ]


One of the main methods of pinpointing a  NOTCH2  mutation that leads to HCS is through whole genome sequencing. This is then followed by exome capture by means of in-solution hybridization. The exome part of the genome consists of exons. Parallel sequencing follows the hybridization, which results in about 3.5 Gb of sequence data. These sequence data are then analyzed. Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis. [ citation needed ]


Laboratory testing reveals multiple mutations of HCS. Two genetic variants result in sporadic HCS symptoms, which are HCS-02 and HCS-03. These mutations produce symptoms that come and go, but have been present  de novo . HCS-03 was identified as the variant that is passed through affected family members and presents symptoms throughout the lifetime of the individual. All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of  NOTCH2 .  NOTCH  has four different receptors, which have an affinity for similar ligands. They are classified as single-pass transmembrane receptors. [ citation needed ]


Since about 2002, some patients with this disorder have been offered drug therapy with  bisphosphonates  (a class of osteoporosis drugs) to treat problems with bone resorption associated with the bone breakdown and skeletal malformations that characterize this disorder. Brand names include Actonel (risedronate/alendronate), made by Merck Pharmaceuticals. Other drugs include Pamidronate, made by Novartis and Strontium Ranelate, made by Eli Lilly. However, for more progressive cases, surgery and bone grafting are necessary. [ citation needed ]


It is named after Nicholas Hajdu (1908–1987), a Hungarian-English radiologist working in the UK and William D. Cheney, MD (1899–1985), a US radiologist. [ citation needed ]


The  Hancock Aortic Tissue Valve  is a  prosthetic heart valve  used in  cardiac surgery  to replace a damaged or diseased aortic valve. [ 1 ]  It is a bioprosthetic valve, meaning it is constructed using biological tissues, specifically  porcine  (pig) valve tissue. [ 2 ]  This valve is widely utilized in the field of cardiovascular surgery to restore proper blood flow through the heart. [ 3 ]


The Hancock Aortic Tissue Valve was invented by  Warren Hancock . [ 4 ]  In the late 1960s and early 1970s, Warren Hancock, an American engineer, collaborated with the medical community to develop a cutting-edge bioprosthetic heart valve. The valve was first introduced by the American company  Medtronic . [ 1 ]  The design of the Hancock valve is based on the concept of xenografts, utilizing pig tissue due to its structural similarities to human heart valves. [ 5 ]


The Hancock Aortic Tissue Valve is composed of  porcine  valve tissue mounted within a supporting stent frame. [ 6 ]  The valve is sewn into a fabric-covered sewing ring, facilitating secure attachment within the patient's aortic annulus during the implantation procedure. The design aims to closely mimic the natural function of the human aortic valve, allowing for efficient blood flow and minimizing the risk of complications. [ 2 ]


The Hancock Aortic Tissue Valve is commonly used in patients requiring aortic valve replacement due to conditions such as aortic stenosis or aortic regurgitation. [ 7 ]  The choice between a mechanical or bioprosthetic valve depends on various factors, including the patient's age, lifestyle, and medical history. [ 8 ]


Prosthetic heart valves, including the Hancock Aortic Tissue Valve, are not without drawbacks. Structural degradation is a risk, potentially necessitating reoperation. [ 13 ] [ 3 ]  Studies have indicated the need for ongoing research and improvement in bioprosthetic valve technology to address such concerns [ 13 ]


The implantation of the Hancock Aortic Tissue Valve typically involves  open-heart surgery . [ 14 ]  During the procedure, the damaged or diseased native aortic valve is removed, and the prosthetic valve is sutured in its place. The secure attachment of the valve is crucial to ensure proper functionality and prevent complications such as leakage.


The  HDL-Atherosclerosis Treatment Study , also known as  HATS , was a three-year double-blind trial involving 160 people with coronary heart disease (CHD) who had a low HDL and near normal LDL. The study compared  a combination of  simvastatin  and  niacin  with antioxidant vitamin therapy. Using angiography, coronary artery stenosis progressed when using placebo or antioxidant alone, and regressed with the combination of simvastatin and niacin. The study demonstrated a 90% reduction in CHD death, nonfatal heart attacks,  stroke , or revascularization for worsening  angina . It was published in 2001. [ 1 ] [ 2 ] [ 3 ] [ 4 ]


This  medical  article is a  stub . You can help Wikipedia by  expanding it .


The  Heart Failure Society of America  is an American organization of heart failure experts who have an interest in heart function and  heart failure .   Founded in 1995, [ 1 ]  it provides a forum for experts and patients with the aim of reducing the burden of heart failure. [ 2 ]
It has produced advice on categorizing heart failure [ 3 ]  and it produces guidelines including the 2010 comprehensive heart failure practice guidelines when  Douglas L. Mann  was served as the president [ 4 ]  and the 2013 Guideline for the Management of Heart Failure. [ 5 ]  In 2018, a forum was created with people of various stages of advanced heart failure and specialists in cardiology. [ 6 ]
Past presidents have included  Mandeep R. Mehra , who took up the position in 2016. [ 7 ]


The  Heart Protection Study  was a  randomized controlled trial  run by the  Clinical Trial Service Unit , and funded by the  Medical Research Council  (MRC) and the  British Heart Foundation  (BHF) in the  United Kingdom . It studied the use of the  cholesterol lowering drug ,  simvastatin  40 mg and  vitamin  supplementation ( vitamin E ,  vitamin C  and  beta carotene ) in people who were at risk of  cardiovascular disease . It was led by  Jane Armitage , an epidemiologist at the  Clinical Trial Service Unit . [ 1 ] [ 2 ]


An outline of the study protocol was published in 1999. [ 3 ]  Initial results [ 4 ]  were published in 2002, which indicated that vitamins made little difference in modifying cardiovascular risk, but that simvastatin could significantly reduce the risk of cardiovascular events. Further publications, from 2003 and 2004, were concerned with the efficacy of simvastatin in diabetes patients [ 5 ]  and preventing stroke. [ 6 ]  A 2005 paper analyses the cost-effectiveness of a prescribing strategy similar to the one employed in the study. [ 7 ]


The HPS is to date the largest study to investigate the use of  statins  in the prevention of  cardiovascular disease . While there have been concerns about side-effects associated with statins ( myopathy  and  rhabdomyolysis ), these were rare in this study. [ citation needed ]


The  number needed to treat  in the study was 57 to postpone one death and 19 to prevent one cardiovascular "event" (in those taking the drug simvastatin for 5 years). There was no mortality benefit in women with a statistical "p-value" that did not reach significance (0.08) while the Kaplan-Meier mortality curves, for men and women separately, have not been published as of 2016.  Cancer  risk was not significantly lower in the treatment group; in fact, there was no difference except for non-melanoma skin cancers, wherein the placebo group had a barely-significant lower risk of diagnosis. No worsening of  lung disease  was found, an initial concern with statin drugs, and simvastatin did not decrease  osteoporosis . [ citation needed ]


£5.5M plus drug supply was received from Merck and £5.5M plus drug supply from Roche.
 [ 8 ]


Redirect to:


Heart rate turbulence (HRT)  is a baroreflex-mediated adjustment of  heart rate  which acts as a counter-mechanism to  premature ventricular contraction  (PVC). [ 1 ]  It consists of a brief speed-up in heart rate, followed by a slow decrease back to the baseline rate. PVCs can occur naturally in most otherwise-healthy adults, so measuring the characteristics of a given person's HRT can offer a non-invasive way to evaluate certain aspects of their cardiac or autonomic function without applying artificial external stimuli. [ citation needed ]


The measured values of HRT parameters have been shown to be a  statistically significant  prediction of the probability of dying from cardiac disease after a patient suffers a  myocardial infarction . [ 2 ]  HRT can also be used to predict death in patients with  congestive heart failure  from a lethal  arrhythmia . [ 3 ]


The concept of HRT was introduced to the medical community by Georg Schmidt and colleagues from the  Technical University of Munich  in 1999 in the British medical journal  the Lancet . [ 4 ]  While studying PVC characteristics, Schmidt and his colleagues noticed that heart rate seemed to speed up after a  PVC . To clarify, they listed the time from one heartbeat's  R-wave  to the next R-wave (called RR intervals) and synchronized these lists to the time of the PVC beat and averaged the values in the list. A plot of this averaged RR interval list (called a PVC tachogram) not only confirmed their observation that heart rate sped up for a few beats after a PVC, but highlighted another less obvious feature, that heart rate then slows down beyond what it was before the PVC, before returning to the original heart rate.


Schmidt reasoned that just as loss of variability in heart rate indicated patients more likely to be at high risk of dying after a heart attack, this phenomenon might also be an indicator of a healthy control of heart rate in such patients. They proceeded to test this hypothesis using 24-hour electrocardiogram ( Holter monitor ) recordings from one hundred survivors of  heart attacks  with frequent PVCs. Greater turbulence seemed correlated with better prognosis. They then used this data to determine the optimal discriminating threshold between normal and abnormal HRT values, and came up with the values TS=2.5, TO=0%. Now came the test. These thresholds were applied to Holter records from a total of 1191 patients who had experienced a heart attack. There were 162 deaths (13.6%) during the follow-up period of about two years. Patients with abnormal HRTs were approximately three-times more likely to die than those with normal HRTs, beating out some other commonly used predictors.


HRT is widely considered [ by whom? ]  to be a  baroreflex  phenomenon. A PVC interrupts the normal  cardiac cycle , so the  ventricles  of the  heart  do not have time to fill up to their normal level, before contracting and pumping their contents out. This results in a pulse ( blood pressure ) weaker than expected and triggers normal homeostatic mechanisms that try to compensate by constricting arteries and increasing heart rate (the turbulence onset part of HRT). This is accomplished by the brain reflexively withdrawing the  parasympathetic  nerve signals and increasing the  sympathetic  nerve signals it sends to the heart. The compensatory  constriction of the arteries  and increased heart rate can cause blood pressure to overshoot normal values, triggering the opposite baroreflex. This time, the brain increases parasympathetic signalling and decreases sympathetic signalling, causing a decrease in heart rate (the turbulence slope part of HRT).


The exact quantitative contribution of the parasympathetic and sympathetic nervous flow to the heart to HRT is unknown. Some researchers [ like whom? ]  assert that HRT is solely dependent upon parasympathetic activity because  atropine , a parasympathetic activity blocker abolishes HRT while a  beta-blocker  (sympathetic blocker) has no effect on HRT. [ citation needed ]  The contribution of the  compensatory pause , the pause between the PVC and the next normal beat, to HRT is also unknown. Whether the single beat blood pressure increase after a compensatory pause occurs in both normal and compromised hearts as well is at present uncertain. To date, no physiological parameter has been linked in a quantitative manner to turbulence slope [ citation needed ] , whereas turbulence onset was shown by researchers in  Calgary , Canada, to be linearly dependent upon duration of subnormal blood pressure in a well designed experiment. [ 5 ]


The reason that the size of HRT after a PVC can be used as a predictor of cardiac death is suggested by its mechanism. Parasympathetic nervous activity to the heart is believed to be protective and sympathetic nervous activity, deleterious, to the heart. [ citation needed ]  Especially after a heart attack, sympathetic nervous activity tends to be increased. A healthy HRT indicates the presence of a healthy amount of  parasympathetic  activity, countering sympathetic activity. To take a wider view, however, it may be that a healthy HRT is also an indication of a healthy brain, and is the reason a small HRT also predicts a likelihood of death from non-cardiac causes as well as from cardiac causes. [ editorializing ]


Heart rate variability  ( HRV ) is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval.


Other terms used include "cycle length variability", "R–R variability" (where R is a point corresponding to the peak of the  QRS complex  of the  ECG  wave; and R–R is the interval between successive Rs), and "heart period variability". [ 1 ]  Measurement of the RR interval is used to derive heart rate variability. [ 1 ]


Methods used to detect beats include ECG, blood pressure,
 ballistocardiograms , [ 2 ] [ 3 ]
and the pulse wave signal derived from a  photoplethysmograph  (PPG). ECG is considered the gold standard for HRV measurement [ 4 ]   because it provides a direct reflection of cardiac electric activity. [ 5 ]


Reduced HRV has been shown to be a predictor of mortality after  myocardial infarction [ 6 ] [ 7 ]  although others have shown that the information in HRV relevant to acute myocardial infarction survival is fully contained in the mean  heart rate . [ 8 ]
A range of other outcomes and conditions may also be associated with modified (usually lower) HRV, including  congestive heart failure ,  diabetic neuropathy , post– cardiac-transplant  depression, susceptibility to  SIDS  and poor survival in  premature babies , [ citation needed ]  as well as fatigue severity in  chronic fatigue syndrome . [ 9 ]  On the other hand, for patients having high blood pressure ( hypertension ), higher HRV is a risk factor for  atrial fibrillation . [ 10 ]


There is interest in HRV in the field of  psychophysiology . For example, HRV is related to emotional arousal. High-frequency (HF) activity has been found to decrease under conditions of acute time pressure and emotional strain [ 12 ]  and elevated anxiety state, [ 13 ]  presumably related to focused attention and motor inhibition. [ 13 ]  HRV has been shown to be reduced in individuals reporting to worry more. [ 14 ]  In individuals with  post-traumatic stress disorder  (PTSD), HRV and its HF component (see below) is reduced whilst the low-frequency (LF) component is elevated. Furthermore, PTSD patients demonstrated no LF or HF reactivity to recalling a traumatic event. [ 15 ]  Statistical quantitative differences have also been found among healthy, depressed, and psychotic people.  [ 16 ]


The neurovisceral integration is a model of HRV that views the central autonomic network as the decision maker of cognitive, behavioral and physiological regulation as they pertain to a continuum of emotion. [ 17 ]  The neurovisceral integration model describes how the  prefrontal cortex  regulates activity in  limbic structures  which act to suppress parasympathetic nervous system (PSNS) activity and activate sympathetic nervous system (SNS) circuits. [ 18 ]  Variation in the output of these two branches of the autonomic system produces HRV [ 19 ]  and activity in the prefrontal cortex can hence modulate HRV. [ 20 ]


HRV is reported to be an index of the influence of both the parasympathetic and the sympathetic nervous system. [ 21 ]  For example, high HRV is shown to reflect proper emotion regulation, decision-making, and attention, and low HRV reflects the opposite. [ 21 ]  The parasympathetic nervous system works to decrease the heart rate, while the SNS works to increase the heart rate. [ 17 ]  For example, someone with high HRV may reflect increased parasympathetic activity, and someone with low HRV may reflect increased sympathetic activity. [ 22 ]


Emotions stem from the time and impact of a situation on a person. [ 23 ]  The ability to regulate emotions is essential for social environments and well-being. [ 17 ]  HRV has provided a window to the physiological components associated with emotional regulation. [ 21 ]  HRV has been shown to reflect emotional regulation at two different levels, while resting and while completing a task. Research suggests that a person with higher HRV while resting can provide more appropriate emotional responses compared to those that have low HRV at rest. [ 21 ]  Empirical research found that HRV can reflect better emotional regulation by those with higher resting HRV, particularly with  negative emotions . [ 24 ]  However, HRV is elevated by negative news in persons who react more strongly to negative news than to positive news. [ 25 ]  When completing a task, HRV is subject to change, especially when people need to regulate their emotions. Most importantly, individual differences are related to the ability to regulate emotions. [ 26 ]


Previous research has suggested that a large part of the attention regulation is due to the default inhibitory properties of the prefrontal cortex. [ 21 ]  Top-down processes from the prefrontal cortex provide parasympathetic influences, and if for some reason, those influences are active, attention can suffer. [ 21 ]  Researchers have suggested that HRV can index attention. It was found that groups with high anxiety and low HRV have poor attention. [ 27 ]  In line with this research, it has also been suggested that increased attention has been linked to high HRV and increased vagus nerve activity. [ 21 ]  The vagus nerve activity reflects the physiological modulation of the parasympathetic and sympathetic nervous system. [ 17 ]  The activity behind the prefrontal cortex and the parasympathetic and sympathetic nervous system can influence heart activity. However, people are not all affected the same. A systematic review of HRV and cognitive function suggested that resting HRV can predict individual differences in attentional performance. Furthermore, HRV has been able to index the role of attention and performance, supporting high HRV as a biomarker of increased attention and performance. [ 28 ]


Decision-making skills are found to be indexed by HRV in several studies. Previous research has suggested that both emotion and attention are linked to decision making; for example, poor decision making is linked to the inability to regulate or control emotions and attention and vice versa. [ 27 ]  Decision making is negatively affected by lower HRV and positively affected by higher levels of HRV. Most importantly, resting-state HRV was found to be a significant predictor of cognitive functions such as decision making. [ 29 ]  HRV, accompanied by a psychological state such as anxiety, has been found to lead to poor decisions. For example, a group of researchers found that low HRV was an index of higher uncertainty leading to poor decision-making skills, especially those with higher levels of anxiety. [ 27 ]  HRV was also used to assess decision-making skills in a high-risk game and was found to be an index higher sympathetic activation (lower HRV) when making decisions involving risk. [ 30 ]  HRV can index psychological concepts, such as the ones outlined above, to assess the demand for the situations that people experience.


The  polyvagal theory [ 31 ] [ 32 ]  is another way to describe the pathways in the  autonomic nervous system  that mediate HRV. The polyvagal theory highlights three main ordinal processes, inactive response to an environmental threat, the active response to an environmental threat, and the fluctuation between the connect and disconnect to an environmental threat. [ 17 ]  This theory, like others, [ 33 ]  decomposes heart rate variability based on frequency domain characteristics. However, it places more emphasis on respiratory sinus arrhythmia and its transmission by a hypothesized neural pathway distinct from other components of HRV. [ 34 ]   There is anatomic [ 35 ]   and physiological [ 36 ]  evidence for a polyvagal control of the heart.


Variation in the beat-to-beat interval is a physiological phenomenon. The  SA node  receives several different inputs and the instantaneous heart rate or RR interval and its variation are the results of these inputs. [ 37 ]  Contribution of the respiratory rhythm to sinus arrhythmia in normal unanesthetized subjects during mechanical hyperventilation with positive pressure. [ 37 ]


The main inputs are the  sympathetic  and the  parasympathetic nervous system  (PSNS) and  humoral factors . Respiration gives rise to waves in heart rate mediated primarily via the PSNS, and it is thought that the lag in the  baroreceptor  feedback loop may give rise to 10 second waves in heart rate (associated with  Mayer waves  of blood pressure), but this remains controversial. [ citation needed ]


Factors that affect the input are the  baroreflex ,  thermoregulation ,  hormones ,  sleep–wake cycle , meals, physical activity, and  stress .


Decreased PSNS activity or increased SNS activity will result in reduced HRV. High frequency (HF) activity (0.15 to 0.40 Hz), especially, has been linked to PSNS activity. Activity in this range is associated with the respiratory sinus arrhythmia (RSA), a vagally mediated modulation of heart rate such that it increases during inspiration and decreases during expiration. Less is known about the physiological inputs of the low frequency (LF) activity (0.04 to 0.15 Hz). Though previously thought to reflect SNS activity, it is now widely accepted that it reflects a mixture of both the SNS and PSNS. [ 38 ]


There are two primary fluctuations:


The regulation of heart rate, encompassing both acceleration and deceleration of the heartbeat, is highly specific. Distinct patterns in heart rate can be observed during everyday movements, such as kneeling down or standing up. These patterns reflect highly sensitive physiological regulatory mechanisms that enable a healthy heart to adapt to various life influences. [ 42 ]


Errors in the location of the instantaneous heart beat will result in errors in the calculation of the HRV. HRV is highly sensitive to artifact and errors in as low as even 2% of the data will result in unwanted biases in HRV calculations. To ensure accurate results therefore it is critical to manage artifact and RR errors appropriately prior to performing any HRV analyses. [ 43 ] [ 44 ]


Robust management of artifacts, including RWave identification, interpolation and exclusion requires a high degree of care and precision. This can be very time-consuming in large studies with data recorded over long durations. Software packages are able to assist users with a variety of robust and tested artifact management tools.  These software programs also include some automated capability but it is important that a human review any automated artifact management and edit accordingly.


The most widely used methods can be grouped under time-domain and frequency-domain. A joint European and American task-force described standards in HRV measurements in 1996. [ 19 ]  Other methods have been proposed, such as non-linear methods.


These [ 45 ]  are based on the beat-to-beat or NN intervals, which are analysed to give variables such as: [ 45 ]


The series of NN intervals also can be converted into a geometric pattern such as:
Geometric Measures HRV triangular index: integral of density distribution / maximum of density distribution maximum
HRV triangular index = Number of all NN intervals / maximum number. Dependent on the length of the bin -> quote the bin size+ relative insensitive to the analytic quality of the series of NN intervals – need of reasonable number of NN intervals to generate the geometric pattern (in practice 20 min to 24 h) – not appropriate to assess short-term changes in HRV


Frequency domain methods [ 45 ]  assign bands of frequency and then count the number of NN intervals that match each band. The bands are typically high frequency (HF) from 0.15 to 0.4 Hz, low frequency (LF) from 0.04 to 0.15 Hz, and the very low frequency (VLF) from 0.0033 to 0.04 Hz. [ 50 ]  HF power reflects stimulation by the  parasympathetic nervous system  (PNS), whereas LF power reflects stimulation by both the  sympathetic nervous system  (SNS) and the PNS. [ 50 ]  VLF power is associated with  thermoregulation , the  renin–angiotensin system . and peripheral  vasomotor  activity. [ 50 ]


Several methods of analysis are available.  Power spectral density  (PSD), using parametric or nonparametric methods, provides basic information on the power distribution across frequencies. One of the most commonly used PSD methods is the  discrete Fourier transform .
Methods for the calculation of PSD may be generally classified as nonparametric and parametric. In most instances, both methods provide comparable results. The advantages of the  nonparametric  methods are (1) the simplicity of the algorithm used ( fast Fourier transform  [FFT] in most of the cases) and (2) the high processing speed.  The advantages of  parametric  methods are (1) smoother spectral components that can be distinguished independent of preselected frequency bands, (2) easy postprocessing of the spectrum with an automatic calculation of low- and high-frequency power components with an easy identification of the central frequency of each component, and (3) an accurate estimation of PSD even on a small number of samples on which the signal is supposed to maintain stationarity. The basic disadvantage of parametric methods is the need of verification of the suitability of the chosen model and of its complexity (that is, the order of the model).


In addition to classical FFT-based methods used for the calculation of frequency parameters, a more appropriate PSD estimation method is the  Lomb–Scargle periodogram . [ 51 ]  Analysis has shown that the LS periodogram can produce a more accurate estimate of the PSD than FFT methods for typical RR data. Since the RR data is an unevenly sampled data, another advantage of the LS method is that in contrast to FFT-based methods it is able to be used without the need to resample and detrend the RR data.


Alternatively, to avoid artefacts that are created when calculating the power of a signal that includes a single high-intensity peak (for example caused by an arrhythmic heart beat), the concept of the 'instantaneous Amplitude' has been introduced, which is based on the Hilbert transform of the RR data. [ 52 ]


A newly used HRV index, [ citation needed ]  which depends on the wavelet entropy measures, is an alternative choice. The wavelet entropy measures are calculated using a three-step procedure defined in the literature. First, the wavelet packet algorithm is implemented using the Daubechies 4 (DB4) function as the mother wavelet with a scale of 7. Once the wavelet coefficients are obtained, the energy for each coefficient are calculated as described in the literature. After calculating the normalized values of wavelet energies, which represent the relative wavelet energy (or the probability distribution), the wavelet entropies are obtained using the definition of entropy given by Shannon.


Given the complexity of the mechanisms regulating heart rate, it is reasonable to assume that applying HRV analysis based on methods of non-linear dynamics will yield valuable information. Although  chaotic behavior  has been assumed, more rigorous testing has shown that heart rate variability cannot be described as a low dimensional chaotic process. [ 53 ]  However, application of chaotic globals to HRV has been shown to predict diabetes status. [ 54 ]  The most commonly used non-linear method of analysing heart rate variability is the  Poincaré plot . Each data point represents a pair of successive beats, the x-axis is the current RR interval, while the y-axis is the previous RR interval. HRV is quantified by fitting mathematically defined geometric shapes to the data. [ 55 ]  Other methods used are the  correlation dimension , symbolic dynamics, [ 56 ]  nonlinear predictability, [ 53 ]  pointwise correlation dimension, [ 57 ]   approximate entropy,  sample entropy , [ 58 ]  multiscale entropy analysis, [ 59 ]  sample asymmetry [ 60 ]  and memory length (based on inverse statistical analysis). [ 61 ] [ 62 ]  It is also possible to represent long range correlations geometrically. [ 63 ]


Sequences of RR intervals have been found to have long-term correlations. [ 63 ]  However, one flaw with these analyses is their lack of goodness-of-fit statistics, i.e. values are derived that may or may not have adequate statistical rigor. Different types of correlations have been found during different sleep stages. [ 63 ]


A basic problem is that all the parameters used to characterize HRV strongly depend on heart rate, [ 64 ]  but many articles have not adjusted properly or at all for HR differences when comparing HRV in multiple circumstances. [ 65 ]


However, the exact HRV(HR) relationship is still a matter of debate. For time domain parameters (RMSSD, SDNN, etc.) the results imply that, if there exists a universal function, it should be either exponential or hyperbolic in nature. [ 66 ] [ 64 ] [ 65 ]  The evaluation procedures used to determine HRV(HR) function have not allowed to decide between these options, so far.


A new evaluation method has recently allowed to determine a HRV(HR) function with unprecedented precision: [ 67 ]  it can be described by two descending exponential components for healthy individuals, in general.


Time domain methods are preferred to frequency domain methods when short-term recordings are investigated. This is due to the fact that the recording should be at least 10 times the wavelength of the lowest frequency bound of interest. Thus, recording of approximately 1 minute is needed to assess the HF components of HRV (i.e., a lowest bound of 0.15 Hz is a cycle of 6.6 seconds and so 10 cycles require ~60 seconds), while more than 4 minutes are needed to address the LF component (with a lower bound of 0.04 Hz). [ citation needed ]


Although time domain methods, especially the SDNN and RMSSD methods, can be used to investigate recordings of long durations, a substantial part of the long-term variability is day–night differences. Thus, long-term recordings analyzed by time domain methods should contain at least 18 hours of analyzable ECG data that include the whole night. [ citation needed ]


Although  cardiac automaticity  is intrinsic to various pacemaker tissues, heart rate and rhythm are largely under the control of the autonomic nervous system. The parasympathetic influence on heart rate is mediated via release of acetylcholine by the vagus nerve. Muscarinic acetylcholine receptors respond to this release mostly by an increase in cell membrane K+ conductance. Acetylcholine also inhibits the hyperpolarization-activated "pacemaker" current. The "Ik decay" hypothesis proposes that pacemaker depolarization results from slow deactivation of the delayed rectifier current, Ik, which, due to a time-independent background inward current, causes diastolic depolarization. Conversely, the "If activation" hypothesis suggests that after action potential termination, If provides a slowly activating inward current predominating over decaying Ik, thus initiating slow diastolic depolarization. [ citation needed ]


The sympathetic influence on heart rate is mediated by release of epinephrine and norepinephrine. Activation of β-adrenergic receptors results in cAMP-mediated phosphorylation of membrane proteins and increases in ICaL and in If the result is an acceleration of the slow diastolic depolarization.


Under resting conditions, vagal tone prevails and variations in heart period are largely dependent on vagal modulation. The vagal and sympathetic activity constantly interact. Because the sinus node is rich in acetylcholinesterase, the effect of any vagal impulse is brief because the acetylcholine is rapidly hydrolyzed. Parasympathetic influences exceed sympathetic effects probably through two independent mechanisms: a cholinergically induced reduction of norepinephrine released in response to sympathetic activity, and a cholinergic attenuation of the response to an adrenergic stimulus.


The RR interval variations present during resting conditions represent beat-by-beat variations in cardiac autonomic inputs. However, efferent vagal (parasympathetic) activity is a major contributor to the HF component, as seen in clinical and experimental observations of autonomic maneuvers such as electrical vagal stimulation, muscarinic receptor blockade, and vagotomy. More problematic is the interpretation of the LF component, which was considered by some as a marker of sympathetic modulation (especially when expressed in normalized units) but is now known to include both sympathetic and vagal influences. For example, during sympathetic activation the resulting tachycardia is usually accompanied by a marked reduction in total power, whereas the reverse occurs during vagal activation. Thus the spectral components change in the same direction and do not indicate that LF faithfully reflects sympathetic effects.


HRV measures fluctuations in autonomic inputs to the heart rather than the mean level of autonomic inputs. Thus, both withdrawal and saturatingly high levels of autonomic input to the heart can lead to diminished HRV.


A reduction of HRV has been reported in several cardiovascular and noncardiovascular diseases.


Depressed HRV after MI may reflect a decrease in vagal activity directed to the heart. HRV in patients surviving an acute MI reveal a reduction in total and in the individual power of spectral components. The presence of an alteration in neural control is also reflected in a blunting of day-night variations of RR interval. In post-MI patients with a very depressed HRV, most of the residual energy is distributed in the VLF frequency range below 0.03 Hz, with only a small respiration-related variations.


In neuropathy associated with diabetes mellitus characterized by alteration in small nerve fibers, a reduction in time domain parameters of HRV seems not only to carry negative prognostic value but also to precede the clinical expression of autonomic neuropathy. In diabetic patients without evidence of autonomic neuropathy, reduction of the absolute power of LF and HF during controlled conditions was also reported. Similarly, diabetic patients can be differentiated from normal controls on the basis of reduction in HRV. [ 54 ]


A very reduced HRV with no definite spectral components has been reported in patients with a recent heart transplant. The appearance of discrete spectral components in a few patients is considered to reflect cardiac reinnervation. This reinnervation may occur as early as 1 to 2 years after transplantation and is assumed to be of sympathetic origin. In addition, a correlation between respiratory rate and the HF component of HRV observed in some transplanted patients also indicates that a nonneural mechanism may generate a respiration-related rhythmic oscillation.


A reduced HRV has been observed consistently in patients with cardiac failure. In this condition characterized by signs of sympathetic activation such as faster heart rates and high levels of circulating catecholamines, a relation between changes in HRV and the extent of left ventricular dysfunction was reported. In fact, whereas the reduction in time domain measures of HRV seemed to parallel the severity of the disease, the relationship between spectral components and indices of ventricular dysfunction appears to be more complex. In particular, in most patients with a very advanced phase of the disease and with a drastic reduction in HRV, an LF component could not be detected despite the clinical signs of sympathetic activation. This reflects that, as stated above, the LF may not accurately reflect cardiac sympathetic tone.


Liver  cirrhosis  is associated with decreased HRV. Decreased HRV in patients with cirrhosis has a prognostic value and predicts mortality. Loss of HRV is also associated with higher plasma pro-inflammatory cytokine levels and impaired neurocognitive function in this patient population. [ 68 ]


HRV is decreased in patients with sepsis. Loss of HRV has both diagnostic and prognostic value in neonates with sepsis. [ 69 ]  The pathophysiology of decreased HRV in sepsis is not well understood but there is experimental evidence to show that partial uncoupling of cardiac pacemaker cells from autonomic neural control may play a role in decreased HRV during acute systemic inflammation. [ 70 ]  (Decreased HRV is generally lower in inflammatory conditions [ 1 ] ).


Patients with chronic complete high cervical spinal cord lesions have intact efferent vagal neural pathways directed to the sinus node. However, an LF component can be detected in HRV and arterial pressure variabilities of some tetraplegic patients. Thus, the LF component of HRV in those without intact sympathetic inputs to the heart represent vagal modulation.


Victims of  sudden cardiac death  have been found to have had lower HRV than healthy individuals. [ 71 ] [ 63 ]  HRV can be observed to be depressed prior to the development of SCD, which raises questions about whether or not altered autonomic function plays a role in the development of electrical instability. HRV is also depressed in SCD survivors, who are at high risk for subsequent episodes. [ 72 ]  HRV is markedly decreased prior to both fatal and non-fatal  arrhythmias . [ 1 ]


HRV correlates with the progression of disease and outcome of cancer patients, according to a systematic review of published studies. [ 73 ]  Patients in the early stages of cancer have a significantly higher HRV when compared to patients in the later stages of cancer, suggesting disease severity influences HRV. Different ranges of HRV can be observed between cancer types. [ 74 ]


HRV alterations occur in healthy pregnancies as well as similar changes in pregnancies with gestational diabetes that include lower HRV mean values. [ 75 ] [ 76 ] [ 77 ] [ 78 ] [ 79 ] [ 80 ] [ 81 ]


Low RMSSD, thought to represent vagal tone, have been associated with major depression. [ 82 ]  Lower SDNN and elevated LF/HF were found in those with bipolar disorder, and in particular those characterized as having greater illness severity due to greater number of episodes, illness duration and whether there had been psychosis. [ 83 ] [ 84 ]  Patients with PTSD also had lower HF, a measure of vagal tone. [ 84 ]


Interventions that augment HRV may be protective against cardiac mortality and sudden cardiac death. Although the rationale for changing HRV is sound, it also contains the inherent danger of leading to the unwarranted assumption that modification of HRV translates directly into cardiac protection, which may not be the case. Despite the growing consensus that increases in vagal activity can be beneficial, it is not as yet known how much vagal activity (or HRV as a marker) has to increase in order to provide adequate protection.


The data on the effect of β-blockers on HRV in post-MI patients are surprisingly scant. Despite the observation of statistically significant increases, the actual changes are very modest. In conscious post-MI dogs, β-blockers do not modify HRV. The unexpected observation that before MI, β-blockade increases HRV only in the animals destined to be at low risk for lethal arrhythmias after MI may suggest novel approaches to post-MI risk stratification.


Data exist for several antiarrhythmic drugs. Flecainide and propafenone but not amiodarone were reported to decrease time domain measures of HRV in patients with chronic ventricular arrhythmia. In another study, propafenone reduced HRV and decreased LF much more than HF. A larger study confirmed that flecainide, also encainide and moricizine, decreased HRV in post-MI patients but found no correlation between the change in HRV and mortality during follow-up. Thus, some antiarrhythmic drugs associated with increased mortality can reduce HRV. However, it is not known whether these changes in HRV have any direct prognostic significance.


Low-dose muscarinic receptor blockers, such as atropine and  scopolamine , may produce a paradoxical increase in vagal effects on the heart, as suggested by a decrease in heart rate. In addition, scopolamine and low dose atropine can markedly increase HRV. However, though the heart rate slowing in proportional to the (low) dose of atropine, the increase in HRV varies widely across and within individuals. This suggests that even for vagal activity to the heart, HRV may be a limited marker.


The effect of  thrombolysis  on HRV (assessed by pNN50) was reported in 95 patients with acute MI. HRV was higher 90 minutes after thrombolysis in the patients with patency of the infarct-related artery. However, this difference was no longer evident when the entire 24 hours were analyzed.


Exercise training may decrease cardiovascular mortality and sudden cardiac death. Regular exercise training is also thought to modify cardiac autonomic control. Individuals who exercise regularly have a 'training bradycardia' (i.e., low resting heart rate) and generally have higher HRV than sedentary individuals. [ 85 ]


The technique called  resonant breathing  biofeedback  teaches how to recognize and control involuntary heart rate variability. A randomized study by Sutarto et al. assessed the effect of resonant breathing biofeedback among manufacturing operators; depression, anxiety and stress significantly decreased. [ 86 ]  A first overall meta-analysis by Goessl VC et al. (24 studies, 484 individuals, 2017) indicates ''HRV biofeedback training is associated with a large reduction in self-reported stress and anxiety'', while mentioning that more well-controlled studies are needed. [ 87 ]


One study that surveyed the physiological effects of playing  Native American flutes  found a significant HRV increase when playing both low-pitched and high-pitched flutes. [ 88 ]


Even though there are no widely accepted standard values for HRV that can be used for clinical purposes, multiple studies have measured and reported normal values for various populations: [ 1 ] [ 89 ] [ 90 ] [ 91 ]


Time Domain Analysis Abbreviations


IBI  is InterBeat Interval, the time period between successive heartbeats (Normal-to-Normal interbeat interval, also known as the R–R interval), measured in milliseconds (ms).  SDNN  is Standard Deviation of Normal-to-Normal interbeat intervals measured in milliseconds.  RMSSD  is Root Mean Square of Successive Differences between normal heartbeats measured in milliseconds. [ 89 ] [ 1 ]  The conventional recording time is five minutes. [ 89 ] [ 1 ]


Spectral Analysis Abbreviations


LF  is Power of the Low Frequency range [ms squared (ms 2 ) or normal units (nu)]  HF  is Power of the High Frequency range [ms squared (ms 2 ) or normal units (nu)]  LF/HF  is the ratio of LF-to-HF power [ 89 ]


Heart sounds  are the noises generated by the beating  heart  and the resultant flow of blood through it. Specifically, the sounds reflect the turbulence created when the  heart valves  snap shut. In cardiac  auscultation , an examiner may use a  stethoscope  to listen for these unique and distinct sounds that provide important  auditory  data regarding the condition of the heart.


In healthy adults, there are two normal heart sounds, often described as a  lub  and a  dub  that occur in sequence with each heartbeat. These are the  first heart sound  (S 1 ) and  second heart sound  (S 2 ),
produced by the closing of the  atrioventricular valves  and  semilunar valves , respectively. In addition to these normal sounds, a variety of other sounds may be present including  heart murmurs ,  adventitious sounds , and  gallop rhythms   S 3  and  S 4 .


Heart murmurs  are generated by turbulent flow of blood and a murmur to be heard as turbulent flow must require pressure difference of at least 30  mm of Hg  between the chambers and the pressure dominant chamber will outflow the blood to non-dominant chamber in diseased condition which leads to  Left-to-right shunt  or  Right-to-left shunt  based on the pressure dominance. Turbulence may occur inside or outside the heart; if it occurs outside the heart then the turbulence is called  bruit  or  vascular murmur . Murmurs may be physiological (benign) or pathological (abnormal). Abnormal murmurs can be caused by  stenosis  restricting the opening of a heart valve, resulting in turbulence as blood flows through it. Abnormal murmurs may also occur with valvular insufficiency ( regurgitation ), which allows backflow of blood when the incompetent valve closes with only partial effectiveness. Different murmurs are audible in different parts of the  cardiac cycle , depending on the cause of the murmur.


Normal heart sounds are associated with heart valves closing:


The  first heart sound , or  S 1 , forms the "lub" of "lub-dub" and is composed of components M 1  (mitral valve closure) and T 1  (tricuspid valve closure). Normally M 1  precedes T 1  slightly. It is caused by the  closure of the atrioventricular  valves , i.e.  tricuspid  and  mitral  (bicuspid), at the beginning of ventricular contraction, or  systole . When the ventricles begin to contract, so do the papillary muscles in each ventricle. The papillary muscles are attached to the cusps or leaflets of the tricuspid and mitral valves via  chordae tendineae  (heart strings). When the papillary muscles contract, the chordae tendineae become tense and thereby prevent the backflow of blood into the lower pressure environment of the atria. The chordae tendineae act a bit like the strings on a parachute, and allow the leaflets of the valve to balloon up into the atria slightly, but not so much as to evert the cusp edges and allow backflow of blood. It is the pressure created from ventricular contraction that closes the valve, not the papillary muscles themselves. The contraction of the ventricle begins just prior to AV valves closing and prior to the opening of the semilunar valves. The sudden tensing of the chordae tendineae and the squeezing of the ventricles against closed semilunar valves, send blood rushing back toward the atria, and the parachute-like valves catch the rush of blood in their leaflets causing the valve to snap shut. The S1 sound results from reverberation within the blood associated with the sudden block of flow reversal by the valves. The delay of T1 even more than normally causes the split S1 which is heard in a  right bundle branch block . [ 1 ]


The  second heart sound , or  S 2 , forms the "dub" of "lub-dub" and is composed of components A 2  (aortic valve closure) and P 2  (pulmonary valve closure). Normally A 2  precedes P 2  especially during inspiration where a split of S 2  can be heard. It is caused by the closure of the  semilunar valves  (the  aortic valve  and  pulmonary valve ) at the end of ventricular systole and the beginning of ventricular  diastole . As the  left ventricle  empties, its pressure falls below the pressure in the  aorta .  Aortic blood flow quickly reverses back toward the left ventricle, catching the pocket-like cusps of the aortic valve, and is stopped by aortic valve closure.  Similarly, as the pressure in the  right ventricle  falls below the pressure in the  pulmonary artery , the pulmonary valve closes. The  S 2  sound results from reverberation within the blood associated with the sudden block of flow reversal. [ 1 ]


Splitting of S2 , also known as physiological split, normally occurs during inhalation because the decrease in intrathoracic pressure increases the time needed for pulmonary pressure to exceed that of the right ventricular pressure.  A widely split S2 can be associated with several different cardiovascular conditions, and the split is sometimes wide and variable whereas, sometimes wide and fixed. The wide and variable split occurs in  Right bundle branch block ,  pulmonary stenosis , pulmonary hypertension and  ventricular septal defects . The wide and fixed splitting of S2 occurs in  atrial septal defect . Pulmonary S2 (P2) will be accentuated (loud P2) in pulmonary hypertension and pulmonary embolism. S2 becomes softer in aortic stenosis. [ 1 ]


The rarer extra heart sounds form  gallop rhythms  and are heard in both normal and abnormal situations. [ 1 ]


The  third heart sound , or  S 3  is rarely heard, and is also called a protodiastolic gallop, ventricular gallop, or informally the " Kentucky " gallop as an  onomatopoeic  reference to the rhythm and stress of S1 followed by S2 and S3 together (S1=Ken; S2=tuck; S3=y). [ 2 ]


"lub-dub-ta" or "slosh-ing-in"  If new, indicates heart failure or volume overload. [ citation needed ]


It occurs at the beginning of diastole after S2 and is lower in pitch than S1 or S2 as it is not of valvular origin. The third heart sound is benign in youth, some trained athletes, and sometimes in pregnancy but if it re-emerges later in life it may signal cardiac problems, such as a failing left ventricle as in dilated  congestive heart failure  (CHF). S3 is thought to be caused by the oscillation of blood back and forth between the walls of the ventricles initiated by blood rushing in from the atria. The reason the third heart sound does not occur until the middle third of diastole is probably that during the early part of diastole, the ventricles are not filled sufficiently to create enough tension for reverberation. [ 1 ]


It may also be a result of tensing of the chordae tendineae during rapid filling and expansion of the ventricle. In other words, an S3 heart sound indicates increased volume of blood within the ventricle. An S3 heart sound is best heard with the bell-side of the stethoscope (used for lower frequency sounds). A left-sided S3 is best heard in the left lateral decubitus position and at the apex of the heart, which is normally located in the 5th left intercostal space at the midclavicular line. A right-sided S3 is best heard at the lower left sternal border. The way to distinguish between left and right-sided S3 is to observe whether it increases in intensity with inhalation or exhalation. A right-sided S3 will increase on inhalation, while a left-sided S3 will increase on exhalation. [ 1 ]


S3 can be a normal finding in young patients but is generally pathologic over the age of 40. The most common cause of pathologic S3 is congestive heart failure. [ 1 ]


The  fourth heart sound , or  S 4  when audible in an adult is called a presystolic gallop or atrial gallop. This gallop is produced by the sound of blood being forced into a stiff or hypertrophic ventricle. [ 1 ]


"ta-lub-dub" or "a-stiff-wall"


It is a sign of a pathologic state, usually a failing or hypertrophic left ventricle, as in systemic hypertension, severe valvular  aortic stenosis , and  hypertrophic cardiomyopathy . The sound occurs just after atrial contraction at the end of diastole and immediately before S1, producing a rhythm sometimes referred to as the " Tennessee " gallop where S4 represents the "Ten-" syllable. [ 2 ]  It is best heard at the cardiac apex with the patient in the left lateral decubitus position and holding their breath.  The combined presence of S3 and S4 is a quadruple gallop, also known as the "Hello-Goodbye" gallop. At rapid heart rates, S3 and S4 may merge to produce a summation gallop, sometimes referred to as S7. [ 1 ]


Atrial contraction must be present for production of an S4. It is absent in  atrial fibrillation  and in other rhythms in which atrial contraction does not precede ventricular contraction. [ 1 ]


Heart murmurs  are produced as a result of turbulent flow of blood strong enough to produce audible noise. They are usually heard as a whooshing sound. The term murmur only refers to a sound believed to originate within blood flow through or near the heart; rapid blood velocity is necessary to produce a murmur. Most heart problems do not produce any murmur and most valve problems also do not produce an audible murmur. [ 3 ]


Murmurs can be heard in many situations in adults without major congenital heart abnormalities: [ 3 ]


Though several different  cardiac  conditions can cause heart murmurs, the murmurs can change markedly with the severity of the cardiac disease.  An astute physician can sometimes diagnose cardiac conditions with some accuracy based largely on the murmur, related  physical examination , and experience with the relative frequency of different heart conditions. However, with the advent of better quality and wider availability of  echocardiography  and other techniques, heart status can be recognized and quantified much more accurately than formerly possible with only a stethoscope, examination, and experience. Another advantage to the use of the echocardiogram is that the devices can be handheld. [ 5 ]


Inhalation  decreases intrathoracic pressure which allows more venous blood to return to the right heart (pulling blood into the right side of the heart via a vacuum-like effect). Therefore, right-sided heart murmurs generally increase in intensity with inhalation. The decreased (more negative) intrathoracic pressure has an opposite effect on the left side of the heart, making it harder for the blood to exit into circulation. Therefore, left-sided murmurs generally decrease in intensity during inhalation. Increasing venous blood return to the right side of the heart by raising a patient's legs to a 45-degree while lying supine produces similar effect which occurs during inhalation. Inhalation can also produce a non-pathological  split S2  which will be heard upon auscultation. [ citation needed ]


With  exhalation , the opposite haemodynamic changes occur: left-sided murmurs generally increase in intensity with exhalation. [ citation needed ]


There are a number of interventions that can be performed that alter the intensity and characteristics of abnormal heart sounds.  These interventions can differentiate the different heart sounds to more effectively obtain a diagnosis of the cardiac anomaly that causes the heart sound. [ citation needed ]


Clicks  – Heart clicks are short, high-pitched sounds that can be appreciated with modern non-invasive imaging techniques. [ citation needed ]


Rubs  – The pericardial friction rub can be heard in  pericarditis , an  inflammation  of the  pericardium , the sac surrounding the heart. This is a characteristic scratching, creaking, high-pitched sound emanating from the rubbing of both layers of inflamed pericardium. It is the loudest in systole, but can often be heard at the beginning and at the end of diastole. It is very dependent on body position and breathing, and changes from hour to hour. [ citation needed ]


The aortic area, pulmonic area, tricuspid area and mitral area are areas on the surface of the chest where the heart is auscultated. [ 6 ]
Heart sounds result from reverberation within the blood associated with the sudden block of flow reversal by the valves closing. Because of this, auscultation to determine function of a valve is usually not performed at the position of the valve, but at the position to where the sound waves reverberate. [ citation needed ]


Using electronic stethoscopes, it is possible to record heart sounds via direct output to an external recording device, such as a  laptop  or  MP3  recorder. The same connection can be used to listen to the previously recorded auscultation through the stethoscope headphones, allowing for a more detailed study of murmurs and other heart sounds, for general research as well as evaluation of a particular patient's condition. [ citation needed ]


1G5W ,  1HMR ,  1HMS ,  1HMT ,  2HMB ,  3RSW ,  3WBG ,  3WVM ,  3WXQ ,  4TJZ ,  4TKB ,  4TKH ,  4TKJ ,  4WBK ,  5CE4


NM_004102 NM_001320996


NP_001307925 NP_004093


Heart-type fatty acid binding protein  (hFABP) also known as  mammary-derived growth inhibitor  is a  protein   that in humans is encoded by the  FABP3   gene . [ 5 ] [ 6 ]


Heart-type Fatty Acid-Binding Protein (H-FABP) is a small cytoplasmic protein (15 kDa) released from cardiac  myocytes  following an  ischemic  episode. [ 7 ]   Like the nine other distinct FABPs that have been identified, H-FABP is involved in active  fatty acid  metabolism where it transports fatty acids from the cell membrane to  mitochondria  for oxidation. [ 7 ]   See  FABP3  for biochemical details.


The intracellular fatty acid-binding proteins ( FABPs ) belongs to a multigene family. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of  long-chain fatty acids . They may also be responsible in the modulation of cell growth and proliferation. Fatty acid-binding protein 3 gene contains four exons and its function is to arrest growth of mammary  epithelial cells . This gene is also a candidate tumor suppressor gene for human  breast cancer . [ 6 ]


FABP3 is known to interact with  TNNI3K  in the context of interacting with cardiac troponin I. [ 8 ]  The protein also interacts with,  VPS28 ,  KIAA159 , [ 9 ]   NUP62 , [ 10 ]   PLK1 ,  UBC , and  Xpo1 . [ 6 ]


In HIV, a synthetic peptide corresponding to the immunosuppressive domain (amino acids 574-592) of HIV-1 gp41 downregulates the expression of fatty acid binding protein 3 (FABP3) in peptide-treated PBMCs. [ 11 ]


H-FABP is a sensitive  biomarker  for  myocardial infarction [ 12 ] [ 13 ]  and can be detected in the blood within one to three hours of the pain.


The diagnostic potential of the biomarker H-FABP for heart injury was discovered in 1988 by Professor Jan Glatz (Maastricht, Netherlands). [ 14 ]   H-FABP is 20 times more specific to cardiac muscle than  myoglobin , [ 14 ]  it is found at 10-fold lower levels in skeletal muscle than heart muscle and the amounts in the kidney, liver and small intestine are even lower again. [ 15 ] [ 16 ]


H-FABP is recommended to be measured with  troponin  to identify myocardial infarction and acute coronary syndrome in patients presenting with chest pain.  H-FABP measured with troponin shows increased sensitivity of 20.6% over troponin at 3–6 hours following chest pain onset. [ 17 ]    This sensitivity may be explained by the high concentration of H-FABP in myocardium compared to other tissues, the stability and solubility of H-FABP, its low molecular weight; 15kDa compared to 18, 80 and 37kDa for  MYO ,  CK-MB  and  cTnT  respectively, [ 18 ] [ 19 ] [ 20 ]  its rapid release into plasma after myocardial injury – 60 minutes after an ischemic episode, [ 21 ]  and its relative tissue specificity. [ 22 ]   Similarly this study showed that measuring H-FABP in combination with troponin increased the diagnostic accuracy and with a negative predictive value of 98% could be used to identify those not suffering from MI at the early time point of 3–6 hours post chest pain onset. [ 17 ]  The effectiveness of using the combination of H-FABP with troponin to diagnose MI within 6 hours is well reported. [ 23 ] [ 24 ] [ 25 ]


In addition to its diagnostic potential, H-FABP also has prognostic value.  Alongside D-dimer, NT-proBNP and peak troponin T, it was the only cardiac biomarker that proved to be a statistically significant predictor of death or MI at one year.  This prognostic information was independent of troponin T, ECG and clinical examination. [ 24 ]    The risk associated with raised H-FABP is dependent upon its concentration. [ 26 ] [ 27 ]    Patients who were TnI  negative but  H-FABP positive had 17% increased risk of all cause mortality within one year compared to those patients who were TnI positive but H-FABP negative. [ 26 ]   Currently these TnI positive patients are prioritised for angioplasty, and the TnI negative patients are considered to be of a lower priority, yet the addition of the H-FABP test helps identify patients who are currently slipping through the net and allows physicians to more appropriately manage this hidden high risk group.  If both biomarkers were negative, there is 0% mortality at 6 months, in the authors own words this “represents a particularly worthwhile clinical outcome, especially because it was observed in patients admitted into hospital for suspected ACS.”  H-FABP indicates risk across the ACS spectrum including UA, NSTEMI or STEMI where low H-FABP concentrations confer low risk whereas high H-FABP concentrations indicate patients who are at a much higher risk of future events. [ 26 ]


H-FABP has been proven to significantly predict 30-day mortality in acute  pulmonary embolism . [ 28 ]   H-FABP is more effective than Troponin T in risk stratifying Chronic Heart Failure patients. [ 29 ]   H-FABP is beginning to create interest with researchers who have found emerging evidence that indicates a role in differentiating between different neurodegenerative diseases. [ 30 ] [ 31 ]


To obtain diagnostic and prognostic information a precise and fully quantitative measurement of H-FABP is required. Commercial tests include a Cardiac Array on Evidence MultiStat; and an automated biochemistry assay  [ citation needed ]


Heart: A History  is a 2018 book by  Sandeep Jauhar . In the book Jauhar discusses the historical experiments and procedures done in the past and how innovations can be taken for granted. [ 1 ]


The book begins with Jauhar discussing his personal health and family history, focusing on heart-related issues. He gives his opinion and talks about the advances in technology that have come about in the past few decades and how they have shaped the way doctors practice  cardiology  today.  Jauhar also discusses the old views that people had about the heart and why this was the last organ that was operated upon due to cultural perspectives and the level of difficulty.  He further notes several of his personal experiences as a cardiologist and states that the heart is still the center of attention of the body. Jauhar mentions research and experiments conducted on animals and humans, which he sees as unethical by modern standards while stating that without them society would not have the experience or procedures that are currently used.


Jauhar also covers the effects of emotions on the heart and how he believes stressors can significantly damage a person's heart. He states that doctors have lowered the risk of dying from a heart attack in a hospital to 3 percent, which he does not believe can be improved much further. He notes the difficulty for physicians to help patients prevent common stressors and that it has become easy to prescribe medicine for cholesterol. Finally, Jauhar advises that  yoga , meditation, and activities that help emotions should be taught in schools and the medical field.


Critical reception for the book has been positive, [ 2 ] [ 3 ] [ 4 ]  and received reviews from  The New Statesman ,  The Globe and Mail ,  and  Financial Express . [ 5 ] [ 6 ] [ 7 ]   The Washington Post  and  Business Standard  both wrote favorable reviews, with the former stating that it was "a fascinating education for those of us who harbor this most hallowed organ but know little about it.” [ 8 ] [ 9 ]


HeartScore  is a cardiovascular disease risk assessment and management tool developed by the  European Society of Cardiology , aimed at supporting clinicians in optimising individual cardiovascular risk reduction.


HeartScore is the interactive version of SCORE - Systematic COronary Risk Evaluation  [ 1 ]  - a cardiovascular disease risk assessment system initiated by the European Society of Cardiology, using data from 12 European cohort studies (N=205,178) covering a wide geographic spread of countries at different levels of cardiovascular risks. The SCORE data contains some 3-million person-years of observation and 7,934 fatal cardiovascular events. [ citation needed ]


The SCORE risk estimation is based on the following risk factors:  gender ,  age ,  smoking ,  systolic blood pressure , total  cholesterol , and estimates fatal  cardiovascular disease  events over a ten-year period. [ citation needed ]


HeartScore is one of the tools developed to implement the  2007 European guidelines on CVD prevention in clinical practice . [ 2 ]


In addition to two European versions for high/low risk countries, HeartScore now counts 13 national versions. HeartScore Sweden was the first national version to be launched in 2005, followed by versions in Germany, Greece, Poland, Spain, Cyprus, Slovakia, Czech Republic and Turkey. Translated versions now exist in Bosnia and Herzegovina, Russia, Romania and Croatia. [ citation needed ]


A roll-out plan of additional national versions has been defined for 2009–2010 within the framework of the EuroHeart Programme of the European Commission and according to countries specific requests. Further updates will be produced as knowledge evolves (new cohort studies, risk factors, end points) [ citation needed ]


Three formats have been developed to cater for different users’ needs:  [ citation needed ]


The  hexaxial reference system , better known as the  Cabrera system , is a convention to present the extremity leads of the 12 lead  electrocardiogram , [ 1 ]  that provides an illustrative logical sequence that helps interpretation of the ECG, especially to determine the heart's electrical axis in the frontal plane.
The most practical way of using this is by arranging extremity leads according to the Cabrera system, reversing polarity of lead aVR and presenting ECG complexes in the order (aVL, I, -aVR, II, aVF, III). Then determine the direction the maximal ECG vector is "pointing", i.e. in which lead there are most positive amplitude - this direction is the electrical axis - see diagram.
Example: If lead I has the highest amplitude (higher than aVL or -aVR), the axis is approximately 0°.
Conversely, if lead III has the most negative amplitude it means the vector is pointing away from this lead, i.e. towards -60°. [ citation needed ]


An alternative use is to locate the most isoelectric (or equiphasic) [ clarification needed ]  lead (I, II, III, aVR, aVL, or aVF) on a diagnostic quality  ECG  with proper lead placement. Then find the corresponding spoke on the hexaxial reference system. The perpendicular spoke will point to the heart's electrical axis. To determine which numerical value should be used, observe the polarity of the perpendicular lead on the  ECG . [ clarification needed ]


For example, if the most isoelectric (or equiphasic) lead is aVL, the perpendicular lead on the hexaxial reference system is lead II. If lead II is positively deflected on the  ECG , the heart's electrical axis in the frontal plane will be approximately +60°.


High-density lipoprotein  ( HDL ) is one of the five major groups of  lipoproteins . [ 1 ]  Lipoproteins are complex particles composed of multiple proteins which transport all  fat  molecules ( lipids ) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle (organized by one, two or three  ApoA ). HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle. [ 2 ]


Lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. Unlike the larger lipoprotein particles, which deliver fat molecules to cells, HDL particles remove fat molecules from cells. The lipids carried include  cholesterol ,  phospholipids , and  triglycerides , amounts of each are variable. [ 3 ]


Increasing concentrations of HDL particles are associated with decreasing accumulation of  atherosclerosis  within the walls of arteries, [ 4 ]  reducing the risk of  sudden plaque ruptures ,  cardiovascular disease ,  stroke  and other  vascular diseases . [ 2 ]  HDL particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reduce  macrophage  accumulation, and thus help prevent or even regress atherosclerosis. [ 5 ]  Higher HDL-C may not necessarily be protective against cardiovascular disease and may even be harmful in extremely high quantities, [ 6 ]  with an increased cardiovascular risk, especially in hypertensive patients. [ 7 ]


Because of the high cost of directly measuring HDL and LDL ( low-density lipoprotein ) protein particles,  blood tests  are commonly performed for the surrogate value, HDL-C, i.e. the cholesterol associated with  ApoA-1 /HDL particles. In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by HDL. [ 5 ]  This is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles,  LDL , and called LDL-C. HDL particles remove fats and cholesterol from cells, including within  artery  wall  atheroma , and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol" (despite being the same as cholesterol in LDL particles). Those with higher levels of HDL-C tend to have fewer problems with  cardiovascular diseases , while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. [ 8 ] [ needs update ]  Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people. [ 9 ] [ needs update ]


The remainder of the serum cholesterol after subtracting the HDL is the  non-HDL cholesterol . The concentration of these other components, which may cause  atheroma , is known as the  non-HDL-C . This is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated. [ 10 ]


With a size ranging from 5 to 17 nm, HDL is the smallest of the  lipoprotein  particles. [ 2 ]  It is the densest because it contains the highest proportion of  protein  to  lipids . [ 2 ]  Its most abundant  apolipoproteins  are  apo A-I  and  apo A-II . A rare genetic variant,  ApoA-1 Milano , has been documented to be far more effective in both protecting against and regressing arterial disease,  atherosclerosis .


The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles, [ 2 ]  whose NMR structure was published; [ 11 ]  the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the  ATP-binding cassette transporter A1 (ABCA1) . [ 12 ]  A  plasma  enzyme called  lecithin-cholesterol acyltransferase  (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized HDL to assume a spherical shape. HDL particles increase in size as they circulate through the blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with the  ABCG1  transporter and the  phospholipid transport protein (PLTP) . [ 2 ]


HDL transports cholesterol mostly to the  liver  or  steroidogenic organs  such as  adrenals ,  ovary , and  testes  by both direct and indirect pathways. HDL is removed by HDL receptors such as  scavenger receptor BI  (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by  cholesteryl ester transfer protein (CETP) . [ 2 ]  This protein exchanges triglycerides of  VLDL  against cholesteryl esters of HDL. As the result, VLDLs are processed to  LDL , which are removed from the circulation by the  LDL receptor  pathway. The triglycerides are not stable in HDL, but are degraded by  hepatic lipase  so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells. [ 2 ]


The cholesterol delivered to the liver is excreted into the  bile  and, hence,  intestine  either directly or indirectly after conversion into  bile acids . Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of  steroid hormones . [ 2 ]


Several steps in the metabolism of HDL can participate in the transport of cholesterol from lipid-laden  macrophages  of  atherosclerotic   arteries , termed  foam cells , to the liver for secretion into the bile. This pathway has been termed  reverse cholesterol transport  and is considered as the classical protective function of HDL toward atherosclerosis.


HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and its protein and lipid constituents help to inhibit  oxidation ,  inflammation ,  activation of the endothelium ,  coagulation , and  platelet aggregation . All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In addition, a small subfraction of HDL lends protection against the protozoan parasite  Trypanosoma brucei  brucei . This HDL subfraction, termed trypanosome lytic factor (TLF), contains specialized proteins that, while very active, are unique to the TLF molecule. [ 13 ]


In the  stress response ,  serum amyloid A , which is one of the  acute-phase proteins  and an apolipoprotein, is under the stimulation of  cytokines  ( interleukin 1 ,  interleukin 6 ), and  cortisol  produced in the  adrenal cortex  and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as  amyloidosis .


It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles. [ 14 ]  This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either  electrophoresis  (the original method developed in the 1970s) or newer  NMR spectroscopy  methods (See also  nuclear magnetic resonance  and  spectroscopy ), developed in the 1990s.


Five subfractions of HDL have been identified.  From largest (and most effective in cholesterol removal) to smallest (and least effective), the types are 2a, 2b, 3a, 3b, and 3c. [ 15 ]


Men tend to have noticeably lower HDL concentrations, with smaller size and lower cholesterol content, than women. Men also have a greater incidence of  atherosclerotic  heart disease. Studies confirm the fact that HDL has a buffering role in balancing the effects of the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular complications in these patients. Also, the results obtained in this study revealed that there was a significant negative correlation between HDL and  activated partial thromboplastin time  (APTT). [ citation needed ]


Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against  cardiovascular diseases  such as ischemic stroke and  myocardial infarction . Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk for  atherosclerotic  diseases. [ 16 ]


Data from the landmark  Framingham Heart Study  showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high. [ 17 ] [ 18 ]


Even people with very low LDL levels achieved by  statin  treatment are exposed to increased risk if their HDL levels are not high enough. [ 19 ] [ non-primary source needed ]


Clinical laboratories formerly measured HDL cholesterol by separating other lipoprotein fractions using either ultracentrifugation or chemical precipitation with divalent ions such as Mg 2+ , then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The reference method still uses a combination of these techniques. [ 20 ]  Most laboratories now use automated homogeneous analytical methods in which lipoproteins containing  apo B  are blocked using antibodies to apo B, then a  colorimetric  enzyme reaction measures cholesterol in the non-blocked HDL particles. [ 21 ]   HPLC  can also be used. [ 22 ]  Subfractions (HDL-2C, HDL-3C) can be measured, [ 23 ]  but clinical significance of these subfractions has not been determined. [ 24 ]   The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate. [ citation needed ]


The  American Heart Association ,  NIH  and  NCEP  provide a set of guidelines for fasting HDL levels and risk for  heart disease . [ 25 ] [ 26 ] [ 27 ]


High LDL with low HDL level is an additional risk factor for cardiovascular disease. [ 28 ]


As technology has reduced costs and clinical trials have continued to demonstrate the importance of HDL, [ 29 ]  methods for directly measuring HDL concentrations and size (which indicates function) at lower costs have become more widely available and increasingly regarded as important for assessing individual risk for progressive  arterial disease  and treatment methods. [ citation needed ]


Since the HDL particles have a net negative charge and vary by density & size, ultracentrifugation combined with  electrophoresis  have been utilized since before 1950 to enumerate the concentration of HDL particles and sort them by size with a specific volume of blood plasma. Larger HDL particles are carrying more cholesterol.


Concentration and sizes of lipoprotein particles can be estimated using  nuclear magnetic resonance  fingerprinting. [ 30 ]


The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA [ 31 ]  trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.


The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles (the top quarter, >75%) and the highest concentrations of large HDL particles. Multiple additional measures, including LDL particle concentrations, small LDL particle concentrations, VLDL concentrations, estimations of  insulin resistance  and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are routinely provided in clinical testing.


While higher HDL levels are correlated with lower risk of cardiovascular diseases, no medication used to increase HDL has been proven to improve health. [ 2 ] [ 32 ]  As of 2017, numerous lifestyle changes and drugs to increase HDL levels were under study. [ 2 ]


HDL lipoprotein particles that bear  apolipoprotein C3  are associated with increased, rather than decreased, risk for  coronary heart disease . [ 33 ]


Certain changes in diet and exercise may have a positive impact on raising HDL levels: [ 34 ]


Most  saturated fats  increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol. [ 48 ]


HDL levels can be increased by  smoking cessation , [ 40 ]  or mild to moderate  alcohol  intake. [ 49 ] [ 50 ] [ 51 ] [ 52 ] [ 53 ] [ 54 ]


Cannabis  in unadjusted analyses, past and current cannabis use was not associated with higher HDL-C levels. [ 55 ]   A study performed in 4635 patients demonstrated no effect on the HDL-C levels (P=0.78) [the mean (standard error) HDL-C values in control subjects (never used), past users and current users were 53.4 (0.4), 53.9 (0.6) and 53.9 (0.7) mg/dL, respectively]. [ 55 ]


Exogenous  anabolic androgenic steroids , particularly  17α-alkylated anabolic steroids  and others administered orally, can reduce HDL-C by 50 percent or more. [ 56 ]  Other  androgen receptor  agonists such as  selective androgen receptor modulators  can also lower HDL. As there is some evidence that the HDL reduction is caused by increased  reverse cholesterol transport , it is unknown if AR agonists' HDL-lowering effect is pro- or anti-atherogenic. [ 57 ]


Pharmacological therapy  to increase the level of HDL cholesterol includes use of  fibrates  and  niacin . Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids. [ 58 ]


Niacin  (nicotinic acid, a form of  vitamin B3 ) increases HDL by selectively inhibiting hepatic  diacylglycerol acyltransferase  2, reducing  triglyceride  synthesis and  VLDL  secretion through a receptor HM74 [ 59 ]  otherwise known as   niacin receptor 2  and HM74A / GPR109A, [ 60 ]   niacin receptor 1 .


Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%, [ 61 ]  making it the most powerful agent to increase HDL-cholesterol. [ 62 ] [ 63 ]  A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. [ 64 ]  Niacin products sold as "no-flush",  i.e.  not having side-effects such as "niacin  flush ", do not, however, contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. [ 65 ]  Both fibrates and niacin increase artery toxic  homocysteine , an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, but multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates.  A 2011 extended-release niacin (Niaspan) study was halted early because patients adding niacin to their statin treatment showed no increase in heart health, but did experience an increase in the risk of stroke. [ 66 ]


In contrast, while the use of  statins  is effective against high levels of LDL cholesterol, most have little or no effect in raising HDL cholesterol. [ 62 ]   Rosuvastatin  and  pitavastatin , however, have been demonstrated to significantly raise HDL levels. [ 67 ]


Lovaza  has been shown to increase HDL-C. [ 68 ]  However, the best evidence to date suggests it has no benefit for primary or secondary prevention of cardiovascular disease.


The  PPAR  modulator  GW501516  has shown a positive effect on HDL-C [ 69 ]  and an antiatherogenic where LDL is an issue. [ 70 ]  However, research on the drug has been discontinued after it was discovered to cause rapid cancer development in several organs in rats. [ 71 ] [ 72 ]


The  history of invasive and interventional cardiology  is complex, with multiple groups working independently on similar technologies.  Invasive and interventional  cardiology  is currently closely associated with cardiologists ( physicians  who treat the diseases of the  heart ), though the development and most of its early research and procedures were performed by diagnostic and interventional  radiologists .


The history of invasive cardiology begins with the development of  cardiac   catheterization  in 1711, when  Stephen Hales  placed catheters into the  right  and  left ventricles  of a living horse. [ 1 ]  Variations on the technique were performed over the subsequent century, with formal study of cardiac physiology being performed by  Claude Bernard  in the 1840s. [ 2 ]


The technique of angiography itself was first developed in 1927 by the Portuguese physician  Egas Moniz  at the  University of Lisbon  for cerebral angiography, the viewing of brain vasculature by X-ray radiation with the aid of a contrast medium introduced by catheter.  Cardiac catheterization was first performed when  Werner Forssmann , in 1929, created an incision in one of his left  antecubital  veins and inserted a catheter into his venous system.  He then guided the catheter by  fluoroscopy  into his right atrium.  Subsequently, he walked up a flight of stairs to the radiology department and documented the procedure by having a  chest roentgenogram  performed. [ 3 ]   Over the next year, catheters were placed in a similar manner into the right ventricle, and measurements of pressure and  cardiac output  (using the  Fick principle ) were performed. [ 4 ]


In the early 1940s,  André Cournand , in collaboration with  Dickinson Richards , performed more systematic measurements of the  hemodynamics  of the heart. [ 5 ]   For their work in the discovery of cardiac catheterization and hemodynamic measurements, Cournand, Forssmann, and Richards shared the  Nobel Prize in Physiology or Medicine  in 1956. [ 6 ]


In 1958,  Interventional Radiologist , Dr.  Charles Dotter  began working on methods to visualize the coronary anatomy via sequential radiographic films.  He invented a method known as occlusive aortography in an animal model.  Occlusive aortography involved the transient occlusion of the aorta and subsequent injection of a small amount of radiographic contrast agent into the aortic root and subsequent serial x-rays to visualize the coronary arteries. [ 7 ]


Later that same year, while performing an aortic root  aortography ,  Mason Sones , a pediatric cardiologist at the  Cleveland Clinic , noted that the catheter had accidentally entered the patient's right coronary artery.  Before the catheter could be removed, 30cc of  contrast agent  had been injected. [ 8 ]   While the patient went into  ventricular fibrillation , the dangerous arrhythmia was terminated by Dr. Sones promptly performing a  precordial thump  which restored sinus rhythm.


Until the 1950s, placing a catheter into either the arterial or venous system involved a "cut down" procedure, in which the soft tissues were dissected out of the way until the artery or vein was directly visualized and subsequently punctured by a catheter; this was known as the Sones technique.  The  percutaneous  approach that is widely used today was developed by radiologist  Sven-Ivar Seldinger  in 1953. [ 9 ] [ 10 ]  Percutaneous access of the artery or vein is still commonly known as the  Seldinger technique .  The use of the Seldinger technique for visualizing the coronary arteries was described by Ricketts and Abrams in 1962 and Judkins in 1967. [ 11 ] [ 12 ]


By the late 1960s,  Melvin Judkins  had begun work on creating catheters that were specially shaped to reach the coronary arteries to perform selective coronary angiography.  His initial work involved shaping stiff wires and comparing those shapes to radiographs of the ascending aorta to determine if the shape appeared promising.  Then he would place the stiff wire inside a flexible catheter and use a  heat-fixation  method to permanently shape the catheter.  In the first use of these catheters in humans, each catheter was specifically shaped to match the size and shape of the aorta of the subject.  His work was documented in 1967, and by 1968 the Judkins catheters were manufactured in a limited number of fixed tip shapes. [ 13 ]   Catheters in these shapes carry his name and are still used to this day for selective coronary angiography.


The use of tapered Teflon dilating catheters for the treatment of atherosclerotic vascular disease was first described in 1964 by two interventional radiologists, Charles Dotter and Melvin Judkins, when they used it to treat a case of atherosclerotic disease in the  superficial femoral artery  of the left leg. [ 14 ] [ 15 ]   Building on their work and his own research involving balloon-tipped catheters,  Andreas Gruentzig  performed the first success percutaneous transluminal coronary angioplasty (known as PTCA or percutaneous coronary intervention (PCI)) on a human on September 16, 1977 at University Hospital, Zurich. [ 16 ]   The results of the procedure were presented at the  American Heart Association  meeting two months later to a stunned audience of cardiologists.  In the subsequent three years, Dr. Gruentzig performed coronary angioplasties in 169 patients in Zurich, while teaching the practice of coronary angioplasty to a field of budding  interventional cardiologists .  Ten years later, nearly 90 percent of these individuals were still alive. [ 16 ]   By the mid-1980s, over 300,000 PTCAs were being performed on a yearly basis, equalling the number of  bypass surgeries  being performed for coronary artery disease. [ 17 ]


Soon after Andreas Gruentzig began performing percutaneous interventions on individuals with stable coronary artery disease, multiple groups described the use of catheter-delivered  streptokinase  for the treatment of  acute myocardial infarction  (heart attack). [ 18 ] [ 19 ]


From the time of the initial percutaneous balloon angioplasty, it was theorized that devices could be placed inside the arteries as scaffolds to keep them open after a successful balloon angioplasty. [ 14 ]   This did not become a reality in the cardiac realm until  the first intracoronary  stents  were successfully deployed in coronary arteries in 1986. [ 20 ] [ 21 ]   The first stents used were self-expanding Wallstents.  The use of intracoronary stents was quickly identified as a method to treat some complications due to PTCA, [ 20 ]  and their use can decrease the incidence of emergency bypass surgery for acute complications post balloon angioplasty. [ 22 ]


It was quickly realized that restenosis rates were significantly lower in individuals who received an intracoronary stent when compared to those who underwent just balloon angioplasty. [ 23 ]   A damper on the immediate use of intracoronary stents was subacute  thrombosis .  Subacute thrombosis rates with intracoronary stents proved to be about 3.7 percent, higher than the rates seen after balloon angioplasty. [ 21 ]   Post-procedure bleeding was also an issue, due to the intense combination of  anticoagulation  and  anti-platelet agents  used to prevent stent thrombosis. [ medical citation needed ]


Stent technology improved rapidly, and in 1989 the Palmaz-Schatz balloon-expandable intracoronary stent was developed. [ 24 ] [ 25 ]   Initial results with the Palmaz-Schatz stents were excellent when compared to balloon angioplasty, with a significantly lower incidence of abrupt closure and peri-procedure heart attack. [ 26 ]   Late restenosis rates with Palmaz-Schatz stents were also significantly improved when compared with balloon angioplasty. [ 27 ] [ 28 ]   However,  mortality  rates were unchanged compared to balloon angioplasty. [ 29 ]   While the rates of subacute thrombosis and bleeding complications associated with stent placement were high, by 1999 nearly 85% of all PCI procedures included intracoronary stenting. [ 30 ]


In recognition of the focused training required by cardiologists to perform percutaneous coronary interventions and the rapid progression in the field of percutaneous coronary interventions, specialized fellowship training in the field of Interventional Cardiology was instituted in 1999. [ 17 ]


Through the 1990s and beyond, various incremental improvements were made in balloon and stent technology, as well as newer devices, some of which are still in use today while many more have fallen into disuse.  As important as balloon and stent technology had been, it was becoming obvious that the anticoagulation and anti-platelet regimen that individuals received post-intervention was at least as important.  Trials in the late 1990s revealed that anticoagulation with  warfarin  was not required post balloon angioplasty or stent implantation, while intense anti-platelet regimens and changes in procedural technique (most importantly, making sure that the stent was well opposed to the walls of the coronary artery) improved short term and long term outcomes. [ 31 ]   Many different antiplatelet regimens were evaluated in the 1990s and the turn of the 21st century, with the optimal regimen in an individual patient still being up for debate.


With the high use of intracoronary stents during PCI procedures, the focus of treatment changed from procedural success to prevention of recurrence of disease in the treated area (in-stent restenosis). By the late 1990s, it was generally acknowledged among cardiologists that the incidence of in-stent restenosis was between 15 and 30%, and possibly higher in certain subgroups of individuals. [ 30 ]  Stent manufacturers experimented with (and continue to experiment with) a number of chemical agents to prevent the neointimal hyperplasia that is the cause of in-stent restenosis. [ medical citation needed ]


One of the first products of the new focus on preventing late events (such as in stent restenosis and late thrombosis) was the  heparin -coated Palmaz-Schatz stent. [ 32 ]   These coated stents were found to have a lower incidence of subacute thrombosis than bare metal stents. [ 33 ]