Dimitrios Konstantinidis

Non-pharmacological Modulation of the Autonomic Nervous System for Heart Failure Treatment: Where do We Stand?

INTRODUCTIONnAn imbalance in the Autonomic Nervous System (ANS) is a central pathophysiologic mechanism in Heart Failure (HF) and has been a principal target of treatment in these patients. Traditional pharmacologic agents do not provide specific modulation of discrete arms of the ANS, while side effects may lead to poor tolerance. Technological advances have provided a series of invasive methods that may provide a focused effect on the ANS in selected patient groups. Renal denervation, initially targeted for patients with resistant hypertension, has given positive preliminary results in terms of heart structure and function. Baroreceptor stimulation also has ongoing research with respect to its efficacy and longer term effects in HF patients. Vagal nerve stimulation and spinal cord stimulation have limited data but represent novel treatments that target the hard to reach parasympathetic system.nnnCONCLUSIONnThe present review overviews the pathophysiologic basis, current preclinical and clinical data and future expectations of these promising treatments.

Effects of oral paricalcitol therapy on arterial stiffness and osteopontin in hypertensive patients with chronic kidney disease and secondary hyperparathyroidism

BACKGROUNDnArterial stiffness is linked to the progression of atherosclerosis, while activation of vitamin D receptor exerts favorable cardiovascular effects in patients with renal insufficiency. In this study, we investigated the effects of oral treatment with paricalcitol, a potent vitamin D receptor activator, on arterial stiffness and osteopontin, a marker of atherosclerosis, in hypertensive patients with chronic kidney disease (CKD) and secondary hyperparathyroidism.nnnMETHODSnWe followed up 29 treated hypertensive patients (mean age: 74.1xa0years, 19 men, office blood pressurexa0=xa0132/85xa0mmHg) with CKD stages 3-5 (mean glomerular filtration rate [GFR]xa0=xa019.4xa0ml/min/1.73xa0m2) who were on therapy with oral paricalcitol for 1xa0year. The control group consisted of 10 age-, sex-, and GFR-matched hypertensive patients with secondary hyperparathyroidism.nnnRESULTSnAfter 1xa0year of treatment with paricalcitol compared to baseline, there was no statistical difference in levels of GFR, office blood pressure, and osteopontin (pxa0=xa0NS for all), while carotid-femoral PWV was reduced from 11.8xa0±xa02.6xa0m/s to 11.2xa0±xa02.4xa0m/s (pxa0<xa00.05). The control group exhibited no significant changes in carotid-femoral PWV (pxa0=xa0NS).nnnCONCLUSIONSnTreatment with oral paricalcitol in hypertensive subjects suffering from CKD stages 3-5 and secondary hyperparathyroidism is accompanied by amelioration of arterial stiffness as reflected by the reduction of carotid-femoral PWV.

Biomarkers of Atrial Fibrillation in Hypertension

BACKGROUNDnAtrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia globally and substantially increases the risk for thromboembolic disease. Albeit, 20% of all cases of AF remain undiagnosed. On the other hand, hypertension amplifies the risk for both AF occurrences through hemodynamic and non-hemodynamic mechanisms and cerebrovascular ischemia. Under this prism, prompt diagnosis of undetected AF in hypertensive patients is of pivotal importance.nnnMETHODnWe conducted a review of the literature for studies with biomarkers that could be used in AF diagnosis as well as in predicting the transition of paroxysmal AF to sustained AF, especially in hypertensive patients.nnnRESULTSnPotential biomarkers for AF can be broadly categorized into electrophysiological, morphological and molecular markers that reflect the underlying mechanisms of adverse atrial remodeling. We focused on P-wave duration and dispersion as electrophysiological markers, and left atrial (LA) and LA appendage size, atrial fibrosis, left ventricular hypertrophy and aortic stiffness as structural biomarkers, respectively. The heterogeneous group of molecular biomarkers of AF encompasses products of the neurohormonal cascade, including NT-pro BNP, BNP, MR-pro ANP, polymorphisms of the ACE and convertases such as corin and furin. In addition, soluble biomarkers of inflammation (i.e. CRP, IL-6) and fibrosis (i.e. TGF-1 and matrix metalloproteinases) were assessed for predicting AF.nnnCONCLUSIONnThe reviewed individual biomarkers might be a valuable addition to current diagnostic tools but the ideal candidate is expected to combine multiple indices of atrial remodeling in order to effectively detect both AF and adverse characteristics of high risk patients with hypertension.

Cardiovascular morbidity of severe resistant hypertension among treated uncontrolled hypertensives: a 4-year follow-up study

Data regarding the prognosis of resistant hypertension (RHTN) with respect to its severity is limited. We investigated the cardiovascular risk of severe RHTN in a prospective observational study. A cohort of 1700 hypertensive patient with treated uncontrolled HTN was followed for a mean period of 3.6u2009±u20091.8 years. At baseline, standard clinical and laboratory workup was performed, including testing for secondary causes of RHT where applicable. Three groups were identified depending on presence of RHTN (office-based uncontrolled HTN under at least three drugs including a diuretic) and levels of office systolic blood pressure (BP): 1187 patients (70%) without RHTN, 313 (18%) with not-severe RHTN (systolic BPu2009<u2009160u2009mmHg) and 200 (12%) with severe RHTN (systolic BPu2009≥u2009160u2009mmHg). Endpoint of interest was cardiovascular morbidity set as the composite of coronary heart disease and stroke. During follow-up, incidence rates of cardiovascular events per 1000 person-years were 7.1 cases in the non-RHTN group, 12.4 cases in the not-severe RHTN group and 18 cases in the severe RHTN group. Unadjusted analysis showed that compared to uncontrolled patients without RHTN, patients with not-severe RHTN exhibited a similar risk but patients with severe RHTN had a significantly higher risk, by 2.5 times (CI: 1.28–4.73, pu2009=u20090.007). Even after multivariate adjustment for established risk factors including BP levels and isolated systolic HTN, severe RHTN remained as an independent predictor of the cardiovascular outcome (OR: 2.30, CI: 1.00–5.29, pu2009=u20090.05). In conclusion, among treated yet uncontrolled hypertensive patients, severe RHTN exhibits a significantly higher cardiovascular risk indicating the need for prompt management.

Risk Factors of Atherosclerosis: Pathophysiological Mechanisms

Atherosclerosis represents a progressive inflammatory disease, which is characterized by complex hemodynamic, molecular, genetic, and cell interaction mechanisms. The latter trigger diverse proinflammatory and pro-oxidant pathways all of which give birth to the key feature of atherosclerosis, the injury and inevitably the dysfunction of the endothelial layer.Atherosclerosis represents a progressive inflammatory disease, which is characterized by complex hemodynamic, molecular, genetic, and cell interaction mechanisms. The latter trigger diverse proinflammatory and pro-oxidant pathways all of which give birth to the key feature of atherosclerosis, the injury and inevitably the dysfunction of the endothelial layer. n nA variety of risk factors have been established for atherosclerosis including the traditional ones and numerous emerging. Regardless of their nature all the established risk factors share similar proatherogenic properties and exhibit interesting complex links and interactions where endothelial dysfunction is always the common denominator. n nThis chapter is an attempt to describe from a pathophysiological standpoint the separate and combined impact of these risk factors on the development of atherosclerosis starting from the early subclinical phases and ending up to the lethal complications of the disease.

Uric acid as an independent predictor of coronary artery disease in essential hypertension: Data from an 8-year-follow-up study

The role of serum uric acid (SUA) in cardiovascular risk prediction remains to be further determined. We assessed the predictive value of SUA for the incidence of coronary artery disease (CAD) in 2287 essential hypertensive patients who were followed up for a mean period of 8 years. The distribution of SUA levels at baseline was split by the median (5.2 mg/dL) and subjects were classified into those with high and low values. Hypertensives who developed CAD (n = 57) compared to those without CAD at follow‐up (n = 2230) had at baseline higher SUA. In multivariate Cox regression model, among established confounders, high SUA (hazard ratio = 1.216, P = .016) turned out to be independent predictor of CAD. In essential hypertensive patients SUA independently predicts CAD.

Heart Rate and Blood Pressure: “Connecting the Dots” in Epidemiology and Pathophysiology

There is robust evidence from epidemiological and clinical studies showing that elevated heart rate (HR) constitutes a powerful predictor of morbidity and mortality in patients with hypertension, underlining the significance of HR measurement in them. Autonomous nervous system dysfunction and atherosclerosis are important features in the pathogenesis of the untoward events. However, the relationship between HR and blood pressure (BP) is complex and differs depending on the type of BP measurement which is considered. This differentiation implicates complex physiological mechanisms and is of clinical importance regarding the divergent effect of the different types of antihypertensive agents on these parameters. The aim of this review is to summarize the current evidence on the relationship between HR and BP based on epidemiological, clinical, and experimental studies.

Hypertension and Heart Failure with Preserved Ejection Fraction: Connecting the Dots

INTRODUCTIONnHeart failure (HF) with preserved ejection fraction (EF) (HFpEF) accounts for approximately 50% of HF cases and its prevalence relative to HF with reduced EF is rising. Hypertension (HT) is the most common co-morbidity in HFpEF patients and it is implicated in both the pathogenesis and the prognosis of the disease. Therefore, HT is a modifiable risk factor of high yield in HFpEF. We reviewed the literature for epidemiologic data supporting the co-aggregation of the two entities as well as patho-physiologic mechanisms linking HT to HFpEF. Most importantly, we focused on treatment options targeting HT as a preventive strategy for delaying the progression of diastolic dysfunction or decreasing the odds for developing HFpEF.nnnCONCLUSIONnAlong this line, we summarized the evidence and efficacy associated with different classes of antihypertensive medications in HFpEF patients. Finally, non-pharmacological approaches, including renal denervation and lifestyle modifications, to achieve optimal blood pressure (BP) control in HFpEF patients are reported. Unfortunately, no specific antihypertensive treatment has established a major survival benefit in this high risk subjects. Until the results of the efficacy of the novel drug LCZ696 (valsartan/ sacubitril) are available, the continuous monitoring and lowering of the BP by pharmacological and non-pharmacological means should be considered the major preventive and treatment strategy in HFpEF patients.